Positive modulation of cerebellar α6GABAA receptors for treating essential tremor: a proof-of-concept study in harmaline-treated mice

Abstract

AbstractBackgroundThe 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.MethodsEmploying 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 antitremor effect of intraperitoneal (i.p.) Compound 6, furosemide, an α6GABAAR antagonist, was intracerebellarly (i.cb.) co-administered with Compound 6. The burrowing activity, an indicator of wellbeing in rodents, was measured concurrently.ResultsHarmaline (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.Conclusionα6GABAAR-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.