👤 Monavareh Soti

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 movement disorder characterized by persistent limb tremors. Currently, no effective treatment for ET exists. Natural plant-derived compounds, like the flavonoid, quercetin may provide therapeutic benefits, particularly when delivered in nanoemulsion formulations that enhance bioavailability and efficacy. This study evaluated the neuroprotective potential of quercetin nanoemulsion (Que-NE) in a harmaline-induced mouse model of ET. Thirty-two male Swiss mice were randomly divided into four groups (n = 8 each): Control, Harmaline (10 mg/kg, i.p., on days 3, 5, and 7), Que-NE (20 mg/kg, i.p., for 7 days), and Harmaline + Que-NE. Harmaline was used to reliably induce tremor via olivocerebellar hyperexcitability. Behavioral performance was assessed using the open field, elevated plus maze, tail suspension, wire grip, rotarod, and passive avoidance tests. Expression of NF-κB, TNF-α, IL-1β, IL-6, NMDA receptor, and Lingo-1 was determined by RT-PCR. Que-NE significantly reduced harmaline-induced tremor severity (p < 0.0001), decreased immobility time in the tail suspension test (p = 0.0003), and improved open field anxiety-like behaviors compared with harmaline alone (P = 0.0012). Que-NE downregulated pro-inflammatory mediators (P < 0.0001) and reduced Lingo-1 gene expression (P < 0.0001). However, Que-NE showed limited efficacy in severe motor coordination tasks (rotarod, wire grip) and passive avoidance memory. Que-NE exerts measurable anti-inflammatory, anxiolytic, and antidepressant-like effects in the harmaline model of ET. The impact of Que-NE on improving motor deficits, reducing inflammatory markers, and suppressing inhibitors of synaptic plasticity highlights the potential of Que-NE as a disease-modifying strategy. However, dose-response, protein-level, and long-term studies are needed to evaluate the therapeutic potential of Que-NE for ET management. Show less