PDF(Pubmed)
Abstract：
Ethanol has been shown to suppress essential tremor (ET) in patients at low-to-moderate doses, but its mechanism(s) of action remain unknown. One of the ET hypotheses attributes the ET tremorgenesis to the over-activated firing of inferior olivary neurons, causing synchronic rhythmic firings of cerebellar Purkinje cells. Purkinje cells, however, also receive excitatory inputs from granule cells where the α6 subunit-containing GABAA receptors (α6GABAARs) are abundantly expressed. Since ethanol is a positive allosteric modulator (PAM) of α6GABAARs, such action may mediate its anti-tremor effect. Employing the harmaline-induced ET model in male ICR mice, we evaluated the possible anti-tremor effects of ethanol and α6GABAAR-selective pyrazoloquinolinone PAMs. The burrowing activity, an indicator of well-being in rodents, was measured concurrently. Ethanol significantly and dose-dependently attenuated action tremor at non-sedative doses (0.4-2.4 g/kg, i.p.). Propranolol and α6GABAAR-selective pyrazoloquinolinones also significantly suppressed tremor activity. Neither ethanol nor propranolol, but only pyrazoloquinolinones, restored burrowing activity in harmaline-treated mice. Importantly, intra-cerebellar micro-injection of furosemide (an α6GABAAR antagonist) had a trend of blocking the effect of pyrazoloquinolinone Compound 6 or ethanol on harmaline-induced tremor. In addition, the anti-tremor effects of Compound 6 and ethanol were synergistic. These results suggest that low doses of ethanol and α6GABAAR-selective PAMs can attenuate action tremor, at least partially by modulating cerebellar α6GABAARs. Thus, α6GABAARs are potential therapeutic targets for ET, and α6GABAAR-selective PAMs may be a potential mono- or add-on therapy.
摘要：
乙醇已被证明可以在低至中等剂量的患者中抑制特发性震颤（ET），但其作用机制仍然未知。ET假说之一将ET震颤归因于下橄榄神经元的过度激活放电，引起小脑浦肯野细胞的同步节律性放电.浦肯野细胞,然而,还从含有α6亚基的GABAA受体（α6GABAAR）大量表达的颗粒细胞接受兴奋性输入。由于乙醇是α6GABAAR的正变构调节剂（PAM），这种作用可能介导其抗震颤作用。在雄性ICR小鼠中使用harmaline诱导的ET模型，我们评估了乙醇和α6GABAAR选择性吡唑并喹啉酮PAMs的可能的抗震颤作用。啮齿动物健康的指标，同时测量。在非镇静剂量（0.4-2.4g/kg，i.p.）。普萘洛尔和α6GABAAR选择性吡唑并喹啉酮也显着抑制了震颤活性。既不是乙醇也不是普萘洛尔,但只有吡唑并喹啉酮,恢复了harmaline处理的小鼠的挖土活动。重要的是,小脑内微量注射呋塞米(α6GABAAR拮抗剂)有阻断吡唑并喹啉酮化合物6或乙醇对harmaline诱导的震颤的作用的趋势。此外,化合物6和乙醇的抗震颤作用是协同的。这些结果表明，低剂量的乙醇和α6GABAAR选择性PAMs可以减弱震颤，至少部分通过调节小脑α6GABAAR。因此，α6GABAAR是ET的潜在治疗靶点，和α6GABAAR选择性PAMs可能是一种潜在的单一或附加疗法。
