Same old: October 2007

Friday 26 October 2007

Synchronized spontaneous spikes on multi-electrode array show development of cultured neuronal network.

Synchronized spontaneous spikes on multi-electrode array show development of cultured neuronal network.

Conf Proc IEEE Eng Med Biol Soc. 2005;2:2134-7

Authors: Li X, Zhou W, Liu M, Luo Q

Spontaneous firing play an important role in development of neuronal network. Activity-dependent modification of synaptic efficacy is widely recognized as a cellular basis of learning, memory, and development plasticity. Little is known of the activity-dependent modification of the synchronized spontaneous firing of the hippocampal networks. Long-term recording of spontaneous activity in cultured hippocampal neuronal networks was carried out using substrates containing multi-electrode array (MEA). Spontaneous uncorrelated firing appeared within a week and transformed progressively into synchronized pattern. During the development, these synchronized firings became into oscillation pattern and the synchronization has little change. By paired stimulation from adjacent electrodes in the network, the synchronized firing form a larger network burst. These results suggest that synchronized spontaneous spikes show the development of neuronal network and electronical stimulation could change the development.

PMID: 17282651 [PubMed - in process]

Multiresolution bayesian detection of multiunit extracellular spike waveforms in multichannel neuronal recordings.

Multiresolution bayesian detection of multiunit extracellular spike waveforms in multichannel neuronal recordings.

Conf Proc IEEE Eng Med Biol Soc. 2005;1:141-4

Authors: Suhail Y, Oweiss K

We describe multiresolution Bayesian tests for spike detection in multielectrode recordings. We derive results for single channel and multi electrode data, and show that the use of the array model substantially improves the detection performance. The effect of signal and noise spatial correlation characteristics is also discussed. Our approach focuses on blind signal detection without any assumptions about the underlying signal parameters. It is therefore suitable for chronic recordings with electrode arrays where typically temporal and spatial nonstationarity of the extracellular waveforms complicates the estimation of the true action potential.

PMID: 17282131 [PubMed - in process]

Modeling the Nonlinear Dynamic Interactions of the Lateral and the Medial Perforant Path of the Hippocampal Dentate Gyrus.

Modeling the Nonlinear Dynamic Interactions of the Lateral and the Medial Perforant Path of the Hippocampal Dentate Gyrus.

Conf Proc IEEE Eng Med Biol Soc. 2006;1:5539-5542

Authors: Dimoka A, Courellis SH, Marmarelis VZ, Berger TW

We present a new method to characterize the nonlinearities resulting from the co-activity of two pathways that converge on a common postsynaptic element. We investigated the nonlinear dynamic interactions between the lateral perforant pathway (LPP) and the medial perforant pathway (MPP) of the hippocampal dentate gyms, and the effects of these cross-pathway interactions on granule cell output. A third order Volterra-Poisson modeling approach was implemented to capture the interactions between the two pathways. The kernels presented pathway specific signatures as they capture the nonlinear dynamics of each pathway individually in the form of self-kernels, and the nonlinear interactions between the two pathways in the form of cross-kernels. Data were collected in-vitro from acute slices of adult rats via a multi-electrode array recording system. The stimuli were dual-site random impulse trains with Poisson distributed inter-impulse intervals. The recorded responses from the granule cells were population spikes, simplified as discrete impulses with variable amplitudes. Our results indicated that the third order nonlinear interactions between the LPP and the MPP needs to be included in the model in order to achieve adequate predictive accuracy and indicate that this approach can be generalized to complex interactions between distinct inputs to the same set of neurons.

PMID: 17946313 [PubMed - as supplied by publisher]

Imaging of odor perception delineates functional disintegration of the limbic circuits in mesial temporal lobe epilepsy.

Imaging of odor perception delineates functional disintegration of the limbic circuits in mesial temporal lobe epilepsy.

Neuroimage. 2007 Sep 14;

Authors: Ciumas C, Lindström P, Bernard A, Savic I

Metabolic and neuro-receptor abnormalities within the extrafocal limbic circuits are established in mesial temporal lobe epilepsy (MTLE). However, very little is known about how these circuits process external stimuli. We tested whether odor activation can help delineate limbic functional disintegration in MTLE, and measured cerebral blood flow with PET during birhinal smelling of familiar and unfamiliar odors, using smelling of odorless air as the baseline condition. Patients with MTLE (13 left-sided, 10 right-sided) and 21 controls were investigated. In addition to odor activation, the analysis included functional connectivity, using right and left piriform cortex as seed regions. Healthy controls activated the amygdala, piriform, anterior insular, and cingulate cortices on both sides. Smelling of familiar odors engaged, in addition, the right parahippocampus, and the left Brodmann Area (BA) 44, 45, 47. Patients failed to activate the amygdala, piriform and the anterior insular cortex in the epileptogenic hemisphere. Furthermore, those with left MTLE did not activate the left BA 44, 45 and 47 with familiar odors, which they perceived as less familiar than controls. Congruent with the activation data each seed region was in patients functionally disconnected with the contralateral amygdala+piriform+insular cortex. The functional disintegration in patients exceeded the reduced activation, and included the contralateral temporal neocortex, and in subjects with right MTLE also the right orbitofrontal cortex. Imaging of odor perception may be used to delineate functional disintegration of the limbic networks in MTLE. It shows an altered response in several regions, which may underlie some interictal behavioral problems associated with this condition.

PMID: 17951077 [PubMed - as supplied by publisher]

Rhythmic Spontaneous Activity in the Piriform Cortex.

Rhythmic Spontaneous Activity in the Piriform Cortex.

Cereb Cortex. 2007 Oct 8;

Authors: Sanchez-Vives MV, Descalzo VF, Reig R, Figueroa NA, Compte A, Gallego R

Slow spontaneous rhythmic activity is generated and propagates in neocortical slices when bathed in an artificial cerebrospinal fluid with ionic concentrations similar to the ones in vivo. This activity is extraordinarily similar to the activation of the cortex in physiological conditions (e.g., slow-wave sleep), thus representing a unique in vitro model to understand how cortical networks maintain and control ongoing activity. Here we have characterized the activity generated in the olfactory or piriform cortex and endopiriform nucleus (piriform network). Because these structures are prone to generate epileptic discharges, it seems critical to understand how they generate and regulate their physiological rhythmic activity. The piriform network gave rise to rhythmic spontaneous activity consisting of a succession of up and down states at an average frequency of 1.8 Hz, qualitatively similar to the corresponding neocortical activity. This activity originated in the deep layers of the piriform network, which displayed higher excitability and denser connectivity. A remarkable difference with neocortical activity was the speed of horizontal propagation (114 mm/s), one order of magnitude faster in the piriform network. Properties of the piriform cortex subserving fast horizontal propagation may underlie the higher vulnerability of this area to epileptic seizures.

PMID: 17925296 [PubMed - as supplied by publisher]

Neuromodulation by Glutamate and Acetylcholine can Change Circuit Dynamics by Regulating the Relative Influence of Afferent Input and Excitatory Feedback.

Neuromodulation by Glutamate and Acetylcholine can Change Circuit Dynamics by Regulating the Relative Influence of Afferent Input and Excitatory Feedback.

Mol Neurobiol. 2007 Oct;36(2):184-200

Authors: Giocomo LM, Hasselmo ME

Substances such as acetylcholine and glutamate act as both neurotransmitters and neuromodulators. As neuromodulators, they change neural information processing by regulating synaptic transmitter release, altering baseline membrane potential and spiking activity, and modifying long-term synaptic plasticity. Slice physiology research has demonstrated that many neuromodulators differentially modulate afferent, incoming information compared to intrinsic and recurrent processing in cortical structures such as piriform cortex, neocortex, and the hippocampus. The enhancement of afferent (external) pathways versus the suppression at recurrent (internal) pathways could cause cortical dynamics to switch between a predominant influence of external stimulation to a predominant influence of internal recall. Modulation of afferent versus intrinsic processing could contribute to the role of neuromodulators in regulating attention, learning, and memory effects in behavior.

PMID: 17952661 [PubMed - in process]

The endocannabinoid system controls key epileptogenic circuits in the hippocampus.

The endocannabinoid system controls key epileptogenic circuits in the hippocampus.

