The new anticonvulsant Lacosamide ((R) Vimpat) selectively promotes slow inactivation of VGSCs, has a higher affinity for channels involved in sensory/pain transduction than CNS channels and was discovered in NIH in vivo screens. Click chemistry, the new crystal structure for VGSCs, and the profiling of related signalling pathways may further impact on drug discovery (and reveal the physiological process of slow inactivation). The surrogate binding target collapsin response mediator protein (CRMP-2) enhances lacosamide block at VGSCs. CRMP-2 also enhances N-type calcium channel (CaV2.2) expression and novel blocking peptides can reduce inflammatory pain in disease models. Mechanistic understanding and multi-disciplinary engagement is essential for cost-effective drug discovery in the quest to find safe, curative drugs in epilepsy and pain. (C) 2011 Elsevier Ltd. All rights reserved.

The contribution of heme oxygenase (HO)-linked pathways to neurodegeneration following cerebral hypoxia-ischemia (HI) remains unclear. We investigated whether HO modulators affected HI-induced brain damage and explored potential mechanisms involved. HI was induced in 26-day-old male Wistar rats by left common carotid artery ligation, followed by exposure to a humidified atmosphere of 8% oxygen for 1 hr. Tin protoporphyrin (SnPP; an HO inhibitor), ferriprotoporphyrin (FePP; an HO inducer), or saline was administered intraperitoneally once daily from 1 day prior to HI until sacrifice at 3 days post-HI. SnPP reduced (P < 0.05) infarct volume compared with saline-treated animals, but FePP had no effect on brain injury. SnPP did not significantly inhibit HO activity at 3 days post-HI, but SnPP increased (P < 0.001) total nitric oxide synthase (NOS) activity compared with HI + saline. Both inducible NOS and cyclooxygenase activities were attenuated (P < 0.05) by SnPP, whereas mitochondrial complex I and V activities were augmented (P < 0.05) by SnPP. SnPP had no effect on NMDA receptor currents. Overall, like other HO inhibitors, SnPP produced many nonselective effects, such as attenuation of inflammatory enzymes and increased mitochondrial respiratory function, which were associated with a protective response 3 days post-HI.

Background/Aims: Behavioural and psychological symptoms (BPSD) are frequent in people with Alzheimer’s disease and cause considerable stress to patients and their carers. Antipsychotics have been widely used as a first-line treatment, resulting in an estimated 1,800 excess strokes and 1,600 excess deaths in the UK alone. Safe and effective alternatives are urgently needed. Based upon preliminary evidence from clinical trials, aromatherapy with melissa oil may be such an alternative, but initial studies have been modest in size, and adequate blinding has been problematic. Our objective was to assess the efficacy of melissa aromatherapy in the treatment of agitation in people with Alzheimer’s disease in an adequately powered and robustly blinded randomized controlled trial comparing it with donepezil, an anticholinesterase drug used with some benefit to treat BPSD. Methods and Findings: The study was a double-blind parallel-group placebo-controlled randomized trial across 3 specialist old age psychiatry centres in England. Participants had probable or possible Alzheimer’s disease, were resident in a care home, had clinically significant agitation (defined as a score of 39 or above on the Cohen Mansfield Agitation Inventory) and were free of antipsychotics and/or anticholinesterase for at least 2 weeks. Participants were allocated to 1 of 3 groups: placebo medication and active aromatherapy; active medication and placebo aromatherapy or placebo of both. Main Outcome: The primary outcome measure was reduction in agitation as assessed by the Pittsburgh Agitation Scale (PAS) at 4 weeks. This is an observational scale, and raters were required to wear nose clips to ensure that full blinding was maintained. The PAS, Neuropsychiatric Inventory (NPI; another measure of BPSD) and other outcome measures were completed at baseline, 4-week and 12-week follow-ups. 114 participants were randomized, of whom 94 completed the week 4 assessment and 81 completed the week 12 assessment. Aromatherapy and donepezil were well tolerated. There were no significant differences between aromatherapy, donepezil and placebo at week 4 and week 12, but importantly there were substantial improvements in all 3 groups with an 18% improvement in the PAS and a 37% improvement in the NPI over 12 weeks. Conclusion: When assessed using a rigorous design which ensures blinding of treatment arms, there is no evidence that melissa aromatherapy is superior to placebo or donepezil, in the treatment of agitation in people with Alzheimer’s disease. However, the sizeable improvement in the placebo group emphasizes the potential non-specific benefits of touch and interaction in the treatment of agitation in people with Alzheimer’s disease.

