Modulation of Lingo-1 and NMDA receptor expression by memantine and vitamin D3 co-therapy attenuates motor and non-motor symptoms in essential tremor.

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.