Neuron. 2006 Aug 17;51(4):455-66

Authors: Monory K, Massa F, Egertová M, Eder M, Blaudzun H, Westenbroek R, Kelsch W, Jacob W, Marsch R, Ekker M, Long J, Rubenstein JL, Goebbels S, Nave KA, During M, Klugmann M, Wölfel B, Dodt HU, Zieglgänsberger W, Wotjak CT, Mackie K, Elphick MR, Marsicano G, Lutz B

Balanced control of neuronal activity is central in maintaining function and viability of neuronal circuits. The endocannabinoid system tightly controls neuronal excitability. Here, we show that endocannabinoids directly target hippocampal glutamatergic neurons to provide protection against acute epileptiform seizures in mice. Functional CB1 cannabinoid receptors are present on glutamatergic terminals of the hippocampal formation, colocalizing with vesicular glutamate transporter 1 (VGluT1). Conditional deletion of the CB1 gene either in cortical glutamatergic neurons or in forebrain GABAergic neurons, as well as virally induced deletion of the CB1 gene in the hippocampus, demonstrate that the presence of CB1 receptors in glutamatergic hippocampal neurons is both necessary and sufficient to provide substantial endogenous protection against kainic acid (KA)-induced seizures. The direct endocannabinoid-mediated control of hippocampal glutamatergic neurotransmission may constitute a promising therapeutic target for the treatment of disorders associated with excessive excitatory neuronal activity.

PMID: 16908411 [PubMed - indexed for MEDLINE]

Cannabinoid CB1 receptor antagonists cause status epilepticus-like activity in the hippocampal neuronal culture model of acquired epilepsy.

Cannabinoid CB1 receptor antagonists cause status epilepticus-like activity in the hippocampal neuronal culture model of acquired epilepsy.

Neurosci Lett. 2007 Jan 3;411(1):11-6

Authors: Deshpande LS, Sombati S, Blair RE, Carter DS, Martin BR, DeLorenzo RJ

Status epilepticus (SE) is a major medical emergency associated with a significant morbidity and mortality. Little is known about the mechanisms that terminate seizure activity and prevent the development of status epilepticus. Cannabinoids possess anticonvulsant properties and the endocannabinoid system has been implicated in regulating seizure duration and frequency. Endocannabinoids regulate synaptic transmission and dampen seizure activity via activation of the presynaptic cannabinoid receptor 1 (CB1). This study was initiated to evaluate the role of CB1 receptor-dependent endocannabinoid synaptic transmission towards preventing the development of status epilepticus-like activity in the well-characterized hippocampal neuronal culture model of acquired epilepsy using patch clamp electrophysiology. Application of the CB1 receptor antagonists SR141716A (1 microM) or AM251 (1 microM) to "epileptic" neurons caused the development of continuous epileptiform activity, resembling electrographic status epilepticus. The induction of status epilepticus-like activity by CB1 receptor antagonists was reversible and could be overcome by maximal concentrations of CB1 agonists. Similar treatment of control neurons with CB1 receptor antagonists did not produce status epilepticus or hyperexcitability. These findings suggest that CB1 receptor-dependent endocannabinoid endogenous tone plays an important role in modulating seizure frequency and duration and preventing the development of status epilepticus-like activity in populations of epileptic neurons. The regulation of seizure activity and prevention of status epilepticus by the endocannabinoid system offers an important insight into understanding the basic mechanisms that control the development of continuous epileptiform discharges.

PMID: 17110038 [PubMed - indexed for MEDLINE]

Potential therapeutical effects of cannabidiol in children with pharmacoresistant epilepsy.

Potential therapeutical effects of cannabidiol in children with pharmacoresistant epilepsy.

Med Hypotheses. 2007;68(4):920-1

Authors: Cortesi M, Fusar-Poli P

PMID: 17112679 [PubMed - indexed for MEDLINE]

Endocannabinoids block status epilepticus in cultured hippocampal neurons.

Endocannabinoids block status epilepticus in cultured hippocampal neurons.

Eur J Pharmacol. 2007 Mar 8;558(1-3):52-9

Authors: Deshpande LS, Blair RE, Ziobro JM, Sombati S, Martin BR, DeLorenzo RJ

Status epilepticus is a serious neurological disorder associated with a significant morbidity and mortality. Antiepileptic drugs such as diazepam, phenobarbital and phenytoin are the mainstay of status epilepticus treatment. However, over 20% of status epilepticus cases are refractory to the initial treatment with two or more antiepileptic drugs. Endocannabinoids have been implicated as playing an important role in regulating seizure activity and seizure termination. This study evaluated the effects of the major endocannabinoids methanandamide and 2-arachidonylglycerol (2-AG) on status epilepticus in the low-Mg(2+) hippocampal neuronal culture model. Status epilepticus in this model was resistant to treatment with phenobarbital and phenytoin. Methanandamide and 2-AG inhibited status epilepticus in a dose-dependent manner with an EC(50) of 145+/-4.15 nM and 1.68+/-0.19 microM, respectively. In addition, the anti-status epilepticus effects of methanandamide and 2-AG were mediated by activation of the cannabinoid CB(1) receptor since they were blocked by the cannabinoid CB(1) receptor antagonist AM251. These results provide the first evidence that the endocannabinoids, methanandamide and 2-AG, are effective inhibitors of refractory status epilepticus in the hippocampal neuronal culture model and indicate that regulating the endocannabinoid system may provide a novel therapeutic approach for treating refractory status epilepticus.

PMID: 17174949 [PubMed - indexed for MEDLINE]

Prevention of plasticity of endocannabinoid signaling inhibits persistent limbic hyperexcitability caused by developmental seizures.

Prevention of plasticity of endocannabinoid signaling inhibits persistent limbic hyperexcitability caused by developmental seizures.

J Neurosci. 2007 Jan 3;27(1):46-58

Authors: Chen K, Neu A, Howard AL, Földy C, Echegoyen J, Hilgenberg L, Smith M, Mackie K, Soltesz I

Depolarization-induced suppression of inhibition (DSI) is an endocannabinoid-mediated short-term plasticity mechanism that couples postsynaptic Ca2+ rises to decreased presynaptic GABA release. Whether the gain of this retrograde synaptic mechanism is subject to long-term modulation by glutamatergic excitatory inputs is not known. Here, we demonstrate that activity-dependent long-term DSI potentiation takes place in hippocampal slices after tetanic stimulation of Schaffer collateral synapses. This activity-dependent, long-term plasticity of endocannabinoid signaling was specific to GABAergic synapses, as it occurred without increases in the depolarization-induced suppression of excitation. Induction of tetanus-induced DSI potentiation in vitro required a complex pathway involving AMPA/kainate and metabotropic glutamate receptor as well as CB1 receptor activation. Because DSI potentiation has been suggested to play a role in persistent limbic hyperexcitability after prolonged seizures in the developing brain, we used these mechanistic insights into activity-dependent DSI potentiation to test whether interference with the induction of DSI potentiation prevents seizure-induced long-term hyperexcitability. The results showed that the in vitro, tetanus-induced DSI potentiation was occluded by previous in vivo fever-induced (febrile) seizures, indicating a common pathway. Accordingly, application of CB1 receptor antagonists during febrile seizures in vivo blocked the seizure-induced persistent DSI potentiation, abolished the seizure-induced upregulation of CB1 receptors, and prevented the emergence of long-term limbic hyperexcitability. These results reveal a new form of activity-dependent, long-term plasticity of endocannabinoid signaling at perisomatic GABAergic synapses, and demonstrate that blocking the induction of this plasticity abolishes the long-term effects of prolonged febrile seizures in the developing brain.

PMID: 17202471 [PubMed - indexed for MEDLINE]

Development of pharmacoresistance to benzodiazepines but not cannabinoids in the hippocampal neuronal culture model of status epilepticus.

Development of pharmacoresistance to benzodiazepines but not cannabinoids in the hippocampal neuronal culture model of status epilepticus.

Exp Neurol. 2007 Apr;204(2):705-13

Authors: Deshpande LS, Blair RE, Nagarkatti N, Sombati S, Martin BR, DeLorenzo RJ

Status epilepticus (SE) is a life-threatening neurological disorder associated with a significant morbidity and mortality. Benzodiazepines are the initial drugs of choice for the treatment of SE. Despite aggressive treatment, over 40% of SE cases are refractory to the initial treatment with two or more medications. It would be a major advance in the clinical management of SE to identify novel anticonvulsant agents that do not lose their ability to treat SE with increasing seizure duration. Cannabinoids have recently been demonstrated to regulate seizure activity in brain. However, it remains to be seen whether they develop pharmacoresistance upon prolonged SE. In this study, we used low Mg(2+) to induce SE in hippocampal neuronal cultures and in agreement with animal models and human SE confirm the development of resistance to benzodiazepine with increasing durations of SE. Thus, lorazepam (1 microM) was effective in blocking low Mg(2+) induced high-frequency spiking for up to 30 min into SE. However, by 1 h and 2 h of SE onset it was only 10-15% effective in suppressing SE. In contrast, the cannabinoid type-1 (CB1) receptor agonist, WIN 55,212-2 (1 microM) in a CB1 receptor-dependent manner completely abolished SE at all the time points tested even out to 2 h after SE onset, a condition where resistance developed to lorazepam. Thus, the use of cannabinoids in the treatment of SE may offer a unique approach to controlling SE without the development of pharmacoresistance observed with conventional treatments.

