AimsThe main purpose was to verify the potent capacity of Neurotropin (R) against neuronal damage in hippocampus and to explore its underlying mechanisms. MethodsHT22 cells were treated with 40mol/L A(25-35) in the presence of various concentrations of Neurotropin (R) or in its absence. The cell viability was assessed with a CCK-8 assay, and flow cytometry was used to measure cell apoptosis, intracellular ROS levels, and mitochondrial membrane potential. A plaques were examined by Bielschowsky silver staining, and the activities of antioxidants were detected in hippocampus of APP/PS1 mice after Neurotropin (R) treatment. The expression of proteins, including HIF-1, Bcl-2, Bax, and MAPKs signaling molecules was evaluated by Western blot. ResultsNeurotropin (R) significantly reversed the cell injury induced by A(25-35) through increasing cell viability and mitochondrial membrane potential, decreasing intracellular ROS and cell apoptosis of HT22 cells (P<.05). Furthermore, Neurotropin (R) markedly reduced the formation of A plaques and upregulated the activities of antioxidants (P<.05). Additionally, the protein expression of HIF-1, p-ERK1/2, p-JNK, and p-P38 was significantly inhibited in hippocampus of APP/PS1 mice. ConclusionsNeurotropin (R) exhibited a potent neuroprotective effect on inhibiting A-induced oxidative damage and alleviating A deposition in hippocampus via modulation of HIF-1/MAPK signaling pathway.