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However, its clinical application faces several hurdles that could limit its clinical efficiency such as central and retinal neurotoxicity. Hence, it is crucial to develop antioxidant-based co-therapeutic approaches to mitigate CISP-induced neurotoxicity. Resveratrol (RSV) is a naturally occurring polyphenol that exhibits a plethora of health-promoting activities. The present study aimed to compare the neuroprotective impact of intranasal (IN) and intraperitoneal (IP) doses of RSV on the alleviation of CISP-induced neurotoxicity. Rats were allocated into four groups: Negative control, CISP-rats, treated CISP-rats with IN RSV, and treated CISP-rats with IP RSV. Assessment of lipid peroxides and catalase activities in the brain and ocular tissues were conducted. The brain acetylcholinesterase (AChE) activity and the eye 8-Hydroxy-2-deoxyguanosine (8-OHdG) content were estimated. Furthermore, the gene expression of interleukin-10 (IL-10) and caspase-8 was performed. In addition, serum nuclear factor erythroid 2-related factor 2 (Nrf2) level, as well as the extent of DNA damage in blood cells were evaluated. Histopathological analyses of different regions of the brain and the eye tissues were conducted. Our findings demonstrated that both IN and IP doses of RSV mitigated the central and retinal toxicity as demonstrated biochemically and histopathologically; indicating the anti-oxidant, anti-inflammatory, genoprotective, and anti-apoptotic activities of RSV. Collectively, IP RSV exhibited a superior cumulative neuroprotective activity than IN RSV. 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