Effects of subanesthetic dose of ketamine on motor and cognitive outcomes of harmaline-induced essential tremor model: a focus on Lingo-1 and inflammatory pathways

Abstract

Introduction: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Essential tremor; Harmaline. Lingo-1; Inflammation; Ketamine.

Fig. 1

Experimental timeline and treatment groups. The study consisted of four groups (n = 8/group): Control (saline), Harmaline, Ketamine (8 mg/kg), and Harmaline + Ketamine combination. Tremor was assessed on days 1, 3, and 5. Behavioral tests were conducted on days 5–6, followed by molecular analyses on day 7

Fig. 2

Effect of ketamine on harmaline-induced tremor severity. Tremor scores were evaluated on days 1, 3, and 5 of the experiment in four groups (n = 8/group): Control (Cont), Ketamine (Ket), Harmaline (Harm), and Harmaline + Ketamine combination (Harm + Ket). Data presented as mean ± SEM. ****P < 0.0001 according two-way ANOVA

Fig. 3

Effects of ketamine on muscle strength in harmaline-treated mice as measured by wire grip test. The latency to fall (in seconds) was assessed in four groups (n = 8/group): Control (Cont), Ketamine (Ket), Harmaline (Harm), and Harmaline + Ketamine combination (Harm + Ket). Data presented as mean ± SEM. *P < 0.05 according to one-way ANOVA followed by Tukey’s post-hoc test

Fig. 4

Effects of ketamine on open field test parameters in harmaline-treated mice. Tests performed in four groups (n = 8/group): Control (Cont), Ketamine (Ket), Harmaline (Harm), and Harmaline + Ketamine combination (Harm + Ket). A Number of rearing episodes, B Number of grooming episodes, C Total distance moved (TDM, cm), D Mobility duration (s), E Velocity (cm/s), F Time spent in peripheral zone (s), and G Movement trajectory plots. Data presented as mean ± SEM. *P < 0.05, **P < 0.01, ****P < 0.0001 according to one-way ANOVA followed by Tukey’s post-hoc test

Fig. 5

Effects of ketamine and harmaline on passive avoidance learning and memory. Tests performed in four groups (n = 8/group): Control (Cont), Ketamine (Ket), Harmaline (Harm), and Harmaline + Ketamine combination (Harm + Ket). A Number of shocks received during training session, and B Step-through latency (s) measured during memory test 24 h after training. Data presented as mean ± SEM. No significant differences were observed between groups according to one-way ANOVA

Fig. 6

Effects of ketamine and harmaline on cerebellar IL-6 gene expression. Real-time PCR analysis performed on cerebellar tissue collected on day 7 in four groups (n = 4/group): Control (Cont), Ketamine (Ket), Harmaline (Harm), and Harmaline + Ketamine combination (Harm + Ket). Data presented as mean ± SEM. *P < 0.05 according to one-way ANOVA followed by Tukey’s post-hoc test

Fig. 7

Effects of ketamine and harmaline on cerebellar Lingo-1 gene expression. Real-time PCR analysis performed on cerebellar tissue collected on day 7 in four groups (n = 4/group): Control (Cont), Ketamine (Ket), Harmaline (Harm), and Harmaline + Ketamine combination (Harm + Ket). No statistically significant differences were observed between groups according to one-way ANOVA