Regulatory effect of vitamin D on pro-inflammatory cytokines and anti-oxidative enzymes dysregulations due to chronic mild stress in the rat hippocampus and prefrontal cortical area

Mol Biol Rep. 2021 Dec;48(12):7865-7873. doi: 10.1007/s11033-021-06810-2. Epub 2021 Oct 12.


Background: Chronic stress increases the production of pro-inflammatory cytokines and oxidative stress in the brain, which underlay cognitive and psychological problems. In addition to the anti-depressants, vitamin D is known to act as an anti-inflammatory and anti-oxidative agent. This study investigates the specific effects of vitamin D in protecting hippocampus and pre-frontal cortex (PFC) against chronic mild stress (CMS)-induced activation of pro-inflammatory cytokines IL-6 and TNF-α and decreasing the activation of anti-oxidative enzymes super oxide dismutase (SOD) and glutathione peroxidase (GPx).

Methods and results: Rats were exposed to CMS for 3 weeks. Two groups of rats received vitamin D (5 and 10 μg/kg) and another received fluoxetine (5 mg/kg) along with CMS. Control groups were not exposed to CMS, but received treatments similar to CMS groups. Serum corticosterone and IL-6, TNF-α and SOD and GPx levels in the hippocampus and PFC were measured at the end of three weeks. CMS significantly increased corticosterone, IL-6, TNF-α and decreased SOD and GPx levels (P < 0.0001) in hippocampus and PFC. Vitamin D treatment reduced corticosterone levels (P < 0.01), increased SOD (P < 0.0001) and GPx (P < 0.01) and decreased IL-6 and TNF-α (P < 0.0001) levels in the hippocampus and PFC compared to rats treated with vitamin D vehicle. Vitamin D-10 regulation of SOD and IL-6 levels was more effective than fluoxetine (P < 0.0001 and P < 0.01, respectively, in hippocampus).

Conclusion: This study suggests that vitamin D effectively protects the key regions of the brain related to cognition and affective behavior, against the inflammation and oxidative stress caused by the chronic stress.

Keywords: Anti-oxidative enzymes hippocampus; Chronic mild stress (CMS); Pre-frontal cortex (PFC); Pro-inflammatory cytokines; Vitamin D.

MeSH terms

  • Animals
  • Antioxidants / metabolism
  • Behavior, Animal / drug effects
  • Brain / metabolism
  • Cytokines / metabolism
  • Glutathione Peroxidase / metabolism
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Inflammation
  • Interleukin-6 / metabolism
  • Male
  • Oxidative Stress / drug effects
  • Oxidative Stress / physiology
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / metabolism
  • Rats
  • Rats, Wistar
  • Stress, Psychological / drug therapy*
  • Stress, Psychological / metabolism
  • Stress, Psychological / physiopathology
  • Superoxide Dismutase / metabolism
  • Tumor Necrosis Factor-alpha / metabolism
  • Vitamin D / metabolism
  • Vitamin D / pharmacology*


  • Antioxidants
  • Cytokines
  • Interleukin-6
  • Tumor Necrosis Factor-alpha
  • Vitamin D
  • Glutathione Peroxidase
  • Superoxide Dismutase