Early prediabetes aggravates neuroinflammatory and cognitive dysfunctional responses to chlorpyrifos exposure:...

Chronic exposure to organophosphorus pesticides (OPs) is increasingly implicated in neuroinflammatory and cognitive disorders, yet susceptibility factors and pharmacological modulators remain poorly defined. Given the global rise in metabolic dysfunction, this study investigated whether prediabetes amplifies the neurotoxic impact of chronic chlorpyrifos (CPF) exposure and examined arachidonic acid (AA) as a potential modulator of the associated detrimental phenotype, with emphasis on endocannabinoid system (ECS) perturbation. Male Sprague-Dawley rats were rendered prediabetic and dermally exposed to CPF for 35 days, in the absence or presence of oral AA supplementation (3 mg/kg/day). Chronic CPF exposure induced systemic metabolic dysfunction, cerebrovascular hypoperfusion, adipose inflammation, and marked neuroinflammation accompanied by cognitive and motor impairment, as assessed by behavioral testing, laser speckle imaging, biochemical assays, histopathology, immunohistochemistry, and LC-MS/MS. These effects were exacerbated in prediabetic rats. CPF accumulated preferentially in adipose depots and brain tissue and was associated with elevated IL-1β and oxidative stress. Molecularly, CPF disrupted ECS homeostasis, with increased hippocampal 2-arachidonoylglycerol levels, downregulation of CB1 receptors, and upregulation of CB2 receptors, consistent with a stress-induced but functionally impaired endocannabinoid response. AA supplementation significantly mitigated CPF- and prediabetes-induced dysfunctional phenotype, and rebalanced ECS signaling. Collectively, these findings identify early prediabetes as a critical vulnerability state that aggravates OP neurotoxicity and demonstrate that AA exerts broad neuroprotective and metabolic benefits, in part through modulation of endocannabinoid and inflammatory signaling. This work highlights the ECS-adipose-brain axis as a pharmacologically relevant interface linking environmental toxicant exposure to metabolic and neurocognitive decline.