Expeditions and adventure travel are becoming increasing popular. As these ventures continue to grow in popularity so too do the opportunities for doctors interested in expedition and wilderness medicine. A few doctors manage to make a career in expedition medicine but for the majority it remains a hobby that runs alongside their usual clinical practice. At the same time expedition and wilderness medicine is progressing as a speciality in its own right. This review aims to serve as an introduction to expedition medicine, to raise points for further consideration and to signpost the next steps for those that are interested in acting as an expedition doctor. The requirements of an expedition doctor and the possible medical problems faced are as heterogeneous as the environments travelled to and the groups travelled with. This review outlines a number of principles that hold true in pre-expedition planning, during the expedition and in the post-expedition phase. 2010 Elsevier Ltd. All rights reserved.

Trends in Anaesthesia and Critical Care aims to be a leading biomedical review journal, providing reviews and comment on highly topical subjects and the latest breakthroughs in basic, clinical and translational research. This includes basic and clinical research aimed at understanding disease processes and clinical practice of importance to anaesthesia and critical care. The aim is to stimulate debate on new research, cover controversial topics, or provide a new framework for, or interpretation of, an old problem or current issue, or speculate on the implications of recent research and clinical advances in health care infrastructure concerns at national or international levels.

Inhibitory projections from the striatum and globus pallidus converge onto GABAergic projection neurons of the substantia nigra pars reticulata (SNr). Based on existing structural and functional evidence, these pathways are likely to differentially regulate the firing of SNr neurons. We sought to investigate the functional differences in inhibitory striatonigral and pallidonigral traffic using whole-cell voltage clamp in brain slices with these pathways preserved. We found that striatonigral IPSCs exhibited a high degree of paired-pulse facilitation. We tracked this facilitation over development and found the facilitation as the animal aged, but stabilized by postnatal day 17 (P17), with a paired pulse ratio of 2. We also found that the recovery from facilitation accelerated over development, again, reaching a stable phenotype by P17. In contrast, pallidonigral synapses show paired-pulse depression, and this depression could be solely explained by presynaptic changes. The mean paired-pulse ratio of 0.67 did not change over development, but the recovery from depression slowed over development. Pallidonigral IPSCs were significantly faster than striatonigral IPSCs when measured at the soma. Finally, under current clamp, prolonged bursts of striatal IPSPs were able to consistently silence the pacemaker activity of nigral neurons, whereas pallidal inputs depressed, allowing nigral neurons to reinstate firing. These findings highlight the importance of differential dynamics of neurotransmitter release in regulating the circuit behavior of the basal ganglia.

Neocortical fast-spiking (FS) basket cells form dense autaptic connections that provide inhibitory GABAergic feedback after each action potential. It has been suggested that these autaptic connections are used because synaptic communication is sensitive to neuromodulation, unlike the voltage-sensitive potassium channels in FS cells. Here we show that layer V FS interneurons form autaptic connections that are largely perisomatic, and without perturbing intracellular Cl- homeostasis, that perisomatic GABAergic currents have a reversal potential of -78 +/- 4 mV. Using variance-mean analysis, we demonstrate that autaptic connections have a mean of 14 release sites (range 4-26) with a quantal amplitude of 101 +/- 16 pA and a probability of release of 0.64 (V(command) = -70 mV, [Ca2+](o) = 2 mm, [Mg2+](o) = 1 mm). We found that autaptic GABA release is sensitive to GABA(B) and muscarinic acetylcholine receptors, but not a range of other classical neuromodulators. Our results indicate that GABA transporters do not regulate FS interneuron autapses, yet autaptically released GABA does not act at GABA(B) or extrasynaptic GABA(A) receptors. This research confirms that the autaptic connections of FS cells are indeed susceptible to modulation, though only via specific GABAergic and cholinergic mechanisms.

