Targeting PPAR Signaling for Neurovascular Protection: Advances in Natural Product-Based Therapeutics.

Central nervous system diseases such as ischemic stroke, cerebral hemorrhage and Alzheimer's disease have high fatality and disability rate. Their common pathological mechanisms involve neuroinflammation, oxidative stress, mitochondrial dysfunction and blood-brain barrier damage. As a ligand-dependent nuclear transcription factor, peroxisome proliferator activated receptor (PPARs) plays a key role in lipid metabolism, energy homeostasis and inflammation regulation. In particular, PPAR-γ shows significant neurovascular protective effect through multiple signaling axes such as NF-κB, Nrf2 and AMP-activated protein kinase (AMPK). In recent years, a large number of studies have confirmed that a variety of natural products (e.g., flavonoids, phenolic acids, glycosides and triterpenes) can activate or regulate the PPAR pathway, mediate anti-inflammatory, antioxidant, prevent blood-brain barrier damage and promote neurotrophic factor expression, thereby improving the pathological phenotype of ischemic or degenerative encephalopathy. In addition, some components (such as Stevioside, Catalpol, Morin, etc.) have shown potential PPAR regulatory ability, but lack direct validation in encephalopathy models, and are worth further exploration. In conclusion, natural products targeting PPAR signal have the comprehensive advantages of multiple pathways and multiple targets, which represent an important direction for the intervention of cerebrovascular diseases. In the future, we should strengthen the verification of "component pathway phenotype" association, combine multi-omics and structural optimization strategies, so as to promote the development of natural product PPAR modulators to precision and transformation applications.