PMID: 17289026 [PubMed - indexed for MEDLINE]

On-demand activation of the endocannabinoid system in the control of neuronal excitability and epileptiform seizures.

On-demand activation of the endocannabinoid system in the control of neuronal excitability and epileptiform seizures.

Biochem Pharmacol. 2004 Nov 1;68(9):1691-8

Authors: Lutz B

Neurons intensively exchange information among each other using both inhibitory and excitatory neurotransmitters. However, if the balance of excitation and inhibition is perturbed, the intensity of excitatory transmission may exceed a certain threshold and epileptic seizures can occur. As the occurrence of epilepsy in the human population is about 1%, the search for therapeutic targets to alleviate seizures is warranted. Extracts of Cannabis sativa have a long history in the treatment of various neurological diseases, including epilepsy. However, cannabinoids have been reported to exert both pro- and anti-convulsive activities. The recent progress in understanding the endogenous cannabinoid system has allowed new insights into these opposing effects of cannabinoids. When excessive neuronal activity occurs, endocannabinoids are generated on demand and activate cannabinoid type 1 (CB1) receptors. Using mice lacking CB1 receptors in principal forebrain neurons in a model of epileptiform seizures, it was shown that CB1 receptors expressed on excitatory glutamatergic neurons mediate the anti-convulsive activity of endocannabinoids. Systemic activation of CB1 receptors by exogenous cannabinoids, however, are anti- or pro-convulsive, depending on the seizure model used. The pro-convulsive activity of exogenous cannabinoids might be explained by the notion that CB1 receptors expressed on inhibitory GABAergic neurons are also activated, leading to a decreased release of GABA, and to a concomitant increase in seizure susceptibility. The concept that the endogenous cannabinoid system is activated on demand suggests that a promising strategy to alleviate seizure frequency is the enhancement of endocannabinoid levels by inhibiting the cellular uptake and the degradation of these endogenous compounds.

PMID: 15450934 [PubMed - indexed for MEDLINE]

Altering cannabinoid signaling during development disrupts neuronal activity.

Altering cannabinoid signaling during development disrupts neuronal activity.

Proc Natl Acad Sci U S A. 2005 Jun 28;102(26):9388-93

Authors: Bernard C, Milh M, Morozov YM, Ben-Ari Y, Freund TF, Gozlan H

In adult cortical tissue, recruitment of GABAergic inhibition prevents the progression of synchronous population discharges to epileptic activity. However, at early developmental stages, GABA is excitatory and thus unable to fulfill this role. Here, we report that retrograde signaling involving endocannabinoids is responsible for the homeostatic control of synaptic transmission and the resulting network patterns in the immature hippocampus. Blockade of cannabinoid type 1 (CB1) receptor led to epileptic discharges, whereas overactivation of CB1 reduced network activity in vivo. Endocannabinoid signaling thus is able to keep population discharge patterns within a narrow physiological time window, balancing between epilepsy on one side and sparse activity on the other, which may result in impaired developmental plasticity. Disturbing this delicate balance during pregnancy in either direction, e.g., with marijuana as a CB1 agonist or with an antagonist marketed as an antiobesity drug, can have profound consequences for brain maturation even in human embryos.

PMID: 15964987 [PubMed - indexed for MEDLINE]

Alternative therapies for seizures: promises and dangers.

Alternative therapies for seizures: promises and dangers.

Semin Neurol. 2007 Sep;27(4):325-30

Authors: Sirven JI

Complementary and alternative medicine (CAM) is increasingly being used for a multitude of medical problems, one of them being seizures. This article discusses the prevalence of CAM use for seizures and epilepsy. Evidence-based data regarding CAM for epilepsy are presented as well as potential safety concerns regarding ephedra and cannabis use.

PMID: 17701869 [PubMed - in process]

[Therapeutic use of cannabinoids in neurology]

[Therapeutic use of cannabinoids in neurology]

Schmerz. 2003 Oct;17(5):367-73

Authors: Schwenkreis P, Tegenthoff M

This review gives insight into the potential therapeutical role of cannabinoids in neurology. Preclinical data are presented which could give a rationale for the clinical use of cannabinoids in the fields of multiple sclerosis, spasticity, epilepsy, movement disorders, and neuroprotection after traumatic head injury or ischemic stroke. Besides, clinical data (case reports, open-label and randomised controlled studies) dealing with the therapeutical use of cannabinoids in these fields are reported and discussed. At present, clinical data are insufficient to recommend the use of cannabinoids in any neurological disease as standard therapy. Several questions still have to be answered (which cannabinoid? which way of administration? stimulation of endogenous cannabinoids? separation between desired and undesired effects?), and controlled studies are still needed to clarify the potential therapeutical role of cannabinoids in neurology.

PMID: 14513344 [PubMed - indexed for MEDLINE]

Delta9-tetrahydrocannabinol and epilepsy in the photosensitive baboon, Papio papio.

Delta9-tetrahydrocannabinol and epilepsy in the photosensitive baboon, Papio papio.

Epilepsia. 1974 Jun;15(2):255-64

Authors: Meldrum BS, Fariello RG, Puil EA, Derouaux M, Naquet R

PMID: 4525183 [PubMed - indexed for MEDLINE]

Anticonvulsant effects of cannabinoids in mice: drug interactions within cannabinoids and cannabinoid interactions with phenytoin.

Anticonvulsant effects of cannabinoids in mice: drug interactions within cannabinoids and cannabinoid interactions with phenytoin.

Psychopharmacologia. 1974 Jul 11;37(3):255-64

Authors: Chesher GB, Jackson DM

PMID: 4850601 [PubMed - indexed for MEDLINE]

Letter: Cannabidiol and electroencephalographic epileptic activity.

Letter: Cannabidiol and electroencephalographic epileptic activity.

JAMA. 1974 Dec 23-30;230(12):1635

Authors: Perez-Reyes M, Wingfield M

PMID: 4612180 [PubMed - indexed for MEDLINE]

The pharmacology of the cannabinoid system-a question of efficacy and selectivity.

The pharmacology of the cannabinoid system-a question of efficacy and selectivity.

Mol Neurobiol. 2007 Aug;36(1):15-25

Authors: Fowler CJ

Our knowledge of the function of the cannabinoid system in the body has been aided by the availability of pharmacological agents that affect its function. This has been achieved by the design of agents that either directly interact with the receptor (agonists and antagonist/inverse agonists) and agents that indirectly modulate the receptor output by changing the levels of the endogenous cannabinoids (endocannabinoids). In this review, examples of the most commonly used receptor agonists, antagonists/inverse agonists, and indirectly acting agents (anandamide uptake inhibitors, fatty acid amide hydrolase inhibitors, monoacylglycerol lipase inhibitors) are given, with particular focus upon their selectivity and, in the case of the directly acting compounds, efficacy. Finally, the links between the endocannabinoid and cyclooxygenase pathways are explored, in particular, with respect to agents whose primary function is to inhibit cyclooxygenase activity, but which also interact with the endocannabinoid system.

PMID: 17952646 [PubMed - in process]

Cannabinoid CB(2) Receptor-Mediated Anti-nociception in Models of Acute and Chronic Pain.

Cannabinoid CB(2) Receptor-Mediated Anti-nociception in Models of Acute and Chronic Pain.

