Modulation of CaV2.3 Calcium Channel Currents by Eugenol.

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Modulation of CaV2.3 Calcium Channel Currents by Eugenol.

J Dent Res. 2008 Feb;87(2):137-41

Authors: Chung G, Rhee JN, Jung SJ, Kim JS, Oh SB

Eugenol, a natural congener of capsaicin, is a routine analgesic agent in dentistry. We have recently demonstrated the inhibition of Ca(V)2.2 calcium channel and sodium channel currents to be molecular mechanisms underlying the analgesic effect of eugenol. We hypothesized that Ca(V)2.3 channels are also modulated by eugenol and investigated its mode of action using the whole-cell patch-clamp technique in a heterologous expression system. Eugenol inhibited calcium currents in the E52 cell line, stably expressing the human Ca(V)2.3 calcium channels, where TRPV1 is not endogenously expressed. The extent of current inhibition was not significantly different between naïve E52 cells and TRPV1-expressing E52 cells, suggesting no involvement of TRPV1. In contrast, TRPV1 activation is prerequisite for the inhibition of Ca(V)2.3 calcium channels by capsaicin. The results indicate that eugenol has mechanisms distinct from those of capsaicin for modulating Ca(V)2.3 channels. We suggest that inhibition of Ca(V)2.3 channels by eugenol might contribute to its analgesic effect.

PMID: 18218839 [PubMed - in process]

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The novel antiepileptic drug carisbamate (RWJ 333369) is effective in inhibiting spontaneous recurrent seizure discharges and blocking sustained repetitive firing in cultured hippocampal neurons.

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The novel antiepileptic drug carisbamate (RWJ 333369) is effective in inhibiting spontaneous recurrent seizure discharges and blocking sustained repetitive firing in cultured hippocampal neurons.

Epilepsy Res. 2008 Mar 17;

Authors: Deshpande LS, Nagarkatti N, Sombati S, Delorenzo RJ

This study was initiated to investigate effects of the novel neuromodulator carisbamate (RWJ 333369) in the hippocampal neuronal culture model of status epilepticus and spontaneous epileptiform discharges. Whole-cell current clamp techniques were used to determine the effects of carisbamate on spontaneous recurrent epileptiform discharges (SREDs, in vitro epilepsy), depolarization-induced sustained repetitive firing (SRF) and low Mg(2+)-induced continuous high frequency spiking (in vitro status epilepticus). This in vitro model is an important tool to study the effects of anticonvulsant drugs (AEDs) on SREDs that occur for the life of the neurons in culture. Carisbamate dose dependently blocked the expression and reoccurrence of SREDs. The ED(50) value for its antiepileptic effect was 58.75+/-2.43muM. Inhibition of SRF is considered a common attribute of many AEDs. Carisbamate (100muM) significantly decreased SRF in hippocampal neurons. All these effects of carisbamate were reversed during a 5 to 30min drug washout period. When exposed to low Mg(2+) medium cultured hippocampal neurons exhibit high frequency spiking. This form of in vitro status epilepticus is not effectively blocked by conventional AEDs that are known to be effective in treating status epilepticus in humans. Carisbamate, like phenytoin and phenobarbital, had little or no effect on low Mg(2+)-induced continuous high frequency spiking. These results characterize the effects of carisbamate in the hippocampal neuronal culture model of epileptiform discharges and suggest that the ability of carisbamate to inhibit depolarization-induced SRF may account in part for some of it's anticonvulsant effect.

PMID: 18353614 [PubMed - as supplied by publisher]

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Shaping Embodied Neural Networks for Adaptive Goal-directed Behavior.

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Shaping Embodied Neural Networks for Adaptive Goal-directed Behavior.

PLoS Comput Biol. 2008 Mar;4(3):e1000042

Authors: Chao ZC, Bakkum DJ, Potter SM

The acts of learning and memory are thought to emerge from the modifications of synaptic connections between neurons, as guided by sensory feedback during behavior. However, much is unknown about how such synaptic processes can sculpt and are sculpted by neuronal population dynamics and an interaction with the environment. Here, we embodied a simulated network, inspired by dissociated cortical neuronal cultures, with an artificial animal (an animat) through a sensory-motor loop consisting of structured stimuli, detailed activity metrics incorporating spatial information, and an adaptive training algorithm that takes advantage of spike timing dependent plasticity. By using our design, we demonstrated that the network was capable of learning associations between multiple sensory inputs and motor outputs, and the animat was able to adapt to a new sensory mapping to restore its goal behavior: move toward and stay within a user-defined area. We further showed that successful learning required proper selections of stimuli to encode sensory inputs and a variety of training stimuli with adaptive selection contingent on the animat's behavior. We also found that an individual network had the flexibility to achieve different multi-task goals, and the same goal behavior could be exhibited with different sets of network synaptic strengths. While lacking the characteristic layered structure of in vivo cortical tissue, the biologically inspired simulated networks could tune their activity in behaviorally relevant manners, demonstrating that leaky integrate-and-fire neural networks have an innate ability to process information. This closed-loop hybrid system is a useful tool to study the network properties intermediating synaptic plasticity and behavioral adaptation. The training algorithm provides a stepping stone towards designing future control systems, whether with artificial neural networks or biological animats themselves.