Background and purpose: The histamine H4 receptor is the most recently identified of the G protein‐coupled histamine receptor family and binds several neuroactive drugs, including amitriptyline and clozapine. So far, H4 receptors have been found only on haematopoietic cells, highlighting its importance in inflammatory conditions. Here we investigated the possibility that H4 receptors may be expressed in both the human and mouse CNS.Methods: Immunological and pharmacological studies were performed using a novel anti‐H4 receptor antibody in both human and mouse brains, and electrophysiological techniques in the mouse brain respectively. Pharmacological tools, selective for the H4 receptor and patch clamp electrophysiology, were utilized to confirm functional properties of the H4 receptor in layer IV of the mouse somatosensory cortex.Results: Histamine H4 receptors were prominently expressed in distinct deep laminae, particularly layer VI, in the human cortex, and mouse thalamus, hippocampal CA4 stratum lucidum and layer IV of the cerebral cortex. In layer IV of the mouse somatosensory cortex, the H4 receptor agonist 4‐methyl histamine (20 µmol·L−1) directly hyperpolarized neurons, an effect that was blocked by the selective H4 receptor antagonist JNJ 10191584, and promoted outwardly rectifying currents in these cells. Monosynaptic thalamocortical CNQX‐sensitive excitatory postsynaptic potentials were not altered by 4‐methyl histamine (20 µmol·L−1) suggesting that H4 receptors did not act as hetero‐receptors on thalamocortical glutamatergic terminals.Conclusions and implications: This is the first demonstration that histamine H4 receptors are functionally expressed on neurons, which has major implications for the therapeutic potential of these receptors in neurology and psychiatry.

Voltage-gated sodium channels are important in the pathophysiology of chronic neuropathic pain and as targets for analgesic drugs. This review will cover the molecular structure and signalling roles for this ion channel super-family with a focus on the channels thought to be involved in nociception. We highlight the mode of action of current analgesic drugs and the difficulty of treating chronic inflammatory or neuropathic pain states. The discovery of key channel classes, or familial mutations, associated with chronic pain syndromes has resulted in intensive drug discovery programmes. The quest for selective drugs or toxins which safely and effectively block diseased channels without interfering with normal conduction in the central or peripheral nervous system has been frustratingly difficult. Nevertheless new small molecule drugs or channel selective toxins are in the development pipeline. It remains to be seen whether these will represent a significant development in the safe and effective treatment of chronic pain states.

Both Melissa officinalis (Mo) and Lavandula angustifolia (La) essential oils have putative anti-agitation properties in humans, indicating common components with a depressant action in the central nervous system. A dual radioligand binding and electrophysiological study, focusing on a range of ligand-gated ion channels, was performed with a chemically validated essential oil derived from La, which has shown clinical benefit in treating agitation. La inhibited [35S] TBPS binding to the rat forebrain gamma aminobutyric acid (GABA)(A) receptor channel (apparent IC50 = 0.040 +/- 0.001 mg mL(-1)), but had no effect on N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) or nicotinic acetylcholine receptors. A 50:50 mixture of Mo and La essential oils inhibited [3H] flunitrazepam binding, whereas the individual oils had no significant effect. Electrophysiological analyses with rat cortical primary cultures demonstrated that La reversibly inhibited GABA-induced currents in a concentration-dependent manner (0.01-1 mg mL(-1)), whereas no inhibition of NMDA- or AMPA-induced currents was noted. La elicited a significant dose-dependent reduction in both inhibitory and excitatory transmission, with a net depressant effect on neurotransmission (in contrast to the classic GABA(A) antagonist picrotoxin which evoked profound epileptiform burst firing in these cells). These properties are similar to those recently reported for Mo. The anti-agitation effects in patients and the depressant effects of La we report in neural membranes in-vitro are unlikely to reflect a sedative interaction with any of the ionotropic receptors examined here. These data suggest that components common to the two oils are worthy of focus to identify the actives underlying the neuronal depressant and anti-agitation activities reported.