Mol Neurobiol. 2007 Aug;36(1):26-35

Authors: Jhaveri MD, Sagar DR, Elmes SJ, Kendall DA, Chapman V

The endocannabinoid system consists of cannabinoid CB(1) and CB(2) receptors, endogenous ligands and their synthesising/metabolising enzymes. Cannabinoid receptors are present at key sites involved in the relay and modulation of nociceptive information. The analgesic effects of cannabinoids have been well documented. The usefulness of nonselective cannabinoid agonists can, however, be limited by psychoactive side effects associated with activation of CB(1) receptors. Following the recent evidence for CB(2) receptors existing in the nervous system and reports of their up-regulation in chronic pain states and neurodegenerative diseases, much research is now aimed at shedding light on the role of the CB(2) receptor in human disease. Recent studies have demonstrated anti-nociceptive effects of selective CB(2) receptor agonists in animal models of pain in the absence of CNS side effects. This review focuses on the analgesic potential of CB(2) receptor agonists for inflammatory, post-operative and neuropathic pain states and discusses their possible sites and mechanisms of action.

PMID: 17952647 [PubMed - in process]

Cannabinoids and gliomas.

Cannabinoids and gliomas.

Mol Neurobiol. 2007 Aug;36(1):60-7

Authors: Velasco G, Carracedo A, Blázquez C, Lorente M, Aguado T, Haro A, Sánchez C, Galve-Roperh I, Guzmán M

Cannabinoids, the active components of Cannabis sativa L., act in the body by mimicking endogenous substances-the endocannabinoids-that activate specific cell surface receptors. Cannabinoids exert various palliative effects in cancer patients. In addition, cannabinoids inhibit the growth of different types of tumor cells, including glioma cells, in laboratory animals. They do so by modulating key cell signaling pathways, mostly the endoplasmic reticulum stress response, thereby inducing antitumoral actions such as the apoptotic death of tumor cells and the inhibition of tumor angiogenesis. Of interest, cannabinoids seem to be selective antitumoral compounds, as they kill glioma cells, but not their non-transformed astroglial counterparts. On the basis of these preclinical findings, a pilot clinical study of Delta(9)-tetrahydrocannabinol (THC) in patients with recurrent glioblastoma multiforme has been recently run. The good safety profile of THC, together with its possible growth-inhibiting action on tumor cells, justifies the setting up of future trials aimed at evaluating the potential antitumoral activity of cannabinoids.

PMID: 17952650 [PubMed - in process]

The endocannabinoid system and Alzheimer's disease.

The endocannabinoid system and Alzheimer's disease.

Mol Neurobiol. 2007 Aug;36(1):75-81

Authors: Benito C, Núñez E, Pazos MR, Tolón RM, Romero J

The importance of the role of the endocannabinoid system (ECS) in neurodegenerative diseases has grown during the past few years. Mostly because of the high density and wide distribution of cannabinoid receptors of the CB(1) type in the central nervous system (CNS), much research focused on the function(s) that these receptors might play in pathophysiological conditions. Our current understanding, however, points to much diverse roles for this system. In particular, other elements of the ECS, such as the fatty acid amide hydrolase (FAAH) or the CB(2) cannabinoid receptor are now considered as promising pharmacological targets for some diseases and new cannabinoids have been incorporated as therapeutic tools. Although still preliminary, recent reports suggest that the modulation of the ECS may constitute a novel approach for the treatment of Alzheimer's disease (AD). Data obtained in vitro, as well as in animal models for this disease and in human samples seem to corroborate the notion that the activation of the ECS, through the use of agonists or by enhancing the endogenous cannabinoid tone, may induce beneficial effects on the evolution of this disease.

PMID: 17952652 [PubMed - in process]

Cannabinoids in eating disorders and obesity.

Cannabinoids in eating disorders and obesity.

Mol Neurobiol. 2007 Aug;36(1):113-28

Authors: Arias Horcajadas F

Cannabinoid system is a crucial mechanism in regulating food intake and energy metabolism. It is involved in central and peripheral mechanisms regulating such behavior, interacting with many other signaling systems with a role in metabolic regulation. Cannabinoid agonists promote food intake, and soon a cannabinoid antagonist, rimonabant, will be marketed for the treatment of obesity. It not only causes weight loss, but also alleviates metabolic syndrome. We present a review of current knowledge on this subject, along with data from our own research: genetic studies on this system in eating disorders and obesity and studies locating cannabinoid receptors in areas related to food intake. Such studies suggest cannabinoid hyperactivity in obesity, and this excessive activity may have prognostic implications.

PMID: 17952656 [PubMed - in process]

Cannabinoid-based medicines for neurological disorders-clinical evidence.

Cannabinoid-based medicines for neurological disorders-clinical evidence.

Mol Neurobiol. 2007 Aug;36(1):129-36

Authors: Wright S

Whereas the cannabis plant has a long history of medicinal use, it is only in recent years that a sufficient understanding of the pharmacology of the main plant constituents has allowed for a better understanding of the most rational therapeutic targets. The distribution of cannabinoid receptors, both within the nervous system and without, and the development of pharmacological tools to investigate their function has lead to a substantial increase in efforts to develop cannabinoids as therapeutic agents. Concomitant with these efforts, the understanding of the pharmacology of plant cannabinoids at receptor and other systems distinct from the cannabinoid receptors suggests that the therapeutic applications of plant-derived cannabinoids (and presumably their synthetic derivatives also) may be diverse. This review aims to discuss the clinical evidence investigating the use of medicines derived, directly or indirectly, from plant cannabinoids with special reference to neurological disorders. Published studies suggest that the oral administration of cannabinoids may not be the preferred route of administration and that plant extracts show greater evidence of efficacy than synthetic compounds. One of these, Sativex(R) (GW Pharmaceuticals), was approved as a prescription medicine in Canada in 2005 and is currently under regulatory review in the EU.

PMID: 17952657 [PubMed - in process]

Functional blockage of the cannabinoid receptor type 1 evokes a kappa-opiate-dependent analgesia.

Functional blockage of the cannabinoid receptor type 1 evokes a kappa-opiate-dependent analgesia.

J Neurochem. 2007 Oct 22;

Authors: Sáez-Cassanelli JL, Fontanella GH, Delgado-García JM, Carrión AM

Progress in the control and treatment of pain may be facilitated by a better understanding of mechanisms underlying nociceptive processing. Cannabinoids and opioids are endogenous modulator of pain sensation, but therapies based in these compounds are not completely exploited because of their side effects. To test the role of cannabinoid receptor type 1 (CB1-R) inhibition in nociception, we performed a subchronic administration of the CB1-R antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM281) in mice. This treatment provoked analgesia in peripheral thermal and visceral models of pain. Analysis of genes encoded for the opioid system in the spinal cord showed an increase in the expression of genes encoded for the kappa-opioid system in AM281-injected mice compared with vehicle-injected ones. Furthermore, systemic administration of nor-binaltorphimine, a kappa-opioid receptor antagonist, blocked AM281-induced analgesia. Finally, c-fos expression in the dorsal spinal cord and higher centers of pain processing after noxious stimulation were significantly lower in AM281-injected mice than in vehicle-injected animals, indicating that dynorphin could block nociceptive information transmission at the spinal cord level. These results indicate the existence of a cross-talk between opioid and cannabinoid systems in nociception. Furthermore, the results suggest that CB1-R antagonists could be useful as a new therapeutic approach for pain relief.

PMID: 17953671 [PubMed - as supplied by publisher]

Expression and Function of CB(1) Receptor in the Rat Striatum: Localization and Effects on D(1) and D(2) Dopamine Receptor-Mediated Motor Behaviors.

Expression and Function of CB(1) Receptor in the Rat Striatum: Localization and Effects on D(1) and D(2) Dopamine Receptor-Mediated Motor Behaviors.

Neuropsychopharmacology. 2007 Oct 24;

Authors: Martín AB, Fernandez-Espejo E, Ferrer B, Gorriti MA, Bilbao A, Navarro M, Rodriguez de Fonseca F, Moratalla R

Cannabinoid CB(1) receptors are densely expressed on striatal projection neurons expressing dopamine D(1) or D(2) receptors. However, the specific neuronal distribution of CB(1) receptors within the striatum is not known. Previous research has established that the endocannabinoid system controls facilitation of behavior by dopamine D(2) receptors, but it is not clear if endocannabinoids also modulate D(1) receptor-mediated motor behavior. In the present study, we show that cannabinoid CB(1) receptor mRNA is present in striatonigral neurons expressing substance P and dopamine D(1) receptors, as well as in striatopallidal neurons expressing enkephalin and dopamine D(2) receptors. We explored the functional relevance of the interaction between dopamine D(1) and D(2) receptors and cannabinoid CB(1) receptors with behavioral pharmacology experiments. Potentiation of endogenous cannabinoid signaling by the uptake blocker AM404 blocked dopamine D(1) receptor-mediated grooming and D(2) receptor-mediated oral stereotypies. In addition, contralateral turning induced by unilateral intrastriatal infusion of D(1) receptor agonists is counteracted by AM404 and potentiated by the cannabinoid antagonist SR141716A. These results indicate that the endocannabinoid system negatively modulates D(1) receptor-mediated behaviors in addition to its previously described effect on dopamine D(2) receptor-mediated behaviors. The effect of AM404 on grooming behavior was absent in dopamine D(1) receptor knockout mice, demonstrating its dependence on D(1) receptors. This study indicates that the endocannabinoid system is a relevant negative modulator of both dopamine D(1) and D(2) receptor-mediated behaviors, a finding that may contribute to our understanding of basal ganglia motor disorders.Neuropsychopharmacology advance online publication, 24 October 2007; doi:10.1038/sj.npp.1301558.

