Brain-Derived Neurotrophic Factor and Its Potential Therapeutic Role in Stroke Comorbidities

Figure 1

A schematic diagram depicting the pathogenesis of stroke in neurons. Upon the onset of stroke, reduced oxygen and nutrient supplies rapidly lead to the failure of ATP-dependent Na⁺/K⁺ pumps causing ionic imbalance and cell membrane depolarization, resulting in presynaptic overrelease of neurotransmitters including glutamate into the synaptic cleft. Activation of postsynaptic glutamate receptors AMPAR, NMDAR, and KAR leads to large volume Na⁺ and Ca²⁺ influxes, further cell membrane depolarization of the postsynaptic neuron, and opening of the membrane potential-sensitive VGNCs and VGCCs. This allows even more Na⁺ and Ca²⁺ to flow into the cell which causes cytoplasmic ion overload, protease activation, production of free radicals, caspase activation, and eventually DNA damage and neuronal cell death. Meanwhile, as the BBB is compromised during stroke, immune cells from the blood start to infiltrate the brain to elicit inflammatory responses, such as cytokine release and microglial cell activation, which further exacerbate the brain damage and injury. BBB: blood-brain barrier; AMPAR: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; NMDAR: N-methyl-D-aspartic acid receptor; KAR: kainic acid receptor; VGCC: voltage-gated calcium channel; VGNC: voltage-gated sodium channel.