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Vitamin K2 (MK‐7) modulated Nrf2/NLRP3/caspase‐1 axis to protect against age‐related structural and cognitive deterioration in naturally aged rats

Ageing process is accompanied by disrupted maintenance of tissue homeostasis. Declined cognitive function is a hallmark of ageing process. Patients with severe dementia and elderly people at an early stage of Alzheimer's disease demonstrated marked reduction in serum concentration of vitamin K. Menaquinone‐7 (MK‐7) is a major form of vitamin K2 that can be found in animal products and fermented food. The present study aimed to evaluate the potential protective effect of MK‐7 against cognitive decline and structural alterations in brain tissue of naturally aged rats and to delineate the potential involved molecular mechanisms. Three months‐aged albino rats were randomly assigned into two groups; ageing control receiving vehicle and ageing group received MK‐7 (30 mg/kg, oral, once daily 5 days per week). Treatment was continued for 17 months. Additional group containing three‐month‐old rats was used as adult control. Modified T‐maze, Crawley's sociability test and modified forced swim test were used to assess cognitive level, anxious and depressive like behaviour, respectively. Dissected brain tissues were used to assess neuroprotective mechanisms of MK‐7 by histopathology and immunohistochemistry, real time polymerase chain reaction, spectrophotometry and Enzyme‐Linked Immunosorbent assay. Behavioural tests showed attenuated cognitive impairment, depression and anxiety and improved spatial memory and learning ability by MK‐7 administration. Additionally, brain expression of NLRP3 inflammasome components (NLRP3, caspase‐1) and production of downstream inflammatory factors (IL‐1β, IL‐6 and TNF‐α) were markedly decreased in MK‐7 treated rats. Further, MK‐7 triggered Nrf‐2 expression, reduced lipid peroxidation and restored antioxidant enzymes levels. Also, MK‐7 dampened microglial activation, modulated hippocampal and cerebral cortical structure alterations and restored tyrosine expression in aged brain. Our findings highlighted MK‐7 as a promising candidate for halting progression of structural and cognitive deterioration in aged population. Activation of Nrf‐2 accompanied by NLRP3/ caspase‐1 suppression participated in neuroprotective effect of MK‐7 in rat aged brain.