PMID: 17957223 [PubMed - as supplied by publisher]

A neutral CB1 receptor antagonist reduces weight gain in rat.

A neutral CB1 receptor antagonist reduces weight gain in rat.

Am J Physiol Regul Integr Comp Physiol. 2007 Oct 24;

Authors: Chambers AP, Vemuri VK, Peng Y, Wood JT, Olzewska T, Pittman QJ, Makriyannis A, Sharkey KA

Cannabinoid (CB) 1 receptor inverse agonists inhibit food intake in animals and humans, but also potentiate emesis. It is not clear whether these effects result from inverse agonist properties or from the blockade of endogenous cannabinoid signaling. Here, we examine the effect of a neutral CB1 antagonist, AM4113, on food intake, weight gain and emesis. Neutral antagonist and binding properties were confirmed in HEK293 cells transfected with human CB1 or CB2 receptors. AM4113 had no effect on forskolin stimulated cAMP production at concentrations up to 630 nM. The Ki value of AM4113 (0.80+/-0.44nM) in competitive binding assays with the CB1/2 agonist [(3)H]CP55,940 was 100-fold more selective for CB1 over CB2 receptors. We determined that AM4113 antagonized CB1 receptors in brain by blocking hypothermia induced by CP55,940. AM4113 (0-20 mg kg(-1)) significantly reduced food intake and weight gain in rat. Compared with AM251, higher doses of AM4113 were needed to produce similar effects on food intake and body weight. Unlike AM251 (5 mg kg(-1)), a highly anorectic dose of AM4113 (10 mg kg(-1)) did not significantly potentiate vomiting induced by the emetic morphine-6-glucoronide. We show that a centrally active neutral CB1 receptor antagonist shares the appetite suppressant and weight loss effects of inverse agonists. If these compounds display similar properties in humans they could be developed into a new class of anti-obesity agents. Key words: Cannabinoid receptor, Food intake, inverse agonist, obesity, emesis.

PMID: 17959701 [PubMed - as supplied by publisher]

Blogged with Flock

Modulation of pain transmission by G-protein-coupled receptors.

Modulation of pain transmission by G-protein-coupled receptors.

Pharmacol Ther. 2007 Sep 22;

Authors: Pan HL, Wu ZZ, Zhou HY, Chen SR, Zhang HM, Li DP

The heterotrimeric G-protein-coupled receptors (GPCR) represent the largest and most diverse family of cell surface receptors and proteins. GPCR are widely distributed in the peripheral and central nervous systems and are one of the most important therapeutic targets in pain medicine. GPCR are present on the plasma membrane of neurons and their terminals along the nociceptive pathways and are closely associated with the modulation of pain transmission. GPCR that can produce analgesia upon activation include opioid, cannabinoid, alpha(2)-adrenergic, muscarinic acetylcholine, gamma-aminobutyric acid(B) (GABA(B)), groups II and III metabotropic glutamate, and somatostatin receptors. Recent studies have led to a better understanding of the role of these GPCR in the regulation of pain transmission. Here, we review the current knowledge about the cellular and molecular mechanisms that underlie the analgesic actions of GPCR agonists, with a focus on their effects on ion channels expressed on nociceptive sensory neurons and on synaptic transmission at the spinal cord level.

PMID: 17959251 [PubMed - as supplied by publisher]

Saturday 6 October 2007

Organotypic slice culture of the hypothalamic paraventricular nucleus of rat.

Organotypic slice culture of the hypothalamic paraventricular nucleus of rat.

J Vet Sci. 2007 Mar;8(1):15-20

Authors: Cho ES, Lee SY, Park JY, Hong SG, Ryu PD

Organotypic slice cultures have been developed as an alternative to acute brain slices because the neuronal viability and synaptic connectivity in these cultures can be preserved well for a prolonged period of time. This study evaluated a stationary organotypic slice culture developed for the hypothalamic paraventricular nucleus (PVN) of rat. The results showed that the slice cultures maintain the typical shape of the nucleus, the immunocytochemical signals for oxytocin, vasopressin, and corticotropin-releasing hormone, and the electrophysiological properties of PVN neurons for up to 3 weeks in vitro. The PVN neurons in the culture expressed the green fluorescent protein gene that had been delivered by the adenoviral vectors. The results indicate that the cultured slices preserve the properties of the PVN neurons, and can be used in longterm studies on these neurons in vitro.

PMID: 17322769 [PubMed - indexed for MEDLINE]

Paraventricular hypothalamic CB(1) cannabinoid receptors are involved in the feeding stimulatory effects of Delta(9)-tetrahydrocannabinol.

Paraventricular hypothalamic CB(1) cannabinoid receptors are involved in the feeding stimulatory effects of Delta(9)-tetrahydrocannabinol.

Neuropharmacology. 2005 Dec;49(8):1101-9

Authors: Verty AN, McGregor IS, Mallet PE

BACKGROUND/AIMS: The paraventricular nucleus of the hypothalamus (PVN) is the target of converging orexigenic and anorexigenic pathways originating from various hypothalamic sites and is, therefore, considered to be the chief site mediating hypothalamic regulation of energy homeostasis. Although a large body of evidence suggests that central CB(1) cannabinoid receptors mediate food intake, it is not clear whether PVN CB(1) receptors are involved in the control of feeding behaviour. The present study therefore examined the effects of intra-PVN administration of Delta(9)-tetrahydrocannabinol (THC) and the cannabinoid receptor antagonist SR 141716 on feeding. METHODS: After being habituated to the test environment and injection procedure, sated rats were injected with SR 141716 (0.03-3.0 microg, Experiment 1) alone or in combination with THC (5.0 microg, Experiment 2) into the PVN. Food intake and locomotor activity then were recorded for 120 min. RESULTS: Intra-PVN administration of THC produced a significant increase in food intake that was attenuated by SR 141716. Administration of SR 141716 alone did not affect feeding. Locomotor activity was not significantly affected by any drug treatments, suggesting that effects on feeding were not due to a non-specific reduction in motivated behaviour. These findings suggest an important role for PVN cannabinoid signalling in mediating THC-induced feeding behaviour. These results also demonstrate that the blockade of PVN CB(1) receptors alone is insufficient to reduce baseline feeding behaviour under these conditions.

PMID: 16098995 [PubMed - indexed for MEDLINE]

Opposing crosstalk between leptin and glucocorticoids rapidly modulates synaptic excitation via endocannabinoid release.

Opposing crosstalk between leptin and glucocorticoids rapidly modulates synaptic excitation via endocannabinoid release.

J Neurosci. 2006 Jun 14;26(24):6643-50

Authors: Malcher-Lopes R, Di S, Marcheselli VS, Weng FJ, Stuart CT, Bazan NG, Tasker JG

The hypothalamic paraventricular nucleus (PVN) integrates preautonomic and neuroendocrine control of energy homeostasis, fluid balance, and the stress response. We recently demonstrated that glucocorticoids act via a membrane receptor to rapidly cause endocannabinoid-mediated suppression of synaptic excitation in PVN neurosecretory neurons. Leptin, a major signal of nutritional state, suppresses CB(1) cannabinoid receptor-dependent hyperphagia (increased appetite) in fasting animals by reducing hypothalamic levels of endocannabinoids. Here we show that glucocorticoids stimulate endocannabinoid biosynthesis and release via a Galpha(s)-cAMP-protein kinase A-dependent mechanism and that leptin blocks glucocorticoid-induced endocannabinoid biosynthesis and suppression of excitation in the PVN via a phosphodiesterase-3B-mediated reduction in intracellular cAMP levels. We demonstrate this rapid hormonal interaction in both PVN magnocellular and parvocellular neurosecretory cells. Leptin blockade of the glucocorticoid-induced, endocannabinoid-mediated suppression of excitation was absent in leptin receptor-deficient obese Zucker rats. Our findings reveal a novel hormonal crosstalk that rapidly modulates synaptic excitation via endocannabinoid release in the hypothalamus and that provides a nutritional state-sensitive mechanism to integrate the neuroendocrine regulation of energy homeostasis, fluid balance, and the stress response.

