Same old: May 2007

Monday 21 May 2007

Carbonic anhydrase inhibitors and anticonvulsant activity

Carbonic anhydrase inhibitors as anticonvulsant agents.

Carbonic anhydrase inhibitors as anticonvulsant agents.

Curr Top Med Chem. 2007;7(9):855-64

Authors: Thiry A, Dogné JM, Supuran CT, Masereel B

Seizures are one of the most common neurological disorders in clinical medicine. Triggering mechanisms by which seizures form remain unclear, but are related to a rapid change in ionic composition, including an increase of intracellular potassium concentration and pH shifts within the brain. pH buffering of extra- and intracellular spaces is mainly carried out by the CO(2)/ HCO(3)(-) buffer, the equilibration of the two species being assured by the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1). Some carbonic anhydrase inhibitors (CAIs) are used as anticonvulsants in the treatment of epilepsy. In this review, we will describe the link between CA and seizures on the basis of several putative mechanisms. Several CA isozymes have been pointed out for their contribution to epileptiform activity. An overview of the CA isozyme expression in the brain and of their specifics roles is also discussed. This article reviews the research achievements published on CA inhibitors, clinically used as anticonvulsant and those under development.

PMID: 17504130 [PubMed - in process]

Them Yanks again....

Why Americans resist neuroscience more

Science has a special online feature this week on behavioral science. One of the articles is a review by Paul Bloom and Deena Skolnick Weisberg (a fellow SymSys alum!) presents some interesting evidence about how dualistic ideas about mind/brain are present from an early age. They state:

Another consequence of people’s common-sense psychology is dualism, the belief that the mind is fundamentally different from the brain (5). This belief comes naturally to children. Preschool children will claim that the brain is responsible for some aspects of mental life, typically those involving deliberative mental work, such as solving math problems. But preschoolers will also claim that the brain is not involved in a host of other activities, such as pretending to be a kangaroo, loving one’s brother, or brushing one’s teeth (5, 17). Similarly, when told about a brain transplant from a boy to a pig, they believed that you would get a very smart pig, but one with pig beliefs and pig desires (18). For young children, then, much of mental life is not linked to the brain.

And,

For one thing, debates about the moral status of embryos, fetuses, stem cells, and nonhuman animals are sometimes framed in terms of whether or not these entities possess immaterial souls (20, 21). What’s more, certain proposals about the role of evidence from functional magnetic resonance imaging in criminal trials assume a strong form of dualism (22). It has been argued, for instance, that if one could show that a person’s brain is involved in an act, then the person himself or herself is not responsible, an excuse dubbed “my brain made me do it” (23).

The authors conclude that adult resistance to science is strongest in fields where scientific claims are contested by the society (that is, contested by non-science alternatives rather than by scientific uncertainty). They claim that this accounts for the difference in the United States (versus other countries with less vociferous advocacy of non-science) in the resistance to the central tenets of evolutionary biology and neuroscience.

I think this says something important about science education, namely that it should start earlier in life. And there’s no reason that neuroscience should be left as a “college-level” subject. I think modern neuroscience has progressed to the point where we can confidently teach some basics at a high-school or earlier stage. Judging from my own experiences, I think the desire to learn about neuroscience is certainly there in younger children.

Thursday 17 May 2007

LTP and memory: protocols

Electrical stimulation protocols for hippocampal synaptic plasticity and neuronal hyper-excitability: are they effective or relevant?

Electrical stimulation protocols for hippocampal synaptic plasticity and neuronal hyper-excitability: are they effective or relevant?

Exp Neurol. 2007 Mar;204(1):1-13

Authors: Albensi BC, Oliver DR, Toupin J, Odero G

Long-term potentiation (LTP) of synaptic transmission is a widely accepted model that attempts to link synaptic plasticity with memory. LTP models are also now used in order to test how a variety of neurological disorders might affect synaptic plasticity. Interestingly, electrical stimulation protocols that induce LTP appear to display different efficiencies and importantly, some may not be as physiologically relevant as others. In spite of advancements in our understanding of these differences, many types of LTP inducing protocols are still widely used. In addition, in some cases electrical stimulation leads to normal biological phenomena, such as putative memory encoding and in other cases electrical stimulation triggers pathological phenomena, such as epileptic seizures. Kindling, a model of epileptogenesis involving repeated electrical stimulation, leads to seizure activity and has also been thought of, and studied as, a form of long-term neural plasticity and memory. Furthermore, some investigators now use electrical stimulation in order to reduce aspects of seizure activity. In this review, we compare in vitro and in vivo electrical stimulation protocols employed in the hippocampal formation that are utilized in models of synaptic plasticity or neuronal hyperexcitability. Here the effectiveness and physiological relevance of these electrical stimulation protocols are examined in situations involving memory encoding (e.g., LTP/LTD) and epileptiform activity.

