Work

Unravelling the role of cerebellar α6GABAA receptors in anti-tremor pharmacotherapies

Year: 2025

Type: article

Abstract: Essential tremor (ET), characterized by action tremor, is one of the most prevalent movement disorders significantly impacting patients' well-being. However, its pathogenesis has not been fully elucidated, posing challenges for developing targeted pharmacological interventions. We previously found that ethanol significantly suppressed harmaline-induced action tremor in ICR mice at low-to-moderate doses that mimic social-drinking alcohol levels in humans. This effect was antagonized by intra-cerebellarly ( i.cb. )-administered furosemide, an antagonist of the α6 subunit-containing GABA A receptors (α6GABA A Rs), suggesting the involvement of cerebellar α6GABA A Rs. Here, we further demonstrated that the anti-tremor effect of the same dose of ethanol (1.2 g/kg, i.p. ) was nullified in Gabra6 -knockout ICR mice in a gene dose-dependent manner. This supports our proposal that cerebellar α6GABA A Rs are an underexplored anti-tremor target. We therefore further examined whether cerebellar α6GABA A Rs are involved in the anti-tremor effects of clinically-effective ET medications, using the same pharmacological approach in the harmaline model. Results showed that gabapentin (30 mg/kg, i.p. ), topiramate (30 mg/kg, i.p. ), propranolol (20 mg/kg, i.p. ), diazepam (4 mg/kg, i.p. ), zonisamide (20 mg/kg, i.p. ), and oxcarbazepine (15 mg/kg, i.p. ) significantly attenuated harmaline (20 mg/kg, s.c. )-induced action tremor in ICR mice. Interestingly, the anti-tremor effects of gabapentin and topiramate, but not those of other anti-tremor medications, were no longer evident in i.cb.- administered furosemide. Furosemide per se did not alter harmaline tremor. These results suggest that cerebellar α6GABA A Rs contribute, at least partly, to the anti-tremor effects of topiramate and gabapentin and that α6GABA A R-selective positive modulators are a potential novel therapy for ET patients.

Source: Biomedicine & Pharmacotherapy

DOI: 10.1016/j.biopha.2025.118644

Authors: Ya-Hsien Huang, Han-Yun Hsueh, Ming Tatt Lee, Chen-Jiun Yeh, Lih-Chu Chiou

Institutions: National Taiwan University, UCSI University, Chang Jung Christian University, China Medical University

Language: English

Topic: Neurological disorders and treatments

Subfield: Neurology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,610