Activation of Calcium-Activated Chloride Channels Suppresses Inherited Seizure Susceptibility in Genetically Epilepsy-Prone Rats.
Activation of Calcium-Activated Chloride Channels Suppresses Inherited Seizure Susceptibility in Genetically Epilepsy-Prone Rats.
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DOI：
10.3390/biomedicines10020449
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发表时间：
2022-02-15
期刊：
影响因子：
4.7
通讯作者：
N'Gouemo P
中科院分区：
文献类型：
--
作者：
Thomas M;Simms M;N'Gouemo P
遗传性癫痫易感大鼠（GEPR-3s）的遗传性癫痫易感性与电压门控钙通道电流增加有关，提示大量钙流入导致神经元内钙水平升高。反过来，胞质钙激活包括氯离子通道在内的许多过程，以恢复正常的膜兴奋性并限制神经元的重复放电。在这里，我们分别使用钙激活通道跨膜蛋白16A （TMEM16A）的强效激活剂和抑制剂EACT和T16Ainh-A01来探讨这些通道在GEPR-3s声诱发癫痫的病理生理中的作用。我们使用成年男性和女性GEPR-3s。声诱发的癫痫发作包括野跑性癫痫发作（WRSs），随后发展为全身性强直-阵挛性癫痫发作（GTCSs），最终发展为前肢伸展（部分强直性癫痫发作）。我们发现，在相对较高的试验剂量下，急性EACT治疗显著降低了wrs和gtcs的发生率，并降低了男性gepr -3的癫痫发作严重程度。此外，这些抗癫痫作用与延迟癫痫发作和缩短癫痫发作持续时间有关。有趣的是，抑制TMEM16A通道逆转了EACT对癫痫发作潜伏期和癫痫发作持续时间的抗癫痫作用。女性GEPR-3s无明显抗癫痫作用。总之，这些发现表明TMEM16A通道的激活可能代表了抑制gtcs的一种假定的新的细胞机制。
Inherited seizure susceptibility in genetically epilepsy-prone rats (GEPR-3s) is associated with increased voltage-gated calcium channel currents suggesting a massive calcium influx resulting in increased levels of intraneuronal calcium. Cytosolic calcium, in turn, activates many processes, including chloride channels, to restore normal membrane excitability and limit repetitive firing of the neurons. Here we used EACT and T16Ainh-A01, potent activator and inhibitor of calcium-activated channels transmembrane protein 16A (TMEM16A), respectively, to probe the role of these channels in the pathophysiology of acoustically evoked seizures in the GEPR-3s. We used adult male and female GEPR-3s. Acoustically evoked seizures consisted of wild running seizures (WRSs) that evolved into generalized tonic-clonic seizures (GTCSs) and eventually culminated into forelimb extension (partial tonic seizures). We found that acute EACT treatment at relatively higher tested doses significantly reduced the incidences of WRSs and GTCSs, and the seizure severity in male GEPR-3s. Furthermore, these antiseizure effects were associated with delayed seizure onset and reduced seizure duration. Interestingly, the inhibition of TMEM16A channels reversed EACT’s antiseizure effects on seizure latency and seizure duration. No notable antiseizure effects were observed in female GEPR-3s. Together, these findings suggest that activation of TMEM16A channels may represent a putative novel cellular mechanism for suppressing GTCSs.
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影响因子：
2.9
作者：
N'Gouemo, Prosper;Yasuda, Robert;Faingold, Carl L.
通讯作者：
Faingold, Carl L.
影响因子：
5.5
作者：
Cho SJ;Vaca MA;Miranda CJ;N'Gouemo P
通讯作者：
N'Gouemo P
DOI：
10.1016/0306-3623(90)91032-m
发表时间：
1990-01-01
期刊：
GENERAL PHARMACOLOGY-THE VASCULAR SYSTEM
影响因子：
--
作者：
DESARRO, G;DESARRO, A;MELDRUM, BS
通讯作者：
MELDRUM, BS
影响因子：
5.3
作者：
Alfonsa, Hannah;Merricks, Edward M.;Trevelyan, Andrew J.
通讯作者：
Trevelyan, Andrew J.
影响因子：
16.2
作者：
Huang WC;Xiao S;Huang F;Harfe BD;Jan YN;Jan LY
通讯作者：
Jan LY