PMID: 17258711 [PubMed - indexed for MEDLINE]

cannab and glucose

Role of cannabinoid CB(2) receptors in glucose homeostasis in rats.

Role of cannabinoid CB(2) receptors in glucose homeostasis in rats.

Eur J Pharmacol. 2007 Apr 20;

Authors: Bermudez-Silva FJ, Sanchez-Vera I, Suárez J, Serrano A, Fuentes E, Juan-Pico P, Nadal A, Rodríguez de Fonseca F

Here we show that the activation of cannabinoid CB(2) receptors improved glucose tolerance after a glucose load. Blockade of cannabinoid CB(2) receptors counteracted this effect, leading to glucose intolerance. Since blockade of cannabinoid CB(1) receptors mimics the actions of cannabinoid CB(2) receptor agonists, we propose that the endocannabinoid system modulates glucose homeostasis through the coordinated actions of cannabinoid CB(1) and CB(2) receptors. We also describe the presence of both cannabinoid CB(1) and CB(2) receptor immunoreactivity in rat pancreatic beta- and non-beta-cells, adding the endocrine pancreas to adipose tissue and the liver as potential sites for endocannabinoid regulation of glucose homeostasis.

PMID: 17499236 [PubMed - as supplied by publisher]

cannab and spatial WM

The synthetic cannabinoid HU210 induces spatial memory deficits and suppresses hippocampal firing rate in rats.

The synthetic cannabinoid HU210 induces spatial memory deficits and suppresses hippocampal firing rate in rats.

Br J Pharmacol. 2007 May 14;

Authors: Robinson L, Goonawardena AV, Pertwee RG, Hampson RE, Riedel G

Background and purpose:Previous work implied that the hippocampal cannabinoid system was particularly important in some forms of learning, but direct evidence for this hypothesis is scarce. We therefore assessed the effects of the synthetic cannabinoid HU210 on memory and hippocampal activity.Experimental approach:HU210 (100 mug kg(-1)) was administered intraperitoneally to rats under three experimental conditions. One group of animals were pre-trained in spatial working memory using a delayed-matching-to-position task and effects of HU210 were assessed in a within-subject design. In another, rats were injected before acquisition learning of a spatial reference memory task with constant platform location. Finally, a separate group of animals was implanted with electrode bundles in CA1 and CA3 and single unit responses were isolated, before and after HU210 treatment.Key results:HU210 treatment had no effect on working or short-term memory. Relative to its control Tween 80, deficits in acquisition of a reference memory version of the water maze were obtained, along with drug-related effects on anxiety, motor activity and spatial learning. Deficits were not reversed by the CB(1) receptor antagonists SR141716A (3 mg kg(-1)) or AM281 (1.5 mg kg(-1)). Single unit recordings from principal neurons in hippocampal CA3 and CA1 confirmed HU210-induced attenuation of the overall firing activity lowering both the number of complex spikes fired and the occurrence of bursts.Conclusions and implications:These data provide the first direct evidence that the underlying mechanism for the spatial memory deficits induced by HU210 in rats is the accompanying abnormality in hippocampal cell firing.British Journal of Pharmacology advance online publication, 14 May 2007; doi:10.1038/sj.bjp.0707273.

PMID: 17502849 [PubMed - as supplied by publisher]

Cannabs and njury

Antinociceptive effect of cannabinoid agonist WIN 55,212-2 in rats with a spinal cord injury.

Antinociceptive effect of cannabinoid agonist WIN 55,212-2 in rats with a spinal cord injury.

Exp Neurol. 2007 Mar;204(1):454-7

Authors: Hama A, Sagen J

Spinal cord injury (SCI) pain exhibits many symptoms associated with peripheral neuropathic pain, including increased tactile hypersensitivity. One novel approach to ameliorate SCI pain is the use of cannabinoid (CB) ligands. The current study evaluated the efficacy of the nonselective CB receptor agonist WIN 55,212-2 on tactile hypersensitivity in rats following a brief compression to the thoracic spinal cord. The withdrawal thresholds of the hind paws following SCI were significantly decreased, indicating tactile hypersensitivity. Systemic injection of WIN 55,212-2 increased withdrawal thresholds in a dose-dependent manner. Pretreatment with the CB(1) receptor subtype-selective antagonist AM 251 completely abolished the antinociceptive effect of WIN 55,212-2 whereas pretreatment with the CB(2) receptor subtype-selective antagonist AM 630 did not alter the antinociceptive effect of WIN 55,212-2. These data indicate that a CB(1)-selective agonist may be novel therapeutic treatment for clinical SCI pain.

