A novel zebrafish model of hyperthermia-induced seizures reveals a role for TRPV4 channels and NMDA-type glutamate receptors

Hunt, Reid; Hortopan, G.A.; Gillespie, Anna K.; Baraban, Scott C.

doi:10.1016/j.expneurol.2012.06.013

Cited by 121 publications

(59 citation statements)

References 45 publications

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“…To our knowledge, neither TRPV2 nor TRPV3 have been reported to have any involvement in epilepsy, while only a single study to date has suggested the involvement of TRPV4 in epilepsy [135]. Here, TRPV4 blockade was proposed to reduce febrile seizures in larval zebrafish [136], and so, again, the ability of CBD to activate TRPV4 would be in direct contrast to its clear anticonvulsant effects.…”

Section: Cbd Ion Channel Targets In Epilepsymentioning

confidence: 86%

Molecular Targets of Cannabidiol in Neurological Disorders

Bih

Chen

Nunn³

et al. 2015

Neurotherapeutics

449

323

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Cannabis has a long history of anecdotal medicinal use and limited licensed medicinal use. Until recently, alleged clinical effects from anecdotal reports and the use of licensed cannabinoid medicines are most likely mediated by tetrahydrocannabinol by virtue of: 1) this cannabinoid being present in the most significant quantities in these preparations; and b) the proportion:potency relationship between tetrahydrocannabinol and other plant cannabinoids derived from cannabis. However, there has recently been considerable interest in the therapeutic potential for the plant cannabinoid, cannabidiol (CBD), in neurological disorders but the current evidence suggests that CBD does not directly interact with the endocannabinoid system except in vitro at supraphysiological concentrations. Thus, as further evidence for CBD's beneficial effects in neurological disease emerges, there remains an urgent need to establish the molecular targets through which it exerts its therapeutic effects. Here, we conducted a systematic search of the extant literature for original articles describing the molecular pharmacology of CBD. We critically appraised the results for the validity of the molecular targets proposed. Thereafter, we considered whether the molecular targets of CBD identified hold therapeutic potential in relevant neurological diseases. The molecular targets identified include numerous classical ion channels, receptors, transporters, and enzymes. Some CBD effects at these targets in in vitro assays only manifest at high concentrations, which may be difficult to achieve in vivo, particularly given CBD's relatively poor bioavailability. Moreover, several targets were asserted through experimental designs that demonstrate only correlation with a given target rather than a causal proof. When the molecular targets of CBD that were physiologically plausible were considered for their potential for exploitation in neurological therapeutics, the results were variable. In some cases, the targets identified had little or no established link to the diseases considered. In others, molecular targets of CBD were entirely consistent with those already actively exploited in relevant, clinically used, neurological treatments. Finally, CBD was found to act upon a number of targets that are linked to neurological therapeutics but that its actions were not consistent withmodulation of such targets that would derive a therapeutically beneficial outcome. Overall, we find that while >65 discrete molecular targets have been reported in the literature for CBD, a relatively limited number represent plausible targets for the drug's action in neurological disorders when judged by the criteria we set. We conclude that CBD is very unlikely to exert effects in neurological diseases through modulation of the endocannabinoid system. Moreover, a number of other molecular targets of CBD reported in the literature are unlikely to be of relevance owing to effects only being observed at supraphysiological concentrations. Of interest and after excludin...

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Section: Cbd Ion Channel Targets In Epilepsymentioning

confidence: 86%

Molecular Targets of Cannabidiol in Neurological Disorders

Bih

Chen

Nunn³

et al. 2015

Neurotherapeutics

449

323

View full text Add to dashboard Cite

show abstract

“…Recently, it has been reported that hyperthermiainduced seizures recorded in the larval zebrafish forebrain are blocked by the application of TRPV4 and NMDAR antagonists, revealing a possible role for TRPV4 in seizure [42]. Concerning the characteristics of multipolar activation, TRPV4-induced regulation of ion channels or receptors may play an important role in pathological conditions, such as seizure and cerebral ischemia [20,42], thus making TRPV4 a promising target for the development of new drugs.…”

