BME (CDRI-08) mitigates hypoxia-induced hippocampal neurodegeneration and memory impairment via modulating NMDAR-CREB-BDNF signaling and apoptosis reduction

Abstract

Hypoxia severely compromises memory function by initiating a cascade of pathological events, including heightened oxidative stress, impaired mitochondrial bioenergetics and deregulation of glutamate receptor and apoptosis-related protein expression. Current therapies are often insufficient to adddress the complex neurobiological damage caused by hypoxia, emphasizing the need for integrative therapeutic strategies to mitigate-hypoxia induced damage. Our study explored the potential of Bacopa monnieri extract (BME) especially CDRI-08, in mitigating hippocampal neurodegeneration and memory impairment in a CoCl 2 -induced hypoxia mouse model. We found that the activation of extra-synaptic N-methyl-D-aspartate receptors (NMDR), particularly the GluN2B subunit, combined with the downregulation of the NR2A subunit and scaffolding proteins such as postsynaptic density protein-95 (PSD-95), significantly contributed to the activation of apoptotic signaling cascades. Additionally, the suppression of CREB-BDNF signaling further contributed to synaptic dysfunction, memory deficits, enhanced apoptosis and neuronal cell death in the hippocampus of hypoxia-exposed mice compared to controls. BME, administered either preventively or concurrently, restored the expression of NMDA receptor subunits NR2A and NR2B, reversed the suppression of CREB-BDNF signaling and mitigated hypoxia-induced spatial and recognition memory impairment. Mechanistically, BME achieved this by increasing neuronal plasticity, pyramidal neuron spine density, and dendritic arborization. Furthermore, BME significantly reduced neuronal apoptosis by normalizing the expression of key markers: decreasing pro-apoptotic proteins (Cleaved caspase-3, BAD, BAX, Cyt C) and increasing the anti-apoptotic protein (Bcl-2). These findings validate BME’s role as a potent therapeutic agent for enhancing neuronal density, reducing apoptosis, and promoting synaptic plasticity to counteract hypoxia’s detrimental effects.