Evidence-based evaluation of berberine in neurodegenerative diseases: targeting multiple signaling pathways and modulating neuroinflammation, oxidative stress, and apoptosis

Neurodegenerative diseases (NDs), such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), are characterized by progressive neuronal loss, oxidative stress, mitochondrial dysfunction, and neuroinflammation. Novel neuroprotective drugs are urgently required since existing treatments mainly address symptoms. Berberine (BBR), an isoquinoline alkaloid derived from various medicinal plants, has significant multi-target pharmacological activities. This review demonstrates BBR’s neuroprotective potential by focusing on its role in regulating key cellular signaling pathways and mitigating neurotoxicity. It suppresses pro-inflammatory cytokines, boosts antioxidant defenses, and promotes neuronal survival by controlling the PI3K/Akt, AMPK, MAPK, and Nrf2/HO-1 pathways. Additionally, it also alters mitochondrial dynamics, reduces tau hyperphosphorylation, and inhibits amyloid-β aggregation, thereby mitigating synaptic dysfunction and neuronal death. By inhibiting NF-κB and activating the SIRT1 signaling pathways, it can balance oxidative and inflammatory responses in both in vitro and in vivo. Emerging clinical data suggest that BBR enhances neuronal integrity and cognitive function, despite the current lack of large-scale randomized clinical trials. It may be a viable treatment for controlling and preventing NDs. More clinical research is needed to clarify the pharmacokinetic profile, safety, and synergistic effects of the medication with traditional neuroprotective medications.