An increase in brain antioxidants was observed in CuE-treated rats subjected to CH. CuE decreased acetylcholinesterase activity, glutamate, and increased γ-aminobutyric acid levels in the brain. CuE attenuated CH-triggered lipid peroxidation, 8-hydroxy-2′-deoxyguanosine, protein carbonyls, tumor necrosis factor- α, nuclear factor-kappaB, myeloperoxidase activity, inducible nitric oxide synthase, and matrix metalloproteinase-9 levels in brain resulting in a decrease in cell death biomarkers (lactate dehydrogenase and caspase-3). CH caused impairment of neurological, sensorimotor, and memory functions that were ameliorated by CuE. Wistar rats were subjected to permanent bilateral common carotid artery occlusion to induce CH on day 1 and administered CuE (0.25, 0.5 mg/kg) and/or Bay-K8644 (calcium agonist, 0.5 mg/kg) for 28 days. In the present study, the neuroprotective effects of CuE were explored in a rat model of CH. The vasodilatory, anti-inflammatory, and antioxidant activities of cucurbitacin E (CuE) can alleviate CH-induced neurobehavioral impairments. The sequences linked to ion-channelopathies and calcium and glutamatergic excitotoxicity mechanisms resulting in widespread brain damage and neurobehavioral deficits, including memory, neurological, and sensorimotor functions. Impaired cerebral hemodynamic autoregulation, vasoconstriction, and cardiovascular and metabolic dysfunctions cause cerebral hypoperfusion (CH) that triggers pro-oxidative and inflammatory events. 4University Institute of Pharma Sciences, Chandigarh University, Mohali, India.3Department of Pharmacy, Guru Nanak Institute of Technology, Ambala, India.2Chitkara College of Pharmacy, Chitkara University, Punjab, India.1Henan University of Traditional Chinese Medicine, Zhengzhou, China.Zhiyong Liu 1, Manish Kumar 2* †, Sushma Devi 3 and Atul Kabra 4