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Diabetes mellitus is a prevalent metabolic disorder associated with multiple complications including neuropathy, memory loss and cognitive decline. Despite a long history of studies on diabetic complications, there are no effective therapeutic strategies for neuroprotection in diabetes. Hyperglycemia-induced imbalance in programmed cell death could initiate a decline in neural tissue cells viability. Various nanomaterials can induce either cell death or cell survival dependent on the type and surface features. Pristine C 60 fullerene is a nontoxic nanomaterial, which exhibits antioxidant and cytoprotective properties. However, the precise molecular mechanism with which the C 60 nanoparticle exerts cytoprotective effect in diabetic subjects has not yet been fully addressed. Thus, this study aimed to determine whether C 60 fullerene prevents oxidative stress impairment and to explore the effects of C 60 fullerene on apoptosis and autophagy in diabetes mellitus to clarify its potential mechanisms. These effects have been examined for olive oil extracted C 60 fullerene on the hippocampus of STZ diabetic rats. Up-regulation of Caspase-3, Beclin-1 and oxidative stress indexes and down-regulation of Bcl-2 were observed in the brain of STZ-diabetic rats. The exposure to C 60 fullerene for a period of 12 weeks ameliorate redox imbalance, hyperglycemia-induced disturbances in apoptosis and autophagy flux via modulation of Caspase-3, Bcl-2, Beclin-1 and LC3I/II contents. Furthermore, C 60 fullerene ameliorated the LC3I/II ratio and prevented extremely increased autophagy flux. Contrarily, pristine C 60 fullerene had no modulatory effect on all studied apoptotic and autophagy markers in non-diabetic groups. Therefore, oil extracted C 60 fullerene exhibits cytoprotective effect in hyperglycemia-stressed hippocampal cells. The presented results confirm that pristine C 60 fullerene nanoparticles can protect hippocampal cells against hyperglycemic stress via anti-oxidant, anti-apoptotic effects and amelioration of autophagy flux. Moreover, C 60 fullerene regulates a balance of autophagy via BCL-2/Beclin-1 reciprocal expression that could prevent functional disturbances in hippocampus.