Ethanolic Extract of Watermelon (Citrullus lanatus) Seeds on Diabetic Wistar Rats: A Histological, Histochemical, and Neurobehavioural Study

Abstract Background Diabetes mellitus (DM) affects 11.11% of adults globally in 2024, with prevalence projected to reach 13% by 2050. Chronic hyperglycaemia drives oxidative stress, neuroinflammation and structural brain injury which is termed diabetic encephalopathy, manifesting as anxiety-like behaviour, locomotor deficits and autonomic dysregulation. Conventional therapies have limitations, prompting interest in nutraceuticals like Citrullus lanatus (watermelon) seed, rich in citrulline, phenolics and flavonoids with documented antioxidant and antidiabetic properties. Methods Diabetes was induced with STZ, and rats received EWS or metformin for six weeks alongside untreated diabetic and normal controls; an extract-only non-diabetic group assessed intrinsic extract effects. Parameters assessed included body and brain weight, blood glucose, open-field neurobehavioural indices, oxidative stress markers (MDA, SOD, GSH, CAT), glucose-metabolising enzymes (ALP, ACP, G6PDH, LDH), inflammatory/apoptotic markers (caspase-3, IL-6, TNF-α), and frontal cortical histoarchitecture. Results Diabetic controls exhibited significant weight loss, hyperglycaemia, anxiety-like and hypoactive behaviour, elevated oxidative stress and inflammatory markers, depleted antioxidants and metabolic enzymes, cortical neuronal necrosis, reactive astrogliosis and collagen deposition. Treatment with EWS or metformin significantly attenuated nearly all derangements, normalising blood glucose and restoring behavioural, biochemical and histological parameters close to normal, with only partial mitigation of collagen deposition. The extract-only group showed no differences from normal controls.