PMID: 18369432 [PubMed - in process]

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The phytocannabinoid Delta(9)-tetrahydrocannabivarin modulates inhibitory neurotransmission in the cerebellum.

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The phytocannabinoid Delta(9)-tetrahydrocannabivarin modulates inhibitory neurotransmission in the cerebellum.

Br J Pharmacol. 2008 Mar 3;

Authors: Ma YL, Weston SE, Whalley BJ, Stephens GJ

Background and purposeThe phytocannabinoid Delta(9)-tetrahydrocannabivarin (Delta(9)-THCV) has been reported to exhibit a diverse pharmacology; here, we investigate functional effects of Delta(9)-THCV, extracted from Cannabis sativa, using electrophysiological techniques to define its mechanism of action in the CNS.Experimental approachEffects of Delta(9)-THCV and synthetic cannabinoid agents on inhibitory neurotransmission at interneurone-Purkinje cell (IN-PC) synapses were correlated with effects on spontaneous PC output using single-cell and multi-electrode array (MEA) electrophysiological recordings respectively, in mouse cerebellar brain slices in vitro.Key resultsThe cannabinoid receptor agonist WIN 55,212-2 (WIN55) decreased miniature inhibitory postsynaptic current (mIPSC) frequency at IN-PC synapses. WIN55-induced inhibition was reversed by Delta(9)-THCV, and also by the CB(1) receptor antagonist AM251; Delta(9)-THCV or AM251 acted to increase mIPSC frequency beyond basal values. When applied alone, Delta(9)-THCV, AM251 or rimonabant increased mIPSC frequency. Pre-incubation with Delta(9)-THCV blocked WIN55-induced inhibition. In MEA recordings, WIN55 increased PC spike firing rate; Delta(9)-THCV and AM251 acted in the opposite direction to decrease spike firing. The effects of Delta(9)-THCV and WIN55 were attenuated by the GABA(A) receptor antagonist bicuculline methiodide.Conclusions and implicationsWe show for the first time that Delta(9)-THCV acts as a functional CB(1) receptor antagonist in the CNS to modulate inhibitory neurotransmission at IN-PC synapses and spontaneous PC output. Delta(9)-THCV- and AM251-induced increases in mIPSC frequency beyond basal levels were consistent with basal CB(1) receptor activity. WIN55-induced increases in PC spike firing rate were consistent with synaptic disinhibition; whilst Delta(9)-THCV- and AM251-induced decreases in spike firing suggest a mechanism of PC inhibition.British Journal of Pharmacology advance online publication, 3 March 2008; doi:10.1038/bjp.2008.57.

PMID: 18311186 [PubMed - as supplied by publisher]

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Reciprocal inhibition of G-protein signaling is induced by CB(1) cannabinoid and GABA(B) receptor interactions in rat hippocampal membranes.

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Reciprocal inhibition of G-protein signaling is induced by CB(1) cannabinoid and GABA(B) receptor interactions in rat hippocampal membranes.

Neurochem Int. 2008 Feb 29;

Authors: Cinar R, Freund TF, Katona I, Mackie K, Szucs M

Cannabinoid CB(1) and the metabotropic GABA(B) receptors have been shown to display similar pharmacological effects and co-localization in certain brain regions. Previous studies have reported a functional link between the two systems. As a first step to investigate the underlying molecular mechanism, here we show cross-inhibition of G-protein signaling between GABA(B) and CB(1) receptors in rat hippocampal membranes. The CB(1) agonist R-Win55,212-2 displayed high potency and efficacy in stimulating guanosine-5'-O-(3-[(35)S]thio)triphosphate, [(35)S]GTPgammaS binding. Its effect was completely blocked by the specific CB(1) antagonist AM251 suggesting that the signaling was via CB(1) receptors. The GABA(B) agonists baclofen and SKF97541 also elevated [(35)S]GTPgammaS binding by about 60%, with potency values in the micromolar range. Phaclofen behaved as a low potency antagonist with an ED(50) approximately 1mM. However, phaclofen at low doses (1 and 10nM) slightly but significantly attenuated maximal stimulation of [(35)S]GTPgammaS binding by the CB(1) agonist R-Win55,212-2. The observation that higher concentrations of phaclofen had no such effect rule out the possibility of its direct action on CB(1) receptors. The pharmacologically inactive stereoisomer S-Win55,212-3 had no effect either alone or in combination with phaclofen establishing that the interaction is stereospecific in hippocampus. The specific CB(1) antagonist AM251 at a low dose (1nM) also inhibited the efficacy of G-protein signaling of the GABA(B) receptor agonist SKF97541. Cross-talk of the two receptor systems was not detected in either spinal cord or cerebral cortex membranes. It is speculated that the interaction might occur via an allosteric interaction between a subset of GABA(B) and CB(1) receptors in rat hippocampal membranes. Although the exact molecular mechanism of the reciprocal inhibition between CB(1) and GABA(B) receptors will have to be explored by future studies it is intriguing that the cross-talk might be involved in balance tuning the endocannabinoid and GABAergic signaling in hippocampus.

