Exploring the role of Ranolazine & Levosimendan as anxiolytic and anti-depressant in behavior models of Wistar rats
Authors: Pragya Pandey, Prof Rishi Pal, Dr Bablu Bhargava, Prof Rajendra Nath, Prof Rakesh Kumar Dixit
Keywords: Depression, Anxiety, Ranolazine, Levosimendan, Psychiatric disorder, Cognition.
Abstract:
Introduction: Neuropsychiatric disorders, particularly anxiety and major depressive disorder, share extensive pathophysiological overlaps with chronic cardiovascular diseases, including profound neuroinflammation, oxidative stress, and compromised neuroplasticity. Consequently, repurposing established cardiovascular drugs that exhibit pleiotropic neuroprotective properties represents a highly promising pharmacological strategy. This study aimed to comparatively analyze the anxiolytic and antidepressant-like effects of two distinct cardiovascular agents, ranolazine (a late sodium current inhibitor) and levosimendan (a calcium sensitizer and potassium channel opener), in validated preclinical behavioral models.
Methods: Healthy adult female Wistar rats (130-200 g, 18-20 weeks old) were randomized into respective experimental groups (n=6 per group). The anxiolytic effects were evaluated using the Elevated Plus Maze (EPM) over a 5-day administration period, comparing ranolazine (90 mg/kg) and levosimendan (12 ug/kg) against a normal saline control and standard diazepam (1 mg/kg). The antidepressant effects were evaluated utilizing the Tail Suspension Test (TST) over a 30-day administration period, comparing the same test drugs against a standard imipramine control (10 mg/kg). Comprehensive statistical analyses were conducted utilizing one-way ANOVA followed by Tukey's post-hoc test, as well as paired t-tests for within-group assessments.
Results: In the Elevated Plus Maze, both ranolazine and levosimendan generated substantial anxiolytic effects by Day 5, significantly increasing the frequency of open arm entries and the total duration spent in the open arms compared to their respective baselines, demonstrating efficacy that paralleled the standard diazepam intervention. In the Tail Suspension Test, unmedicated control animals exhibited a severe, progressive increase in immobility time by Day 46, reflecting learned helplessness resulting in behavioral despair. Ranolazine treatment completely arrested this decline and produced a statistically dominant reduction in immobility time. Conversely, levosimendan demonstrated significantly weaker and highly inconsistent antidepressant-like effects throughout the prolonged timeline.
Conclusion: Ranolazine exhibits potent, broad-spectrum neuropsychopharmacological benefits, acting as both a robust anxiolytic and a highly superior antidepressant-like agent. Levosimendan provides significant anxiolytic benefits but lacks durable efficacy in behavioral models of depression. These profound findings strongly advocate for the targeted clinical repurposing of ranolazine in vulnerable patient populations suffering from comorbid cardiovascular and psychiatric dysfunction.
