scholarly journals The Heat Sensing Trpv1 Receptor Is Not a Viable Anticonvulsant Drug Target in the Scn1a+/− Mouse Model of Dravet Syndrome

2021 ◽  
Vol 12 ◽  
Author(s):  
Vaishali Satpute Janve ◽  
Lyndsey L. Anderson ◽  
Dilara Bahceci ◽  
Nicole A. Hawkins ◽  
Jennifer A. Kearney ◽  
...  

Cannabidiol has been approved for the treatment of drug-resistant childhood epilepsies including Dravet syndrome (DS). Although the mechanism of anticonvulsant action of cannabidiol is unknown, emerging data suggests involvement of the transient receptor potential cation channel subfamily V member 1 (Trpv1). Pharmacological and genetic studies in conventional seizure models suggest Trpv1 is a novel anticonvulsant target. However, whether targeting Trpv1 is anticonvulsant in animal models of drug-resistant epilepsies is not known. Thus, we examined whether Trpv1 affects the epilepsy phenotype of the F1.Scn1a+/− mouse model of DS. We found that cortical Trpv1 mRNA expression was increased in seizure susceptible F1.Scn1a+/− mice with a hybrid genetic background compared to seizure resistant 129.Scn1a+/− mice isogenic on 129S6/SvEvTac background, suggesting Trpv1 could be a genetic modifier. Previous studies show functional loss of Trpv1 is anticonvulsant. However, Trpv1 selective antagonist SB-705498 did not affect hyperthermia-induced seizure threshold, frequency of spontaneous seizures or survival of F1.Scn1a+/− mice. Surprisingly, Trpv1 deletion had both pro- and anti-seizure effects. Trpv1 deletion did not affect hyperthermia-induced seizure temperature thresholds of F1.Scn1a+/−; Trpv1+/− at P14-16 but was proconvulsant at P18 as it reduced seizure temperature thresholds. Conversely, Trpv1 deletion did not alter the frequency of spontaneous seizures but reduced their severity. These results suggest that Trpv1 is a modest genetic modifier of spontaneous seizure severity in the F1.Scn1a+/− model of DS. However, the opposing pro- and anti-seizure effects of Trpv1 deletion and the lack of effects of Trpv1 inhibition suggest that Trpv1 is unlikely a viable anticonvulsant drug target in DS.

Epilepsia ◽  
2017 ◽  
Vol 58 (8) ◽  
pp. e111-e115 ◽  
Author(s):  
Jeffrey D. Calhoun ◽  
Nicole A. Hawkins ◽  
Nicole J. Zachwieja ◽  
Jennifer A. Kearney

2020 ◽  
pp. 1-9
Author(s):  
Yuanxin Huang ◽  
Lin Wang ◽  
Siying Ren ◽  
Guofeng Wu ◽  
Jing Wu

<b><i>Objective:</i></b> The first-line treatment for epilepsy, a chronic neurological disorder characterized by spontaneous seizures, includes the application of anticonvulsant drug therapy. Only one-third of patients are incapable of complete controlling of their seizures after the administration of ≥2 pharmaceuticals. Here, we aimed to observe the ultrastructure changes and the expression of ZnT3 and GFAP in the hippocampus of drug-resistant epileptic rats. <b><i>Methods:</i></b> A total of 50 healthy adult male SD rats were used to generate the model of<i></i>epilepsy by amygdala kindling. After the rats were successfully kindled, pharmacoresistant epileptic (PRE) rats were selected according to their response to phenobarbital and phenytoin. The ultrastructure as well as the expression of zinc transporter 3 (ZnT3, a member of a growing family of mammalian zinc transporters) and glial fibrillary acidic protein (GFAP) were compared among PRE, pharmacosensitive epileptic (PRE), and normal (NRC) rats. <b><i>Results:</i></b> The PRE rats displayed severe synapses, neuronal degeneration, and necrosis. Moreover, the expression of ZnT3 and GFAP was significantly increased in both PRE and PSE rats; compared with NRC rats, the promotion of this expression was more pronounced in the PRE rats. <b><i>Conclusions:</i></b> Taken together, obvious synapses, neuronal degeneration, necrosis, mossy fiber sprouting, and astrogliosis were found in the drug-resistant epileptic rat model induced by amygdala kindling.


2021 ◽  
Author(s):  
Nicole A. Hawkins ◽  
Toshihiro Nomura ◽  
Samantha Duarte ◽  
Levi Barse ◽  
Robert W. Williams ◽  
...  

