Neurochemical Mechanisms Underlying Tanshinone-Mediated Neuroprotection and Formulation Strategies in Cerebral...

Cerebral ischemia/reperfusion (I/R) injury represents a major pathological component of ischemic stroke and is driven by a complex cascade of neurochemical and molecular events, including excitotoxicity, oxidative and nitrosative stress, neuroinflammation, blood-brain barrier (BBB) disruption, mitochondrial dysfunction, and regulated cell death pathways such as apoptosis and ferroptosis. Tanshinones, a class of lipophilic diterpenoid quinones derived from Salvia miltiorrhiza (Danshen), have attracted increasing attention as multi-target neuroprotective agents in experimental models of cerebral I/R. Accumulating evidence demonstrates that major tanshinones, including tanshinone I, tanshinone IIA, tanshinone IIB, cryptotanshinone, and dihydrotanshinone I, modulate key neurochemical processes underlying cerebral I/R injury, including redox homeostasis, inflammatory signaling cascades, mitochondrial function, BBB integrity, and cell death regulatory networks. In parallel, recent advances in formulation strategies, including chemically modified derivatives (e.g., sodium tanshinone IIA sulfonate and the cryptotanshinone derivative DST-3), as well as microemulsions, liposomes, and nanoparticle-based delivery systems, have markedly improved aqueous solubility, pharmacokinetic behavior, and brain bioavailability of tanshinones, thereby potentially enhancing their neuroprotective effects in experimental models. This review comprehensively summarizes current evidence on the neurochemical and molecular mechanisms of tanshinones and their formulations in cerebral I/R injury, with an emphasis on signaling pathway modulation, redox regulation, mitochondrial protection, and formulation-driven improvements in brain delivery, and discusses remaining mechanistic challenges and future research directions.