Positive modulation of cerebellar α6GABA_Areceptors for treating essential tremor: a proof-of-concept study in harmaline-treated mice

Abstract

Background: The etiology of essential tremor (ET) remains unclear but may involve abnormal firing of Purkinje cells, which receive excitatory inputs from granule cells in the cerebellum. Since α6 subunit-containing GABAA receptors (α6GABAARs) are abundantly expressed in granule cells, we validated a hypothesis that α6GABAAR-selective positive allosteric modulators (PAMs) are promising pharmacological interventions for ET therapy. Methods: Employing the harmaline-induced ET model in male ICR mice, we evaluated the possible anti-tremor effects of four α6GABAAR-selective PAMs, the pyrazoloquinolinones Compound 6 and LAU-463 and their respective deuterated derivatives. Propranolol, a clinical anti-tremor agent, was employed as positive control. To investigate the involvement of cerebellar α6GABAARs in the anti-tremor effect of intraperitoneal (i.p.) Compound 6, furosemide, an α6GABAAR antagonist, was intra-cerebellarly (i.cb.) co-administered with Compound 6. The burrowing activity, an indicator of well-being in rodents, was measured concurrently. Results: Harmaline (10-30 mg/kg, s.c.) induced action tremor in ICR mice dose-dependently and markedly reduced their burrowing activity. Compound 6 (3 and 10 mg/kg, i.p.) significantly attenuated harmaline (20 mg/kg)-induced action tremor and burrowing activity impairment. Propranolol (20 mg/kg, i.p.) diminished tremor but failed to restore the burrowing activity in harmaline-treated mice. Importantly, both anti-tremor and burrowing activity restorative effects of Compound 6 (10 mg/kg, i.p.) was significantly reversed by co-administration of i.cb. furosemide at a dose (10 nmol/0.5 μl) having no effect per se. All four α6GABAAR PAMs exhibited a similar therapeutic efficacy. Conclusion: α6GABAAR-selective PAMs significantly attenuated action tremor and restored physical well-being in a mouse model mimicking ET by acting in the cerebellum. Thus, α6GABAAR-selective PAMs may be potential therapeutic agents for ET.

Phenols and GABAA receptors: from structure and molecular mechanisms action to neuropsychiatric sequelae

“…In contrast, results from recent studies provide important new clues into tremor suppression mechanisms initiated by the enhancement of GABA-driven inhibition in pathways controlled by the α2/3 GABA A R subunits but not the α1 subunit ( Kosmowska et al, 2023 ). In addition, GABA A R α6 subunit-selective drugs were found to cause a substantial reduction in tremors and restoration of physical wellbeing in a mouse model ( Huang et al, 2021 ).…”