PMID: 16775153 [PubMed - indexed for MEDLINE]

Hippocampal seizure resistance and reduced neuronal excitotoxicity in mice lacking the Cav2.3 E/R-type voltage-gated calcium channel.

Hippocampal seizure resistance and reduced neuronal excitotoxicity in mice lacking the Cav2.3 E/R-type voltage-gated calcium channel.

J Neurophysiol. 2007 May;97(5):3660-9

Authors: Weiergräber M, Henry M, Radhakrishnan K, Hescheler J, Schneider T

Voltage-gated calcium channels are key components in the etiology and pathogenesis of epilepsies. Former studies mainly focused on P/Q-type Ca(v)2.1 and T-type Ca(v)3.2 Ca(2+) channels involved in absence epileptogenesis, but recent findings also point to an intriguing role of the Ca(v)2.3 E/R-type Ca(2+) channel in ictogenesis and seizure propagation. Based on the observation that Ca(v)2.3 is thought to induce plateau potentials in CA1 pyramidal cells, which can trigger epileptiform activity, our recent investigation revealed reduced PTZ-seizure susceptibility and altered seizure architecture in Ca(v)2.3(-/-) mice compared with controls. In the present study we tested hippocampal seizure susceptibility in Ca(v)2.3-deficient mice using surface and deep intrahippocampal telemetric EEG recordings as well as phenotypic seizure video analysis. Administration of kainic acid (30 mg/kg ip) revealed clear alteration in behavioral seizure architecture and dramatic resistance to limbic seizures in Ca(v)2.3(-/-) mice compared with controls, whereas no difference in hippocampal EEG seizure activity between both genotypes could be detected at this suprathreshold dosage. The same tendency was observed for NMDA seizure susceptibility (150 mg/kg ip) approaching the level of significance. In addition, histochemical analysis within the hippocampus revealed that excitotoxic effects after kainic acid administration are absent in Ca(v)2.3(-/-) mice, whereas Ca(v)2.3(+/+) animals exhibited clear and typical signs of excitotoxic cell death. These findings clearly indicate that the Ca(v)2.3 voltage-gated calcium channel plays a crucial role in both hippocampal ictogenesis and seizure generalization and is of central importance in neuronal degeneration after excitotoxic events.

PMID: 17376845 [PubMed - indexed for MEDLINE]

Detecting correlation changes in electrophysiological data.

Detecting correlation changes in electrophysiological data.

J Neurosci Methods. 2007 Mar 30;161(1):155-65

Authors: Wu J, Kendrick K, Feng J

A correlation multi-variate analysis of variance (MANOVA) test to statistically analyze changing patterns of multi-electrode array (MEA) electrophysiology data is developed. The approach enables us not only to detect significant mean changes, but also significant correlation changes in response to external stimuli. Furthermore, a method to single out hot-spot variables in the MEA data both for the mean and correlation is provided. Our methods have been validated using both simulated spike data and recordings from sheep inferotemporal cortex.

PMID: 17137633 [PubMed - indexed for MEDLINE]

The analysis of electrode-recording-horizon in multi-electrode array(MEA).

The analysis of electrode-recording-horizon in multi-electrode array(MEA).

Conf Proc IEEE Eng Med Biol Soc. 2005;7(1):7345-7348

Authors: Lin Y, Chen C, Chen L, Zeng S, Luo Q

There is a problem that can't be ignored in the MEA collected-signal-sorting process: When a neuron positions in two adjacent microelectrodes, can its activity be detected at the same time by both microelectrodes? Under certain conditions, the contact between the electrode and the cultured cell could be simplified as capacitive contact. Because the distance and the covering area affect the capacitance the amplitude of potential decreases rapidly with the increase of distance to the microelectrode. We show that common MEA chip whose spacing of electrodes is 200 μ m can't detect the neuronal potential in its adjacent electrodes simultaneously. About 100-recorded experiments data in our lab confirm this conclusion.

PMID: 17281977 [PubMed - as supplied by publisher]

Cortically controlled brain-machine interface.

Cortically controlled brain-machine interface.

Conf Proc IEEE Eng Med Biol Soc. 2005;7(1):7660-7663

Authors: Hatsopoulos N, Mukand J, Polykoff G, Friehs G, Donoghue J

Over the past ten years, we have tested and helped develop a multi-electrode array for chronic cortical recordings in behaving non-human primates. We have found that it is feasible to record from dozens of single units in the motor cortex for extended periods of time and that these signals can be decoded in a closedloop, real-time system to generate goal-directed behavior of external devices. This work has culminated in a FDA clinical trial that has demonstrated that a tetraplegic patient can voluntarily modulate motor cortical activity in order to move a computer cursor to visual targets. Further advances in BMI technology using non-human primates have focused on using multiple modes of control from signals in different cortical areas. We demonstrate that primary motor cortical activity may be optimized for continuous movement control whereas signals from the premotor cortex may be better suited for discrete target selection. We propose a hybrid BMI whereby decoding can be voluntarily switched from discrete to continuous control modes.

PMID: 17282055 [PubMed - as supplied by publisher]

Synchronized spontaneous spikes on multi-electrode array show development of cultured neuronal network.

Synchronized spontaneous spikes on multi-electrode array show development of cultured neuronal network.

Conf Proc IEEE Eng Med Biol Soc. 2005;2:2134-7

Authors: Li X, Zhou W, Liu M, Luo Q

PMID: 17282651 [PubMed - in process]

Multiresolution bayesian detection of multiunit extracellular spike waveforms in multichannel neuronal recordings.

Multiresolution bayesian detection of multiunit extracellular spike waveforms in multichannel neuronal recordings.

Conf Proc IEEE Eng Med Biol Soc. 2005;1:141-4

Authors: Suhail Y, Oweiss K

PMID: 17282131 [PubMed - in process]

Detection of tetanus-induced effects in linearly lined-up micropatterned neuronal networks: application of a multi-electrode array chip combined with agarose microstructures.

Detection of tetanus-induced effects in linearly lined-up micropatterned neuronal networks: application of a multi-electrode array chip combined with agarose microstructures.

Biochem Biophys Res Commun. 2007 May 4;356(2):470-5

Authors: Suzuki I, Yasuda K

One of the best approaches to understanding the mechanism of information acquisition and storage is to characterize the plasticity of network activity by monitoring and stimulating individual neurons in a topologically defined network and doing this for extended periods of time. We therefore previously developed an on-chip multi-electrode array (MEA) system combined with an array of agarose microchambers (AMCs). It is possible to record the firing at multiple cells simultaneously for long term and topographically control the cells position and their connections. In our present study, we demonstrated the effect of tetanic stimulation in a linearly lined-up patterned network on the AMC/MEA chip. We detected reproducible activity changes that were induced by tetanic stimulation and saw that these changes were maintained for 6-24 h. The results show the advantage of our AMC/MEA cultivation and measurements methods and suggest they will be useful for investigating the long-term plasticity depending on network topology and size.

PMID: 17362877 [PubMed - indexed for MEDLINE]

The slow wave component of retinal activity in rd/rd mice recorded with a multi-electrode array.

The slow wave component of retinal activity in rd/rd mice recorded with a multi-electrode array.

Physiol Meas. 2007 Sep;28(9):1079-88

Authors: Ye JH, Goo YS

We investigated the differences in the retinal activity between normal and degenerate retina. Multi-electrode recordings were performed in in vitro mice retinas. Only short duration (<2 ms) retinal spikes were recorded in normal mice by postnatal day 28. However, in rd/rd mice, a slow wave component with approximately 100 ms duration was also recorded along with the spikes. We attempted to understand the mechanism of this slow wave component in degenerate retina by applying various synaptic blockers. With CNQX/AP-7, the glutamate antagonist (n = 7), the slow wave component disappeared while the normally less-dominant retinal spikes became more apparent. With strychnine, the glycine antagonist (n = 3) or picrotoxin, GABA antagonist (n = 3), the amplitude of the slow wave component increased. These suggest that a stronger excitatory glutamate input from bipolar cells to ganglion cells is the main contributor to this slow wave component in rd/rd mice.