PMID: 18407377 [PubMed - as supplied by publisher]

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Cannabinoids in health and disease.

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Cannabinoids in health and disease.

Dialogues Clin Neurosci. 2007;9(4):413-30

Authors: Kogan NM, Mechoulam R

Cannabis sativa L. preparations have been used in medicine for millenia. However, concern over the dangers of abuse led to the banning of the medicinal use of marijuana in most countries in the 1930s. Only recently, marijuana and individual natural and synthetic cannabinoid receptor agonists and antagonists, as well as chemically related compounds, whose mechanism of action is still obscure, have come back to being considered of therapeutic value. However, their use is highly restricted. Despite the mild addiction to cannabis and the possible enhancement of addiction to other substances of abuse, when combined with cannabis, the therapeutic value of cannabinoids is too high to be put aside. Numerous diseases, such as anorexia, emesis, pain, inflammation, multiple sclerosis, neurodegenerative disorders (Parkinson's disease, Huntington's disease, Tourette's syndrome, Alzheimer's disease), epilepsy, glaucoma, osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, and metabolic syndrome-related disorders, to name just a few, are being treated or have the potential to be treated by cannabinoid agonists/antagonists/cannabinoid-related compounds. In view of the very low toxicity and the generally benign side effects of this group of compounds, neglecting or denying their clinical potential is unacceptable--instead, we need to work on the development of more selective cannabinoid receptor agonists/antagonists and related compounds, as well as on novel drugs of this family with better selectivity, distribution patterns, and pharmacokinetics, and--in cases where it is impossible to separate the desired clinical action and the psychoactivity--just to monitor these side effects carefully.

PMID: 18286801 [PubMed - in process]

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Levetiracetam Inhibits both ryanodine and IP3 receptor activated calcium induced calcium release in hippocampal neurons in culture.

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Levetiracetam Inhibits both ryanodine and IP3 receptor activated calcium induced calcium release in hippocampal neurons in culture.

Neurosci Lett. 2008 Mar 21;

Authors: Nagarkatti N, Deshpande LS, Delorenzo RJ

Epilepsy affects approximately 1% of the population worldwide, and there is a pressing need to develop new anti-epileptic drugs (AEDs) and understand their mechanisms of action. Levetiracetam (LEV) is a novel AED and despite its increasingly widespread clinical use, its mechanism of action is as yet undetermined. Intracellular calcium ([Ca(2+)](i)) regulation by both inositol 1,4,5-triphosphate receptors (IP3R) and ryanodine receptors (RyR) has been implicated in epileptogenesis and the maintenance of epilepsy. To this end, we investigated the effect of LEV on RyR and IP3R activated calcium-induced calcium release (CICR) in hippocampal neuronal cultures. RyR-mediated CICR was stimulated using the well-characterized RyR activator, caffeine. Caffeine (10mM) caused a significant increase in [Ca(2+)](i) in hippocampal neurons. Treatment with LEV (33muM) prior to stimulation of RyR-mediated CICR by caffeine led to a 61% decrease in the caffeine induced peak height of [Ca(2+)](i) when compared to the control. Bradykinin stimulates IP3R-activated CICR-to test the effect of LEV on IP3R-mediated CICR, bradykinin (1muM) was used to stimulate cells pre-treated with LEV (100muM). The data showed that LEV caused a 74% decrease in IP3R-mediated CICR compared to the control. In previous studies we have shown that altered Ca(2+) homeostatic mechanisms play a role in seizure activity and the development of spontaneous recurrent epileptiform discharges (SREDs). Elevations in [Ca(2+)](i) mediated by CICR systems have been associated with neurotoxicity, changes in neuronal plasticity, and the development of AE. Thus, the ability of LEV to modulate the two major CICR systems demonstrates an important molecular effect of this agent on a major second messenger system in neurons.

PMID: 18406528 [PubMed - as supplied by publisher]

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http://www.ncbi.nlm.nih.gov/pubmed/7494858?ordinalpos=79&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

http://www.ncbi.nlm.nih.gov/pubmed/7494858?ordinalpos=79&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

http://www.ncbi.nlm.nih.gov/pubmed/16735757?ordinalpos=5&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

http://www.ncbi.nlm.nih.gov/pubmed/16735757?ordinalpos=5&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

http://www.ncbi.nlm.nih.gov/pubmed/17046694?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

http://www.ncbi.nlm.nih.gov/pubmed/17046694?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

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http://www.ncbi.nlm.nih.gov/pubmed/8680737?ordinalpos=9&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

http://www.ncbi.nlm.nih.gov/pubmed/8680737?ordinalpos=9&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum