Ganaxolone as a promising therapeutic agent for Alzheimer's disease: signaling pathways and mechanistic insights-a narrative review.

Alzheimer’s disease (AD) is a relentless neurodegenerative disorder characterized by progressive cognitive decline, memory loss, and synaptic failure. Its complex pathology involves amyloid-β plaque accumulation, tau hyperphosphorylation, chronic neuroinflammation, and oxidative stress hallmarks that drive neuronal dysfunction and death. Despite decades of research, current therapies deliver only modest symptomatic relief, underscoring the urgency for innovative strategies. Drug repurposing has emerged as a promising shortcut in this search, offering accelerated development timelines and established safety profiles. Ganaxolone (GNX), a synthetic analogue of the neurosteroid allopregnanolone and FDA-approved for epilepsy, has recently garnered attention for its multi-target potential in AD. Beyond its classical role in enhancing GABA type A receptor–mediated inhibition to restore the excitatory-inhibitory balance, Ganaxolone attenuates neuroinflammation by suppressing NLRP3 inflammasome activation and modulating Toll-like receptor–dependent signaling. Moreover, it engages critical neuroprotective cascades, including the PI3K/AKT/GSK-3β axis, thereby mitigating tau pathology, stabilizing synaptic networks, and reducing neuronal loss. By converging on neurotransmission, inflammatory control, and pro-survival signaling, Ganaxolone exemplifies a next-generation, multi-target therapeutic candidate for AD, bridging molecular mechanisms with translational promise.