PMID: 17827655 [PubMed - in process]

A lithographically-patterned, elastic multi-electrode array for surface stimulation of the spinal cord.

A lithographically-patterned, elastic multi-electrode array for surface stimulation of the spinal cord.

Biomed Microdevices. 2007 Oct 4;

Authors: Meacham KW, Giuly RJ, Guo L, Hochman S, Deweerth SP

A new, scalable process for microfabrication of a silicone-based, elastic multi-electrode array (MEA) is presented. The device is constructed by spinning poly(dimethylsiloxane) (PDMS) silicone elastomer onto a glass slide, depositing and patterning gold to construct wires and electrodes, spinning on a second PDMS layer, and then micropatterning the second PDMS layer to expose electrode contacts. The micropatterning of PDMS involves a custom reactive ion etch (RIE) process that preserves the underlying gold thin film. Once completed, the device can be removed from the glass slide for conformal interfacing with neural tissue. Prototype MEAs feature electrodes smaller than those known to be reported on silicone substrate (60 mum diameter exposed electrode area) and were capable of selectively stimulating the surface of the in vitro isolated spinal cord of the juvenile rat. Stretchable serpentine traces were also incorporated into the functional PDMS-based MEA, and their implementation and testing is described.

PMID: 17914674 [PubMed - as supplied by publisher]

Perturbed chloride homeostasis and GABAergic signaling in human temporal lobe epilepsy.

Perturbed chloride homeostasis and GABAergic signaling in human temporal lobe epilepsy.

J Neurosci. 2007 Sep 12;27(37):9866-73

Authors: Huberfeld G, Wittner L, Clemenceau S, Baulac M, Kaila K, Miles R, Rivera C

Changes in chloride (Cl-) homeostasis may be involved in the generation of some epileptic activities. In this study, we asked whether Cl- homeostasis, and thus GABAergic signaling, is altered in tissue from patients with mesial temporal lobe epilepsy associated with hippocampal sclerosis. Slices prepared from this human tissue generated a spontaneous interictal-like activity that was initiated in the subiculum. Records from a minority of subicular pyramidal cells revealed depolarizing GABA(A) receptor-mediated postsynaptic events, indicating a perturbed Cl- homeostasis. We assessed possible contributions of changes in expression of the potassium-chloride cotransporter KCC2. Double in situ hybridization showed that mRNA for KCC2 was absent from approximately 30% of CaMKIIalpha (calcium/calmodulin-dependent protein kinase IIalpha)-positive subicular pyramidal cells. Combining intracellular recordings with biocytin-filled electrodes and KCC2 immunochemistry, we observed that all cells that were hyperpolarized during interictal events were immunopositive for KCC2, whereas the majority of depolarized cells were immunonegative. Bumetanide, at doses that selectively block the chloride-importing potassium-sodium-chloride cotransporter NKCC1, produced a hyperpolarizing shift in GABA(A) reversal potentials and suppressed interictal activity. Changes in Cl- transporter expression thus contribute to human epileptiform activity, and molecules acting on these transporters may be useful antiepileptic drugs.

PMID: 17855601 [PubMed - in process]

[Research on chaotic behavior of epilepsy electroencephalogram of children based on independent component analysis algorithm]

[Research on chaotic behavior of epilepsy electroencephalogram of children based on independent component analysis algorithm]

Sheng Wu Yi Xue Gong Cheng Xue Za Zhi. 2007 Aug;24(4):835-41

Authors: Wang X, Meng J, Qiu T

In this paper, Independent component analysis (ICA) was first adopted to isolate the epileptiform signals from the background Electroencephalogram (EEG) signals. Then, by using the phase space reconstruct techniques from a time series and the quantitative criterions and rules of system chaos, different phases of the epileptiform signals were analyzed and calculated. Through the comparative research with the analyses of the phase plots, the power spectra, the computation of the correlation dimensions and the Lyapunov exponents of the physiologyical and the epileptiform signals, the following conclusions were drawn: (1) The phase plots, the power spectra, the correlation dimensions and the Lyapunov exponents of the EEG independent components reflect the general dynamical characteristics of brains, which can be taken as a quantitative index to weigh the healthy states of brains. (2) Under normal physiological conditions, the EEG signals are chaotic, while under epilepsy conditions the signals approach regularity.

PMID: 17899756 [PubMed - in process]

Enhanced astrocytic Ca2+ signals contribute to neuronal excitotoxicity after status epilepticus.

Enhanced astrocytic Ca2+ signals contribute to neuronal excitotoxicity after status epilepticus.

J Neurosci. 2007 Oct 3;27(40):10674-84

Authors: Ding S, Fellin T, Zhu Y, Lee SY, Auberson YP, Meaney DF, Coulter DA, Carmignoto G, Haydon PG

Status epilepticus (SE), an unremitting seizure, is known to cause a variety of traumatic responses including delayed neuronal death and later cognitive decline. Although excitotoxicity has been implicated in this delayed process, the cellular mechanisms are unclear. Because our previous brain slice studies have shown that chemically induced epileptiform activity can lead to elevated astrocytic Ca2+ signaling and because these signals are able to induce the release of the excitotoxic transmitter glutamate from these glia, we asked whether astrocytes are activated during status epilepticus and whether they contribute to delayed neuronal death in vivo. Using two-photon microscopy in vivo, we show that status epilepticus enhances astrocytic Ca2+ signals for 3 d and that the period of elevated glial Ca2+ signaling is correlated with the period of delayed neuronal death. To ask whether astrocytes contribute to delayed neuronal death, we first administered antagonists which inhibit gliotransmission: MPEP [2-methyl-6-(phenylethynyl)pyridine], a metabotropic glutamate receptor 5 antagonist that blocks astrocytic Ca2+ signals in vivo, and ifenprodil, an NMDA receptor antagonist that reduces the actions of glial-derived glutamate. Administration of these antagonists after SE provided significant neuronal protection raising the potential for a glial contribution to neuronal death. To test this glial hypothesis directly, we loaded Ca2+ chelators selectively into astrocytes after status epilepticus. We demonstrate that the selective attenuation of glial Ca2+ signals leads to neuronal protection. These observations support neurotoxic roles for astrocytic gliotransmission in pathological conditions and identify this process as a novel therapeutic target.

PMID: 17913901 [PubMed - in process]

Genetic and epigenetic mechanisms of gene regulation during lens development.

Genetic and epigenetic mechanisms of gene regulation during lens development.

Prog Retin Eye Res. 2007 Jul 28;

Authors: Cvekl A, Duncan MK

Recent studies demonstrated a number of links between chromatin structure, gene expression, extracellular signaling and cellular differentiation during lens development. Lens progenitor cells originate from a pool of common progenitor cells, the pre-placodal region (PPR) which is formed from a combination of extracellular signaling between the neural plate, naïve ectoderm and mesendoderm. A specific commitment to the lens program over alternate choices such as the formation of olfactory epithelium or the anterior pituitary is manifested by the formation of a thickened surface ectoderm, the lens placode. Mouse lens progenitor cells are characterized by the expression of a complement of lens lineage-specific transcription factors including Pax6, Six3 and Sox2, controlled by FGF and BMP signaling, followed later by c-Maf, Mab21like1, Prox1 and FoxE3. Proliferation of lens progenitors together with their morphogenetic movements results in the formation of the lens vesicle. This transient structure, comprised of lens precursor cells, is polarized with its anterior cells retaining their epithelial morphology and proliferative capacity, whereas the posterior lens precursor cells initiate terminal differentiation forming the primary lens fibers. Lens differentiation is marked by expression and accumulation of crystallins and other structural proteins. The transcriptional control of crystallin genes is characterized by the reiterative use of transcription factors required for the establishment of lens precursors in combination with more ubiquitously expressed factors (e.g. AP-1, AP-2alpha, CREB and USF) and recruitment of histone acetyltransferases (HATs) CBP and p300, and chromatin remodeling complexes SWI/SNF and ISWI. These studies have poised the study of lens development at the forefront of efforts to understand the connections between development, cell signaling, gene transcription and chromatin remodeling.

PMID: 17905638 [PubMed - as supplied by publisher]

Hedonic-specific activity in piriform cortex during odor imagery mimics that during odor perception.

Hedonic-specific activity in piriform cortex during odor imagery mimics that during odor perception.