Spreading depression (SD), whether elicited by local application of high K+ medium to the cortical surface or by other stimuli, can increase the brain's tolerance to a subsequent, severe ischaemic insult in vivo, a phenomenon termed preconditioning. Herein, we have developed and validated a robust in vitro protocol for high-K+-preconditioning of cultured neurones. This new model is especially appropriate to unravel the molecular mechanisms underlying neuronal preconditioning and subsequent ischaemic tolerance. With this new, optimised preparation, preconditioning was found to be dependent upon culture day in vitro, cell density, K+ concentration and duration of treatment. Finally, preconditioning was shown to be dependent upon N-methyl-d-aspartate (NMDA), CAM-kinase II signalling and α7-nicotinic (α7 nACh) receptor function, which is analogous to in vivo preconditioning induced by various stimuli.

We hypothesized that lacosamide modulates voltage-gated sodium channels (VGSCs) at clinical concentrations (32-100 mu M). Lacosamide reduced spiking evoked in cultured rat cortical neurons by 30-s depolarizing ramps but not by 1-s ramps. Carbamazepine and phenytoin reduced spike-firing induced by both ramps. Lacosamide inhibited sustained repetitive firing during a 10-s burst but not within the first second. Tetrodo-toxin-sensitive VGSC currents in N1E-115 cells were reduced by 100 mu M lacosamide, carbamazepine, lamotrigine, and phenytoin from V-h of -60 mV. Hyperpolarization (500 ms) to -100 mV removed the block by carbamazepine, lamotrigine, and phenytoin but not by lacosamide. The voltage-dependence of activation was not changed by lacosamide. The inactive S-stereoisomer did not inhibit VGSCs. Steady-state fast inactivation curves were shifted in the hyperpolarizing direction by carbamazepine, lamotrigine, and phenytoin but not at all by lacosamide. Lacosamide did not retard recovery from fast inactivation in contrast to carbamazepine. Carbamazepine, lamotrigine, and phenytoin but not lacosamide all produced frequency-dependent facilitation of block of a 3-s, 10-Hz pulse train. Lacosamide shifted the slow inactivation voltage curve in the hyperpolarizing direction and significantly promoted the entry of channels into the slow inactivated state (carbamazepine weakly impaired entry into the slow inactivated state) without altering the rate of recovery. Lacosamide is the only analgesic/anticonvulsant drug that reduces VGSC availability by selective enhancement of slow inactivation but without apparent interaction with fast inactivation gating. The implications of this unique profile are being explored in phase III clinical trials for epilepsy and neuropathic pain.

Preparations of Ficus platyphylla have been used in Nigerian traditional medicine for the management of epilepsy for many years and their efficacy is widely acclaimed among the Hausa communities of northern Nigeria. The anticonvulsant properties of the saponin rich fraction (SFG) obtained from the methanol extract of F. platyphylla stem bark were studied on pentylenetetrazole-, strychnine- and maximal electroshock seizures in mice. Effects of SFG were also examined in murine models for neurological disease and on relevant in vitro targets for anticonvulsant drugs. SFG protected mice against pentylenetetrazole- and strychnine-induced seizures; and significantly delayed the onset of myoclonic jerks and tonic seizures. SFG failed to protect mice against maximal electroshock seizures at doses tested. SFG neither abolished the spontaneous discharges induced by 4-aminopyridine in a neonatal rat brain slice model of tonic–clonic epilepsy nor could it modulate chloride currents through GABAA receptor channel complex in cultured cortical cells. However, it was able to non-selectively suppress excitatory and inhibitory synaptic traffic, blocked sustained repetitive firing (SRF) and spontaneous action potential firing in these cultured cells. Our results provide scientific evidence that F. platyphylla stem bark may contain psychoactive principles with potential anticonvulsant properties. SFG impaired membrane excitability; a property shared by most anticonvulsants particularly the voltage-gated sodium channel (VGSC) blocking drugs, thus supporting the isolation and development of the saponin components of this plant as anticonvulsant agents.