Section: Discussionmentioning

confidence: 99%

“…Concerning the characteristics of multipolar activation, TRPV4-induced regulation of ion channels or receptors may play an important role in pathological conditions, such as seizure and cerebral ischemia [20,42], thus making TRPV4 a promising target for the development of new drugs.…”

Section: Discussionmentioning

confidence: 99%

Transient Receptor Potential Vanilloid 4-Induced Modulation of Voltage-Gated Sodium Channels in Hippocampal Neurons

et al. 2014

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Transient receptor potential vanilloid 4 (TRPV4) is reported to control the resting membrane potential and increase excitability in many types of cells. Voltage-gated sodium channels (VGSCs) play an important role in initiating action potentials in neurons. However, whether VGSCs can be modulated by the activation of TRPV4 in hippocampal pyramidal neurons remains unknown. In this study, we tested the effect of TRPV4 agonists (GSK1016790A and 4α-PDD) on voltage-gated sodium current (I Na) in hippocampal CA1 pyramidal neurons and the protein levels of α/β-subunit of VGSCs in the hippocampus of mice subjected to intracerebroventricular (icv.) injection of GSK1016790A (GSK-injected mice). Herein, we report that I Na was inhibited by acute application of GSK1016790A or 4α-PDD. In the presence of TRPV4 agonists, the voltage-dependent inactivation curve shifted to the hyperpolarization, whereas the voltage-dependent activation curve remained unchanged. The TRPV4 agonist-induced inhibition of I Na was blocked by the TRPV4 antagonist or tetrodotoxin. Moreover, blocking protein kinase A (PKA) markedly attenuated the GSK1016790A-induced inhibition of I Na, whereas antagonism of protein kinase C or p38 mitogen-activated protein kinase did not change GSK1016790A action. Finally, the protein levels of Nav1.1, Nav1.2, and Nav1.6 in the hippocampus increased in GSK-injected mice, whereas those of Nav1.3 and Navβ1 remained nearly unchanged. We conclude that I Na is inhibited by the acute activation of TRPV4 through PKA signaling pathway in hippocampal pyramidal neurons, but protein expression of α-subunit of VGSCs is increased by sustained TRPV4 activation, which may compensate for the acute inhibition of I Na and provide a possibility for hyper-excitability upon sustained TRPV4 activation.

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“…These include modulation of the function of specific ions channels. For example, the transient-receptor-potential vanilloid (TRPV) 1 and 4 channels are regulated by brain temperature in the physiological and fever ranges, and have been implicated in febrile seizures in animal models [49] where elevated brain temperature leads to augmented neuronal firing, facilitating seizures. Similarly, HCN channels [22,50] and Cav1.2 calcium channels [51] seem to contribute to the hyperexcitability that results in febrile seizures.…”

Section: How Are Fs Generated?mentioning

confidence: 99%

Origins of Temporal Lobe Epilepsy: Febrile Seizures and Febrile Status Epilepticus

2014

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Temporal lobe epilepsy (TLE) and hippocampal sclerosis (HS) commonly arise following early-life long seizures, and especially febrile status epilepticus (FSE). However, there are major gaps in our knowledge regarding the causal relationships of FSE, TLE, HS and cognitive disturbances that hamper diagnosis, biomarker development and prevention. The critical questions include: What is the true probability of developing TLE after FSE? Are there predictive markers for those at risk? A fundamental question is whether FSE is simply a marker of individuals who are destined to develop TLE, or if FSE contributes to the risk of developing TLE. If FSE does contribute to epileptogenesis, then does this happen only in the setting of a predisposed brain? These questions are addressed within this review, using information gleaned over the past two decades from clinical studies as well as animal models.

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A novel zebrafish model of hyperthermia-induced seizures reveals a role for TRPV4 channels and NMDA-type glutamate receptors

Cited by 121 publications

References 45 publications

Molecular Targets of Cannabidiol in Neurological Disorders

Molecular Targets of Cannabidiol in Neurological Disorders

Transient Receptor Potential Vanilloid 4-Induced Modulation of Voltage-Gated Sodium Channels in Hippocampal Neurons

Origins of Temporal Lobe Epilepsy: Febrile Seizures and Febrile Status Epilepticus

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