J Neurophysiol. 2007 Oct 3;

Authors: Bensafi M, Sobel N, Khan RM

Whereas it is known that visual imagery is accompanied by activity in visual cortical areas, including primary visual cortex, whether olfactory imagery exists remains controversial. Here we asked whether cue-dependent olfactory imagery was similarly accompanied by activity in olfactory cortex, and in particular whether hedonic-specific patterns of activity evident in olfactory perception would also be present during olfactory imagery. We used functional magnetic resonance imaging to measure activity in subjects who alternated between smelling and imagining pleasant and unpleasant odors. Activity induced by imagining odors mimicked that induced by perceiving real odorants, not only in the particular brain regions activated, but also in its hedonic-specific pattern. For both real and imagined odors, unpleasant stimuli induced greater activity than pleasant stimuli in the left frontal portion of piriform cortex and left insula. These findings combine with findings from other modalities to suggest activation of primary sensory cortical structures during mental imagery of sensory events.

PMID: 17913994 [PubMed - as supplied by publisher]

CB1 cannabinoid receptor activity is modulated by the interacting protein CRIP1a.

CB1 cannabinoid receptor activity is modulated by the interacting protein CRIP1a.

Mol Pharmacol. 2007 Sep 25;

Authors: Niehaus JL, Liu Y, Wallis KT, Egertova M, Bhartur SG, Mukhopadhyay S, Shi S, He H, Selley DE, Howlett AC, Elphick MR, Lewis DL

The CB1 cannabinoid receptor is a G-protein coupled receptor (GPCR) that has important physiological roles in synaptic plasticity, analgesia, appetite, and neuroprotection. Here we report the discovery of two structurally related CB1 cannabinoid receptor interacting proteins (CRIP1a and CRIP1b) that bind to the distal C-terminal tail of CB1. CRIP1a and CRIP1b are generated by alternative splicing of a gene located on chromosome 2 in humans and orthologs of CRIP1a occur throughout the vertebrates, whereas CRIP1b appears to be unique to primates. CRIP1a co-immunoprecipitates with CB1 receptors derived from rat brain homogenates, indicating that CRIP1a and CB1 interact in vivo. Furthermore, in superior cervical ganglion neurons co-injected with CB1 and CRIP1a or CRIP1b cDNA, CRIP1a, but not CRIP1b, suppresses CB1-mediated tonic inhibition of voltage-gated Ca(2+) channels. Discovery of CRIP1a provides the basis for a new avenue of research on mechanisms of CB1 regulation in the nervous system and may lead to development of novel drugs to treat disorders where modulation of CB1 activity has therapeutic potential (e.g., chronic pain, obesity and epilepsy).

PMID: 17895407 [PubMed - as supplied by publisher]

Endocannabinoid liberation from neurons in transsynaptic signaling.

Endocannabinoid liberation from neurons in transsynaptic signaling.

J Mol Neurosci. 2007;33(1):87-93

Authors: Lovinger DM

Endocannabinoids are fatty acid derivatives that have a variety of biological actions, most notably via activation of the cannabinoid receptors. These receptors are also targets for drugs derived from Cannabis sativa. In the nervous system, endocannabinoids act as neuromodulators that depress neurotransmitter release at the presynaptic terminal. In most instances of neural endocannabinoid signaling, the compounds appear to be released from the postsynaptic neuron to act on the presynaptic terminal in a "retrograde" manner. Several common mechanisms involved in postsynaptic endocannabinoid production and presynaptic depression produced via activation of the CB1 cannabinoid receptor have been identified. However, significant problems remain in defining the mechanisms underlying endocannabinoid production, release, and movement across the membrane. These issues are discussed in the present review.

PMID: 17901551 [PubMed - in process]

Understanding metabolic homeostasis and imbalance: what is the role of the endocannabinoid system?

Understanding metabolic homeostasis and imbalance: what is the role of the endocannabinoid system?

Am J Med. 2007 Sep;120(9 Suppl 1):S18-24; discussion S24

Authors: Kunos G

Endogenous endocannabinoids (ECs) (anandamide and 2-arachidonoyl glycerol) are part of the leptin-regulated neural circuitry involved in appetite regulation. One of the sites of the orexigenic action of ECs involves activation of cannabinoid-1 (CB1) receptors in the lateral hypothalamus, from which neurons involved in mediating food reward project into the limbic system. In animal models of obesity, pharmacologic blockade or genetic ablation of CB1 receptors causes a transient reduction in food intake accompanied by sustained weight loss, reduced adiposity, and reversal of hormonal/metabolic changes, such as elevated levels of plasma leptin, insulin, glucose, and triglyceride, and reduced levels of plasma adiponectin (Acrp30). However, the beneficial effects of CB1 blockade on weight and metabolism cannot be explained by appetite suppression alone. Animal studies suggest that CB1 blockade exerts a direct peripheral as well as a central effect on fat metabolism. CB1 receptor blockade with rimonabant has been shown to not only reduce weight and adiposity but also to directly modulate fat metabolism at peripheral sites in skeletal muscle, adipose tissue, and the liver. Preclinical animal studies suggest that CB1 blockade acts on adipocytes to increase Acrp30 expression, on hepatocytes to decrease de novo lipogenesis and increase fatty acid oxidation, and on skeletal muscle to reduce blood glucose and insulin levels. Extrapolating from animal studies to the clinic, CB1 receptor blockade offers a promising strategy not only for reducing weight and abdominal adiposity but also for preventing and reversing its metabolic consequences.

PMID: 17720356 [PubMed - in process]

Blogged with Flock

Interaction of a fragment of the cannabinoid CB1 receptor C-terminus with arrestin-2.

Interaction of a fragment of the cannabinoid CB1 receptor C-terminus with arrestin-2.

FEBS Lett. 2007 Sep 24;

Authors: Bakshi K, Mercier RW, Pavlopoulos S

Desensitization of the cannabinoid CB1 receptor is mediated by the interaction with arrestin. In this study, we report the structural changes of a synthetic diphosphorylated peptide corresponding to residues 419-439 of the CB1 C-terminus upon binding to arrestin-2. This segment is pivotal to the desensitization of CB1. Using high-resolution proton NMR, we observe two helical segments in the bound peptide that are separated by the presence a glycine residue. The binding we observe is with a diphoshorylated peptide, whereas a previous study reported binding of a highly phosphorylated rhodopsin fragment to visual arrestin. The arrestin bound conformations of the peptides are compared.

PMID: 17910957 [PubMed - as supplied by publisher]

Acute anorectic response to cannabinoid CB1 receptor antagonist/inverse agonist AM 251 in rats: indirect behavioural mediation.

Acute anorectic response to cannabinoid CB1 receptor antagonist/inverse agonist AM 251 in rats: indirect behavioural mediation.

Behav Pharmacol. 2007 Nov;18(7):591-600

Authors: Tallett AJ, Blundell JE, Rodgers JR

Despite a large and consistent literature on the suppressant effects of cannabinoid CB1 receptor antagonists/inverse agonists (e.g. rimonabant, AM 251) on food intake and weight gain in rodents, surprisingly little is known about the behavioural selectivity of such effects. In this study, ethological scoring was used to characterize the acute behavioural effects of the rimonabant analogue AM 251 (1.5 and 3.0 mg/kg, intraperitoneally) in nondeprived male rats during a 1-h test with palatable mash. Data were also collected on daily weight gain and on retest food intake 7 days after dosing. Results showed that the higher dose of AM 251 significantly inhibited mash consumption (32% decrease relative to vehicle control), reduced time spent feeding during the test and suppressed body weight gain over the 48-h period that followed acute dosing. No effects on mash consumption were observed when the animals were retested drug-free 1 week after drug treatment. Detailed video analysis of the test sessions showed that, over the dose range tested, AM 251 did not significantly interfere with the vast majority of noningestive behaviours. Both doses of the compound, however, significantly increased the incidence of and the time spent on scratching, whereas the higher dose additionally increased both the number and duration of grooming episodes. The latter effect in particular disrupted the normal structure of behaviour (behavioural satiety sequence) with atypically high levels of grooming displacing feeding during the middle part of the test session. Overall, the behavioural profile of AM 251 in a free-feeding context is very similar to (but approximately two-fold less potent than) that recently reported for the parent molecule, rimonabant. Together, these data strongly suggest that the acute anorectic response to CB1 receptor antagonists/inverse agonists is indirectly mediated via major alterations to other components of the behavioural repertoire.

PMID: 17912043 [PubMed - in process]

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