PMID: 17045264 [PubMed - indexed for MEDLINE]

CBD THC antagonism

Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro.

Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro.

Br J Pharmacol. 2007 Mar;150(5):613-23

Authors: Thomas A, Baillie GL, Phillips AM, Razdan RK, Ross RA, Pertwee RG

BACKGROUND AND PURPOSE: A nonpsychoactive constituent of the cannabis plant, cannabidiol has been demonstrated to have low affinity for both cannabinoid CB1 and CB2 receptors. We have shown previously that cannabidiol can enhance electrically evoked contractions of the mouse vas deferens, suggestive of inverse agonism. We have also shown that cannabidiol can antagonize cannabinoid receptor agonists in this tissue with a greater potency than we would expect from its poor affinity for cannabinoid receptors. This study aimed to investigate whether these properties of cannabidiol extend to CB1 receptors expressed in mouse brain and to human CB2 receptors that have been transfected into CHO cells. EXPERIMENTAL APPROACH: The [35S]GTPS binding assay was used to determine both the efficacy of cannabidiol and the ability of cannabidiol to antagonize cannabinoid receptor agonists (CP55940 and R-(+)-WIN55212) at the mouse CB1 and the human CB2 receptor. KEY RESULTS: This paper reports firstly that cannabidiol displays inverse agonism at the human CB2 receptor. Secondly, we demonstrate that cannabidiol is a high potency antagonist of cannabinoid receptor agonists in mouse brain and in membranes from CHO cells transfected with human CB2 receptors. CONCLUSIONS AND IMPLICATIONS: This study has provided the first evidence that cannabidiol can display CB2 receptor inverse agonism, an action that appears to be responsible for its antagonism of CP55940 at the human CB2 receptor. The ability of cannabidiol to behave as a CB2 receptor inverse agonist may contribute to its documented anti-inflammatory properties.

PMID: 17245363 [PubMed - indexed for MEDLINE]

Roger's at it again....

The psychoactive plant cannabinoid, Delta9-tetrahydrocannabinol, is antagonized by Delta8- and Delta9-tetrahydrocannabivarin in mice in vivo.

The psychoactive plant cannabinoid, Delta9-tetrahydrocannabinol, is antagonized by Delta8- and Delta9-tetrahydrocannabivarin in mice in vivo.

Br J Pharmacol. 2007 Mar;150(5):586-94

Authors: Pertwee RG, Thomas A, Stevenson LA, Ross RA, Varvel SA, Lichtman AH, Martin BR, Razdan RK

BACKGROUND AND PURPOSE: To follow up in vitro evidence that Delta(9)-tetrahydrocannabivarin extracted from cannabis (eDelta(9)-THCV) is a CB(1) receptor antagonist by establishing whether synthetic Delta(9)-tetrahydrocannabivarin (O-4394) and Delta(8)-tetrahydrocannabivarin (O-4395) behave as CB(1) antagonists in vivo. EXPERIMENTAL APPROACH: O-4394 and O-4395 were compared with eDelta(9)-THCV as displacers of [(3)H]-CP55940 from specific CB(1) binding sites on mouse brain membranes and as antagonists of CP55940 in [(35)S]GTPgammaS binding assays performed with mouse brain membranes and of R-(+)-WIN55212 in mouse isolated vasa deferentia. Their ability to antagonize in vivo effects of 3 or 10 mg kg(-1) (i.v.) Delta(9)-tetrahydrocannabinol in mice was then investigated. KEY RESULTS: O-4394 and O-4395 exhibited similar potencies to eDelta(9)-THCV as displacers of [(3)H]-CP55940 (K (i)=46.6 and 64.4 nM, respectively) and as antagonists of CP55940 in the [(35)S]GTPgammaS binding assay (apparent K (B)=82.1 and 125.9 nM, respectively) and R-(+)-WIN55212 in the vas deferens (apparent K (B)=4.8 and 3.9 nM respectively). At i.v. doses of 0.1, 0.3, 1.0 and/or 3 mg kg(-1) O-4394 and O-4395 attenuated Delta(9)-tetrahydrocannabinol-induced anti-nociception (tail-flick test) and hypothermia (rectal temperature). O-4395 but not O-4394 also antagonized Delta(9)-tetrahydrocannabinol-induced ring immobility. By themselves, O-4395 and O-4394 induced ring immobility at 3 or 10 mg kg(-1) (i.v.) and antinociception at doses above 10 mg kg(-1) (i.v.). O-4395 also induced hypothermia at 3 mg kg(-1) (i.v.) and above. CONCLUSIONS AND IMPLICATIONS: O-4394 and O-4395 exhibit similar in vitro potencies to eDelta(9)-THCV as CB(1) receptor ligands and as antagonists of cannabinoid receptor agonists and can antagonize Delta(9)-tetrahydrocannabinol in vivo.

