👤 Mehran Ilaghi

Essential tremor (ET) is a common movement disorder, characterized by bilateral postural or kinetic tremor and associated non-motor symptoms including anxiety and cognitive impairment. Current treatments offer limited efficacy and significant side effects, highlighting the need for novel therapeutic approaches. This study investigated the therapeutic potential of memantine and vitamin D3 (vitD3) combination therapy in a harmaline-induced mouse model of essential tremor. Adult male Swiss mice were divided into eight groups (n = 8/group): control, sham, harmaline-induced ET (10 mg/kg, i.p. on days 1, 3, and 5), memantine (5 mg/kg, i.p. for 7 days), vitD3 (0.1 µg/kg, i.p. for 7 days), and combination treatment groups. Tremor severity, footprint analysis, rotarod, and wire grip tests were conducted to assess motor function. Moreover, anxiety-like behavior, depressive-like behavior, and cognitive function were examined. Expression of leucine-rich repeat and immunoglobulin domain-containing protein 1 (Lingo-1) and NMDA receptor expression in cerebellar tissue was evaluated using quantitative real-time PCR. Histological evaluation of Purkinje cell morphology was performed using hematoxylin-eosin staining. Harmaline administration induced significant tremor, motor coordination deficits, anxiety-like behaviors, and cognitive impairments. Treatment with memantine and/or vitD3 significantly reduced tremor scores on days 3 and 5 compared to harmaline alone. Combination therapy restored locomotor activity. Both individual and combination treatments demonstrated significant anxiolytic effects. VitD3 alleviated depressive-like behavior. Moreover, cognitive assessment revealed that combination therapy significantly improved passive avoidance learning and memory retention. Harmaline dramatically upregulated Lingo-1 and NMDA receptor expression, which was effectively normalized by memantine and/or vitD3 treatment. Histological examination demonstrated that vitD3 and combination therapy significantly reduced harmaline-induced Purkinje cell degeneration. Memantine and vitD3 combination therapy ameliorates both motor and non-motor symptoms in a mouse model of ET through modulation of Lingo-1 and NMDA receptor expression pathways. These findings suggest that this combination approach represents a therapeutic strategy that addresses the complex pathophysiology of ET while providing neuroprotective benefits. Show less

Essential tremor (ET) is a common neurodegenerative disorder characterized by action tremors and various non-motor symptoms. This study investigated the potential therapeutic effects of ketamine, an NMDA receptor antagonist with known GABA modulatory and anti-inflammatory properties, in a harmaline-induced model of ET in mice. We also evaluated the changes in expression of inflammatory interleukin 6 (IL-6) as well as Leucine rich repeat and Immunoglobin-like domain-containing protein 1 (Lingo-1), a prominent gene involved in the pathogenesis of ET. Male Swiss Webster mice were divided into four groups: control, harmaline (10 mg/kg), ketamine (8 mg/kg), and harmaline + ketamine. Tremor severity, muscle strength, locomotor activity, anxiety-like behavior, and passive avoidance learning were assessed. Cerebellar expression of Lingo-1 and IL-6 was analyzed using real-time PCR. Ketamine did not significantly reduce harmaline-induced tremors but improved muscle strength deficits in the wire grip test. In the open field test, ketamine normalized some harmaline-induced changes in locomotor activity and grooming behavior. No significant differences were observed in passive avoidance learning across groups. At the molecular level, ketamine did not mitigate the harmaline-induced increase in IL-6 expression, and Lingo-1 expression was not significantly altered by either harmaline or ketamine treatment. Our findings suggest that ketamine has limited efficacy in the harmaline ET model, showing some improvements in motor function and anxiety-like behavior but failing to address core tremor symptoms or modulate inflammatory and Lingo-1 pathways. These results highlight the complex nature of ET pathophysiology and the need for further research into targeted therapeutic approaches. Show less

Essential tremor (ET) is a prevalent movement disorder, yet current therapeutic options remain limited. Emerging evidence implicates leucine-rich repeat and immunoglobulin-like domain-containing protein (Lingo-1) and neuroinflammation in the pathophysiology of ET. This study aimed to investigate whether agmatine, a biogenic amine neuromodulator attenuates tremors and modulates the expression of Lingo-1 and proinflammatory markers in a rodent model of ET. Tremor was induced in male Swiss Webster mice through intraperitoneal injections of harmaline (10 mg/kg) on Days 1, 3, and 5 of the study. During the same period, agmatine (40 mg/kg) was administered for 5 consecutive days. Behavioral assessments of tremor severity, gait, balance, muscular strength, locomotion, anxiety-like behavior, and memory were conducted. Moreover, Lingo-1 and interleukin (IL)-6 gene expression was examined in the cerebellum using real-time polymerase chain reaction (RT-PCR). Our findings demonstrated that agmatine administration significantly reduced tremors, ameliorated anxiety-like behaviors, and attenuated harmaline-induced locomotor deficits. At the molecular level, agmatine treatment significantly suppressed the overexpression of Lingo-1 elicited by harmaline. Moreover, IL-6 expression was attenuated to an extent comparable to control levels. Collectively, this study provides the first evidence that agmatine dampens tremor severity, improves behavioral outcomes, and modulates key pathways implicated in ET pathogenesis in a rodent model. The ability of agmatine to normalize Lingo-1 and IL-6 expression suggests regulation of these pathways could underlie its neuroprotective action. These results suggest promise for agmatine as a prospective therapeutic agent in ET. Show less