Vitamin B6 augments antidepressant activity of venlafaxine by restoring cortical EEG oscillations, behavior and oxidative biomarkers in chronic unpredictable mild stress (CUMS)-induced model of depression-like behavior.

Abstract

Depression is a multifactorial neuropsychiatric disorder associated with chronic stress, disrupted neural oscillations and oxidative stress. The present study investigated whether vitamin B6 (Vit B6) enhances the antidepressant efficacy of venlafaxine (VEN) in a chronic unpredictable mild stress (CUMS)-induced model of depression-like behavior in C57BL/6 mice. A total of 72 mice, divided into two subsets, i.e., with and without EEG electrodes, were treated with VEN and Vit B6 alone and in combination for 28 days. The EEG electrode-bearing mice were tested for electrophysiological changes on day 29. Mice without EEG electrodes were tested for behavioral changes during days 29-32, followed by brain isolation on day 33 for biochemical analysis. The CUMS control demonstrated weight loss, anxiety-like activity in light/dark box, and depression-like behavior in sucrose splash, tail suspension and forced swim tests. Moreover, the EEG showed increased theta and reduced alpha and gamma activity. Further, CUMS resulted in marked elevation in brain oxidative stress in terms of elevated malondialdehyde (MDA) and reduced catalase activity. Monotherapy with VEN and Vit B6 partially mitigated these alterations, but the combined treatment restored behavioral performance in light/dark test with increased grooming in the sucrose splash test, while reducing immobility in the tail suspension and forced swim tests. Biochemically, the combined therapy reduced oxidative stress in the brain by reducing MDA and increasing catalase activity. Additionally, the EEG evaluation revealed the restoration of cortical oscillations, attenuation of theta hyperactivity, and increased alpha and gamma band power, indicating improved neuronal synchronization. The study's outcomes suggest that combining vitamin B6 with venlafaxine enhances its antidepressant effects, possibly by modulating oxidative stress and neural circuitry. This combination strategy might be a promising approach to improve therapeutic outcomes in stress-associated depressive disorder.