Carbenoxolone and mefloquine suppress tremor in the harmaline mouse model of essential tremor

Abstract

Excessive olivo-cerebellar synchrony is implicated in essential tremor. Because synchrony in some networks is mediated by gap junctions, we examined whether the gap junction blockers heptanol, octanol, carbenoxolone, and mefloquine suppress tremor in the mouse harmaline model, and performed an open-treatment clinical study of mefloquine for essential tremor. Digitized motion was used to quantify tremor in mice administered harmaline, 20 mg/kg s.c. In mice the broad-spectrum gap junction blockers heptanol, octanol (350 mg/kg i.p. each), and carbenoxolone (20 mg/kg) suppressed harmaline tremor. Mefloquine (50 mg/kg), which blocks gap junctions containing connexin 36, robustly suppressed harmaline tremor. Glycyrrhizic acid (related to carbenoxolone) and chloroquine (related to mefloquine), which do not block gap junctions, failed to suppress harmaline tremor in mice. Clinically, tremor was assessed with standard rating scales, and subjects asked to take 62.5, 125, and 250 mg mefloquine weekly for 12 weeks at each dose. None of the four human subjects showed a meaningful tremor reduction with mefloquine, likely because clinical levels were below those required for efficacy. In view of recent genetic evidence, the anti-tremor mechanism of these compounds is uncertain but may represent a novel therapeutic target, possibly involving gap junctions other than those containing connexin 36.

Gap junction blockers attenuate beta oscillations and improve forelimb function in hemiparkinsonian rats

“…3, n = 6, p = 0.007), which did not return to pre-CBX values 2 h after injection. As a control, we IP-injected saline or a non-active analog of CBX called oleanolic acid (200 mg/kg) (Martin and Handforth, 2006), into different hemiparkinsonian rats. In the former, we found that β oscillatory A.U.…”

Elevated blood harmane (1-methyl-9H-pyrido[3,4-b]indole) concentrations in essential tremor

“…Acute exposure to β-carboline alkaloids results in an intense and generalized action tremor in a broad range of laboratory species including mice, cats, and monkeys. β-carboline alkaloid administration is the main animal model for ET and new pharmacotherapies are tested using exposed animals (Handforth and Krahl, 2001;Krahl et al, 2004;Martin and Handforth, 2006;Martin et al, 2005;Sinton et al, 1989). The β-carboline alkaloid tremor shares many features with ET.…”

Gap Junction Modulation of Low-Frequency Oscillations in the Cerebellar Granule Cell Layer

“…Mefloquine can result in increased spontaneous synaptic activity by increasing spike frequency of hippocampal interneurons [41], but our gap junction blockers did not alter MUA in the recordings presented here (Fig. 4), and both CBX and mefloquine has previously been used effectively to evaluate the specific role of connexin Cx36 gap junctions [63,64].…”