Effects of vitamin D and exercise on depression: exploring the VEGF-mediated MAPK/ERK pathway

Abstract Background Depression is a prevalent psychiatric disorder associated with oxidative stress (OS), inflammation, and impaired neurogenesis. Vitamin D and exercise are known to improve brain functions and mood. This study aimed to assess their individual and combined effects on experimental depression in rats. Methods Fifty adult Wistar albino rats were divided into five groups: normal control, depression, depression + vitamin D, depression + exercise, and depression + vitamin D + exercise. Malondialdehyde (MDA) and reduced glutathione (GSH) were measured using colorimetry. Tumor necrosis factor-α (TNF-α), dopamine (DA), norepinephrine (NE), and brain-derived neurotrophic factor (BDNF) were determined by enzyme-linked immunosorbent assay (ELISA). Vascular endothelial growth factor (VEGF) and extracellular signal-regulated kinase (ERK) were evaluated using quantitative real-time polymerase chain reaction (qRT-PCR) and ELISA. Behavioral performance was evaluated using the open field test (OFT) and tail suspension test (TST). Results Reserpine administration induced a depressive-like state, evidenced by increased immobility time and reduced locomotor activity in the OFT and TST. Biochemically, it produced marked oxidative and inflammatory alterations, including elevated MDA and TNF-α with decreased GSH. Also, it decreased neurotransmitters; DA and NE, and BDNF. Treatment with either vitamin D or exercise partially ameliorated these alterations, but these improvements were not statistically different from values of the depressed groups. On the other hand, the combined vitamin D and exercise regimen yielded the most pronounced improvement, restoring behavioral, biochemical, and molecular parameters to become statistically indistinguishable from the normal values. Moreover, depression showed significant downregulation of VEGF and ERK at both gene and protein levels as compared to the normal control. Treatment with vitamin D or exercise alone improved VEGF and ERK to a similar extent (not statistically different vs depressed group), with the combined regimen produced the highest treated values to become non-statistically different from the normal. Conclusion Combined vitamin D supplementation and exercise produced greater antidepressant-like effects than either intervention alone, accompanied by improvements in behavioral, antioxidant, inflammatory, and neurotrophic markers. These changes were associated with parallel increases in VEGF and ERK expression, suggesting possible involvement of this signaling pathway. Further studies are needed to confirm the underlying mechanisms and support translation to clinical settings.