AbstractPathogenic variants in epilepsy genes result in a spectrum of clinical severity. One source of phenotypic heterogeneity is modifier genes that affect expressivity of a primary pathogenic variant. Mouse epilepsy models also display varying degrees of clinical severity on different genetic backgrounds. Mice with heterozygous deletion of Scn1a (Scn1a+/−) model Dravet syndrome, a severe epilepsy most often caused by SCN1A haploinsufficiency. Scn1a+/− mice recapitulate features of Dravet syndrome, including spontaneous seizures, sudden death, and cognitive/behavioral deficits. Scn1a+/− mice maintained on the 129S6/SvEvTac (129) strain have normal lifespan and no spontaneous seizures. In contrast, admixture with C57BL/6J (B6) results in epilepsy and premature lethality. We previously mapped Dravet Survival Modifier loci (Dsm1-Dsm5) responsible for strain-dependent differences in survival. Gabra2, encoding the GABAA α2 subunit, was nominated as a candidate modifier at Dsm1. Direct measurement of GABAA receptors found lower abundance of α2-containing receptors in hippocampal synapses of B6 mice relative to 129. We also identified a B6-specific single nucleotide deletion within Gabra2 that lowers mRNA and protein by nearly 50%. Repair of this deletion reestablished normal levels of Gabra2 expression. In this study, we used B6 mice with a repaired Gabra2 allele to evaluate Gabra2 as a genetic modifier of severity in Scn1a+/− mice. Gabra2 repair restored transcript and protein expression, increased abundance of α2-containing GABAA receptors in hippocampal synapses, and rescued epilepsy phenotypes of Scn1a+/− mice. These findings validate Gabra2 as a genetic modifier of Dravet syndrome, and support enhancing function of α2-containing GABAA receptors as treatment strategy for Dravet syndrome.


2020 ◽  
Vol 103 ◽  
pp. 106842
Author(s):  
Dilara Bahceci ◽  
Lyndsey Leigh Anderson ◽  
Cassandra Veronica Occelli Hanbury Brown ◽  
Cilla Zhou ◽  
Jonathon Carl Arnold

Epilepsia ◽  
2021 ◽  
Author(s):  
Nina Miljanovic ◽  
Roelof Maarten van Dijk ◽  
Verena Buchecker ◽  
Heidrun Potschka

2021 ◽  
Vol 14 (7) ◽  
pp. 698
Author(s):  
Tina V. A. Hansen ◽  
Richard K. Grencis ◽  
Mohamed Issouf ◽  
Cédric Neveu ◽  
Claude L. Charvet

The human whipworm, Trichuris trichiura, is estimated to infect 289.6 million people globally. Control of human trichuriasis is a particular challenge, as most anthelmintics have a limited single-dose efficacy, with the striking exception of the narrow-spectrum anthelmintic, oxantel. We recently identified a novel ACR-16-like subunit from the pig whipworm, T. suis which gave rise to a functional acetylcholine receptor (nAChR) preferentially activated by oxantel. However, there is no ion channel described in the mouse model parasite T. muris so far. Here, we have identified the ACR-16-like and ACR-19 subunits from T. muris, and performed the functional characterization of the receptors in Xenopus laevis oocytes using two-electrode voltage-clamp electrophysiology. We found that the ACR-16-like subunit from T. muris formed a homomeric receptor gated by acetylcholine whereas the ACR-19 failed to create a functional channel. The subsequent pharmacological analysis of the Tmu-ACR-16-like receptor revealed that acetylcholine and oxantel were equally potent. The Tmu-ACR-16-like was more responsive to the toxic agonist epibatidine, but insensitive to pyrantel, in contrast to the Tsu-ACR-16-like receptor. These findings confirm that the ACR-16-like nAChR from Trichuris spp. is a preferential drug target for oxantel, and highlights the pharmacological difference between Trichuris species.


2021 ◽  
Vol 19 ◽  
Author(s):  
Lee Hsien Siang ◽  
Alina Arulsamy ◽  
Yeong Keng Yoon ◽  
Mohd. Farooq Shaikh

: Epilepsy is a devastating neurological disorder. Current anti-convulsant drugs are only effective in about 70% of patients, while the rest remain drug-resistant. Thus, alternative methods have been explored to control seizures in these drug-resistant patients. One such method may be through the utilization of fruit phytochemicals. These phytochemicals have been reported to have beneficial properties such as anti-convulsant, anti-oxidant and anti-inflammatory activities. However, some fruits may also elicit harmful effects. This review aims to summarize and elucidate the anti- or pro- convulsant effects of fruits used in relation to seizures, in hopes to provide a good therapeutic reference to epileptic patients and their carers. Three databases; SCOPUS, ScienceDirect and PubMed were utilized for the literature search. Based on the PRISMA guidelines, a total of 40 articles were selected for critical appraisal in this review. Overall, the extracts and phytochemicals of fruits managed to effectively reduce seizure activities in various preclinical seizure models, acting mainly through the activation of the inhibitory neurotransmission and blocking the excitatory neurotransmission. Only star fruit has been identified as a pro-convulsant fruit, which was attributed to the its caramboxin and oxalate compounds. Future studies should focus more on utilizing these fruits as possible treatment strategies for epilepsy.


2019 ◽  
Vol 597 (16) ◽  
pp. 4293-4307 ◽  
Author(s):  
Toshihiro Nomura ◽  
Nicole A. Hawkins ◽  
Jennifer A. Kearney ◽  
Alfred L. George ◽  
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