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Agaro-oligosaccharides, hydrolysates of agarose isolated from red algae, were reported to possess various biological functions and activities, including anti-bacteria, anti-inflammatory and anti-oxidative properties. In this study, the potential neuroprotective effects and underlying molecular mechanisms of agaro-oligosaccharides against neurotoxicity induced by 6-hydroxydopamine in SH-SY5Y cells were explored. The results indicated that pretreatment with agaro-oligosaccharide monomers especially agaropentaose (AOP) considerably enhanced the cell viability and the activities of antioxidant enzymes in SH-SY5Y cells treated by 6-hydroxydopamine. In addition, AOP markedly reduced intracellular reactive oxygen species level and inhibited the loss of mitochondrial membrane potential. Moreover, NF-κB and p38MAPK signaling pathways associated with neuroinflammation were significantly down-regulated by pretreatment with AOP. These findings reflected the protective effects and mechanisms of AOP against neurologic damage in SH-SY5Y cells induced by 6-hydroxydopamine. Hence the marine-derived agaropentaose merits further study as a novel functional food additive or therapeutic agent against some neuronal diseases.