Chronic pregabalin treatment protects against spreading depolarization and alters hippocampal synaptic characteristics in a model of familial hemiplegic migraine-type 1.
Chronic pregabalin treatment protects against spreading depolarization and alters hippocampal synaptic characteristics in a model of familial hemiplegic migraine-type 1.
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DOI：
10.1186/s13041-023-01062-6
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发表时间：
2023-11-03
期刊：
影响因子：
3.6
通讯作者：
中科院分区：
文献类型：
--
作者：
家族性偏瘫性偏头痛1型（FHM-1）是一种由P/Q型（Cav2.1）电压门控钙通道突变引起的具有先兆的偏头痛。临床上用于治疗慢性疼痛和癫痫的普瑞巴林抑制P/Q型钙通道活性，最近的研究表明它可能具有治疗偏头痛的潜力。扩散性去极化（SD）是一种神经生理学现象，可发生在偏头痛与先兆通过传播一波沉默的神经元功能通过皮层，有时皮层下的大脑结构。在这里，利用优化的光遗传学刺激技术以允许皮质SD的非侵入性启动，我们证明了慢性普瑞巴林给药[12 mg/kg/天（s.c.）]体内增加了携带临床相关Cav2.1S218L突变（S218 L）的转基因小鼠的皮层扩展去极化阈值。此外，慢性普瑞巴林治疗限制了野生型和S218 L小鼠纹状体和海马的复发性扩散性去极化事件的皮质下传播。为了研究慢性普瑞巴林的潜在作用机制，我们在用慢性普瑞巴林与载体治疗的小鼠的离体脑切片中的CA 1神经元中进行全细胞膜片钳电生理学。在WT小鼠中，慢性普瑞巴林引起自发兴奋性突触后电流（sEPSC）振幅降低，对频率无影响。相反，在S218 L小鼠中，慢性普瑞巴林引起sEPSC振幅增加和频率降低。这些电生理学研究结果表明，在FHM-1小鼠中，慢性普瑞巴林通过CA 1海马神经元的突触前和突触后机制发挥作用，以引起FHM-1基因型特异性抑制作用。结果突出了慢性普瑞巴林限制复发性SD在遗传正常和FHM-1脑的病理生理事件期间皮层下脑结构的潜力。这项工作进一步提供了对FHM-1病理生理学和慢性普瑞巴林治疗预防偏头痛患者SD的潜力的见解。在线版本包含补充材料，可通过10.1186/s13041-023-01062-6获得。
Familial hemiplegic migraine type-1 (FHM-1) is a form of migraine with aura caused by mutations in the P/Q-type (Cav2.1) voltage-gated calcium channel. Pregabalin, used clinically in the treatment of chronic pain and epilepsy, inhibits P/Q-type calcium channel activity and recent studies suggest that it may have potential for the treatment of migraine. Spreading Depolarization (SD) is a neurophysiological phenomenon that can occur during migraine with aura by propagating a wave of silenced neuronal function through cortex and sometimes subcortical brain structures. Here, utilizing an optogenetic stimulation technique optimized to allow for non-invasive initiation of cortical SD, we demonstrate that chronic pregabalin administration [12 mg/kg/day (s.c.)] in vivo increased the threshold for cortical spreading depolarization in transgenic mice harboring the clinically-relevant Cav2.1S218L mutation (S218L). In addition, chronic pregabalin treatment limited subcortical propagation of recurrent spreading depolarization events to the striatum and hippocampus in both wild-type and S218L mice. To examine contributing underlying mechanisms of action of chronic pregabalin, we performed whole-cell patch-clamp electrophysiology in CA1 neurons in ex vivo brain slices from mice treated with chronic pregabalin vs vehicle. In WT mice, chronic pregabalin produced a decrease in spontaneous excitatory postsynaptic current (sEPSC) amplitude with no effect on frequency. In contrast, in S218L mice chronic pregabalin produced an increase in sEPSC amplitude and decreased frequency. These electrophysiological findings suggest that in FHM-1 mice chronic pregabalin acts through both pre- and post-synaptic mechanisms in CA1 hippocampal neurons to elicit FHM-1 genotype-specific inhibitory action. The results highlight the potential of chronic pregabalin to limit recurrent SD to subcortical brain structures during pathophysiological events in both the genetically-normal and FHM-1 brain. The work further provides insights into FHM-1 pathophysiology and the potential for chronic pregabalin treatment to prevent SD in migraineurs. The online version contains supplementary material available at 10.1186/s13041-023-01062-6.
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影响因子：
3.3
作者：
Alles SR;Garcia E;Balasubramanyan S;Jones K;Tyson JR;Joy T;Snutch TP;Smith PA
通讯作者：
Smith PA
影响因子：
7.4
作者：
Pizzolato, Raffaella;Villani, Veronica;Prosperini, Luca;Ciuffoli, Alessandro;Sette, Giuliano
通讯作者：
Sette, Giuliano
DOI：
10.1073/pnas.1009500107
发表时间：
2010-10-26
影响因子：
11.1
作者：
Adams, Paul J.;Rungta, Ravi L.;Snutch, Terrance P.
通讯作者：
Snutch, Terrance P.
DOI：
10.1073/pnas.0708930105
发表时间：
2008-03-04
影响因子：
11.1
作者：
Hendrich, Jan;Van Minh, Alexandra Tran;Dolphin, Annette C.
通讯作者：
Dolphin, Annette C.
影响因子：
14.5
作者：
Loonen, Inge C. M.;Jansen, Nico A.;Tolner, Else A.
通讯作者：
Tolner, Else A.