PMID: 17245367 [PubMed - indexed for MEDLINE]

Thursday 10 May 2007

Tagged CB1Rs

Generation and functional characterization of fluorescent, N-terminally tagged CB(1) receptor chimeras for live-cell imaging.

Generation and functional characterization of fluorescent, N-terminally tagged CB(1) receptor chimeras for live-cell imaging.

Mol Cell Neurosci. 2007 Mar 3;

Authors: McDonald NA, Henstridge CM, Connolly CN, Irving AJ

N-terminally tagged CB(1) receptor fusion proteins, incorporating enhanced green fluorescent protein (GFP) or super-ecliptic pHluorin (SEP), were generated to study CB(1) receptor trafficking and cell surface receptor expression in live COS7 and HEK293 cells and hippocampal neurons. An artificial signal sequence (SS) was required for efficient surface expression of CB(1) receptor chimeras, which behaved like wild-type CB(1) receptors in functional assays. Treatment with cannabinoid ligands led to a rapid down-regulation of SS-GFP-CB(1) from the plasma membrane in COS7 and HEK293 cells, associated with trafficking into cytosolic vesicles. Activation of CB(1) receptors was also linked with a time-dependent reduction in cell surface SEP-CB(1) fluorescence and incorporation of the construct into acidic endosomes, revealed following exposure to NH(4)Cl. In live hippocampal neurons, SEP-CB(1) fluorescence was largely restricted to the axon, consistent with its polarised surface expression. Thus, these new molecular tools are well suited for studying CB(1) receptor trafficking and a new generation of GPCR chimeras incorporating SEP at the N-terminus will be especially useful for monitoring dynamic changes in cell surface receptor expression in living cells.

PMID: 17467290 [PubMed - as supplied by publisher]

Cannabinoid, hypothalamic

Cannabinoids excite hypothalamic melanin-concentrating hormone but inhibit hypocretin/orexin neurons: implications for cannabinoid actions on food intake and cognitive arousal.

Cannabinoids excite hypothalamic melanin-concentrating hormone but inhibit hypocretin/orexin neurons: implications for cannabinoid actions on food intake and cognitive arousal.

J Neurosci. 2007 May 2;27(18):4870-81

Authors: Huang H, Acuna-Goycolea C, Li Y, Cheng HM, Obrietan K, van den Pol AN

Cannabinoids modulate energy homeostasis and decrease cognitive arousal, possibly by acting on hypothalamic neurons including those that synthesize melanin-concentrating hormone (MCH) or hypocretin/orexin. Using patch-clamp recordings, we compared the actions of cannabinoid agonists and antagonists on identified MCH or hypocretin neurons in green fluorescent protein-expressing transgenic mice. The cannabinoid type-1 receptor (CB1R) agonist R-(+)-[2,3-dihydro-5-methyl-3-(4-morpho linylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate (WIN55,212,2) depolarized MCH cells and increased spike frequency; in contrast, WIN55,212,2 hyperpolarized and reduced spontaneous firing of the neighboring hypocretin cells, both results consistent with reduced activity seen with intracerebral cannabinoid infusions. These effects were prevented by AM251 [N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide], a CB1R antagonist, and by tetrodotoxin, suggesting no postsynaptic effect on either neuron type. In MCH cells, depolarizing WIN55,212,2 actions were abolished by the GABA(A) receptor antagonist bicuculline, suggesting that the CB1R-mediated depolarization was attributable to reduced synaptic GABA release. WIN55,212,2 decreased spontaneous IPSCs, reduced the frequency but not amplitude of miniature IPSCs, and reduced electrically evoked synaptic currents in MCH cells. Glutamate microdrop experiments suggest that WIN55,212,2 acted on axons arising from lateral hypothalamus local inhibitory cells that innervate MCH neurons. In hypocretin neurons, the reduced spike frequency induced by WIN55,212,2 was attributable to presynaptic attenuation of glutamate release; CB1R agonists depressed spontaneous and evoked glutamatergic currents and reduced the frequency of miniature EPSCs. Cannabinoid actions on hypocretin neurons were abolished by ionotropic glutamate receptor antagonists. Together, these results show that cannabinoids have opposite effects on MCH and hypocretin neurons. These opposing actions could help explain the increase in feeding and reduction in arousal induced by cannabinoids.

PMID: 17475795 [PubMed - in process]

Same old