Effect of Andrographolide on behavioural effects and NLRP3 inflammasome pathway in a rat model of chronic Cerebral Hypoperfusion

Alzheimer’s disease (AD) is a neurodegenerative disease and the most common cause of dementia in older people, initiated by chronic cerebral hypoperfusion (CCH). Innate immune activation and the microglial community cells at pathology sites of AD have long been considered a bystander phenomenon; however, it does not actively contribute to disease pathogenesis and progression. The latest data from clinical imaging, in vitro and in vivo experiments point out an intimate and mutual interaction between innate immune mechanisms and neurodegenerative processes. The NOD-like receptor (NLR) family in myeloid cells, the pyrin domain containing 3 and 1 inflammasomes in neurons, plays key components in the innate immune reaction observed in the brains of Alzheimer’s patients. The finding of a beneficial and protective effect of inflammasome inhibition on cognitive deficits and neuronal death in cell culture and animal models of AD recently opens a new perspective for therapeutic intervention. The present study was conducted to evaluate the potential therapeutic effects of Andrographolide (AG) with anti-inflammatory activity on CCH–induced hippocampal neuronal damage and cognitive dysfunction. The CCH model was developed in male Sprague Dawley (SD) rats using permanent occlusion of bilateral common carotid arteries (POBCCA) surgery. After two weeks of CCH, the effects of AG (0.1, 1 and 5 mg/kg) on spatial learning and memory were assessed in Morris Water Maze (MWM) tests. The behavioural task results revealed that, AG treatment (1 and 5 mg/kg) improved spatial and reference memory in MWM test. Automated open field task showed that AG did not impair motor and exploratory function in POBCCA rats. The expression of NLRP3, ASC, caspase-1 and cathepsin B genes were elucidated using real-time polymerase chain reaction. The results showed that the expression of all the above genes was upregulated after POBCCA surgery. Significantly, AG treatment at a 5 mg/kg dosage downregulated the gene expression in both hippocampus and frontal cortex. The NLRP3, ASC and caspase-1 protein expression was examined using western blot. Although the expressions of these proteins in both regions increased significantly after POBCCA surgery, this promotion reduced considerably after AG treatment (5 mg/kg). The expression levels of the pro- inflammatory cytokine such as interleukin 1 beta (IL-1β), interleukin 18 (IL-18), and interleukin 6 (IL-6), were assessed in an ELISA experiment. The results from both regions revealed that AG treatment significantly reduced the level of these interleukins which was increased due to POBCCA surgery. The structural damage to the hippocampus was evaluated using Congo-red staining. The slides showed that the numbers of pyknotic neurons with cytoplasmic shrinkage and disrupted cellular in hippocampal CA1 increased significantly after POBCCA surgery. Instead, AG treatment during CCH notably reduced these pathological damages in hippocampal CA1 compared to CCH-induced rats. Although the ELISA results showed a significant excess in the protein level of Aβ1-42, which is an Aβ precursor, Congo-red staining has not shown the Aβ-plaques and Aβ- aggregation 22 days after POBCCA surgery. In conclusion, AG treatment executes its learning and memory function via the inhibition of NLRP3 inflammasome and reduction of IL-1β, IL-18, IL-6 and Aβ1-42 consistently in the POBCCA rat model. The findings of this study support the therapeutic potential of AG treatment in the treatment of AD.

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