Brain-derived neurotrophic factor via TRPM2 inhibition reduces amyloid-beta-mediated increases of apoptosis and mitochondrial oxidative neurotoxicity in neuronal cells.

Brain-derived neurotrophic factor (BDNF) has particular importance in the modulation of Alzheimer's disease (AD)-related pathologies such as apoptosis and mitochondrial reactive oxygen species (mROS). The cation channel, transient receptor potential melastatin 2 (TRPM2), stimulation is important for the generation of AD-related pathologies. Antioxidant treatments through the inhibition of TRPM2 play an essential role in the inhibition of Ca²⁺ entry, mROS, and apoptosis changes in the SH-SY5Y neuronal cells. However, the effects of antioxidant and antiapoptotic roles of BDNF have not yet been studied in SH-SY5Y treated with amyloid-beta (Aβ). The aim of the present study was to investigate the protective action of BDNF via TRPM2 inhibition on the apoptotic and oxidant values in Aβ-induced SH-SY5Y cells. Five groups of SH-SY5Y cells were established: control, BDNF, Aβ, Aβ + BDNF, and Aβ + TRPM2 channel blockers. The Aβ-induced increases in intracellular Ca2+ and TRPM2 currents were decreased by BDNF and PARP-1 inhibition. The levels of mROS, intracellular ROS, dysfunction of mitochondrial membrane, SH-SY5Y death, apoptosis, and caspases (caspases-3, -8, and - 9) were increased in the cells treated with Aβ, although glutathione (GSH) and glutathione peroxidase (GSH-Px) were decreased by the treatment. However, the levels of these oxidative and apoptotic markers through the increases in GSH and GSH-Px were reduced in the cells by the incubations of BDNF and TRPM2 channel blockers. Finally, it was shown that BDNF protects neuronal cells against Aβ-induced excessive Ca2+ entry, oxidative stress, and apoptotic parameters via inhibiting TRPM2. Treatment with BDNF appears to have the capacity to reduce apoptosis and oxidative stress caused by Aβ through inhibiting TRPM2.