The psychopharmacological effects of a saponin-rich fraction (SFG) obtained from crude methanolic extract of Ficus platyphylla stem bark were studied on spontaneous motor activity (SMA), pentobarbitalinduced sleep, motor coordination, amphetamine-induced hyperactivity and stereotyped behaviour, catalepsy, forced swim and tail suspension tests in rodents.SFG reduced SMA dose dependently, suggesting that it may contain psychoactive principles with sedative effects.The fraction shortened the onset and prolonged the duration of pentobarbital-induced sleep, which confirmed its sedative properties.The fraction diminished immobility time in forced swim and tail suspension tests, which is indicative of antidepressant properties.It attenuated amphetamine-induced hyperactivity and stereotyped behaviour, induced catalepsy and exacerbated haloperidol-induced catalepsy in rodents, but had no effect on motor coordination in the treadmill experiment at the doses tested.These effects were similar to those of classical neuroleptics and antidepressants.Our study provides scientific evidence of psychopharmacological effects of the saponin fraction of Ficus platyphylla stem bark and therefore supports further development of its psychoactive components as antipsychotics and antidepressants.

European Journal of PainVolume 11, Issue S1 p. S155-S155 349 NOVEL DUAL MECHANISM OF ACTION OF THE ANTIEPILEPTIC LACOSAMIDE C. Heers, C. Heers Department of Pharmacology and Toxicology, Schwarz BioSciences GmbH, Monheim, GermanySearch for more papers by this authorB. Beyreuther, B. Beyreuther Department of Pharmacology and Toxicology, Schwarz BioSciences GmbH, Monheim, GermanySearch for more papers by this authorJ. Freitag, J. Freitag Department of Pharmacology and Toxicology, Schwarz BioSciences GmbH, Monheim, GermanySearch for more papers by this authorG. Lees, G. Lees University of Otago, Dunedin, New ZealandSearch for more papers by this authorA. Errington, A. Errington University of Otago, Dunedin, New ZealandSearch for more papers by this authorT. Stoehr, T. Stoehr Department of Pharmacology and Toxicology, Schwarz BioSciences GmbH, Monheim, GermanySearch for more papers by this author C. Heers, C. Heers Department of Pharmacology and Toxicology, Schwarz BioSciences GmbH, Monheim, GermanySearch for more papers by this authorB. Beyreuther, B. Beyreuther Department of Pharmacology and Toxicology, Schwarz BioSciences GmbH, Monheim, GermanySearch for more papers by this authorJ. Freitag, J. Freitag Department of Pharmacology and Toxicology, Schwarz BioSciences GmbH, Monheim, GermanySearch for more papers by this authorG. Lees, G. Lees University of Otago, Dunedin, New ZealandSearch for more papers by this authorA. Errington, A. Errington University of Otago, Dunedin, New ZealandSearch for more papers by this authorT. Stoehr, T. Stoehr Department of Pharmacology and Toxicology, Schwarz BioSciences GmbH, Monheim, GermanySearch for more papers by this author First published: 16 January 2012 https://doi.org/10.1016/j.ejpain.2007.03.364Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume11, IssueS1June 2007Pages S155-S155 RelatedInformation

Stargazer mice fail to express the γ2 isoform of transmembrane α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate (AMPA) receptor regulatory proteins that has been shown to be absolutely required for the trafficking and synaptic targeting of excitatory AMPA receptors in adult murine cerebellar granule cells. Here we show that 30 ± 6% fewer inhibitory γ-aminobutyric acid, type A (GABAA), receptors were expressed in adult stargazer cerebellum compared with controls because of a specific loss of GABAA receptor expression in the cerebellar granule cell layer. Radioligand binding assays allied to in situ immunogold-EM analysis and furosemide-sensitive tonic current estimates revealed that expression of the extrasynaptic (α6βxδ) α6-containing GABAA receptor were markedly and selectively reduced in stargazer. These observations were compatible with a marked reduction in expression of GABAA receptor α6, δ (mature cerebellar granule cell-specific proteins), and β3 subunit expression in stargazer. The subunit composition of the residual α6-containing GABAA receptors was unaffected by the stargazer mutation. However, we did find evidence of an ∼4-fold up-regulation of α1βδ receptors that may compensate for the loss of α6-containing GABAA receptors. PCR analysis identified a dramatic reduction in the steady-state level of α6 mRNA, compatible with α6 being the primary target of the stargazer mutation-mediated GABAA receptor abnormalities. We propose that some aspects of assembly, trafficking, targeting, and/or expression of extrasynaptic α6-containing GABAA receptors in cerebellar granule cells are selectively regulated by AMPA receptor-mediated signaling.