Targeting Emerging Pathogenic Mechanisms by Natural Molecules as Potential Therapeutics for Neurodegenerative Diseases.

Natural molecules with favorable safety profile and broad pharmacological activities have shown great promise in the treatment of various neurodegenerative diseases (NDDs). Current studies applying natural molecules against NDDs mainly focus on well-recognized conventional pathogenesis, such as toxic protein aggregation, oxidative stress, and neuroinflammation. However, accumulating evidence reveals that some underlying pathogenic mechanisms are involved earlier and more deeply in the occurrence and development of NDDs, such as ferroptosis, energy metabolism disorders, autophagy-lysosomal dysfunction, endoplasmic reticulum stress, and gut dysbiosis. Therefore, determining whether natural molecules can play therapeutic roles in these emerging pathogenic mechanisms will help clarify the actual targets of natural molecules and their future clinical translation. Furthermore, how to overcome the inability of most poorly water-soluble natural molecules to cross the blood-brain barrier is also critical for effective NDD treatment. This review summarizes emerging pathogenic mechanisms targeted by natural molecules for NDD treatment, proposes nanocarrier-based drug delivery and intranasal administration to enhance the intracerebral bioavailability of natural molecules, and summarizes the current state of clinical research on natural product-based therapeutics.