Targeting PKC/NF-κB/NLRP3-driven NcRNA neuroinflammatory crosstalk by condensed tannins in global cerebral ischemia.

PKC-NF-κB-NLRP3 inflammasome axis and its non-coding RNA (ncRNA) regulatory network triggers robust innate immune activation and neuroinflammation, culminating in neuronal apoptosis and death during Global cerebral ischemia (GCI). The present mechanistic overview illustrates how condensed and hydrolysable tannins, along with related polyphenols, modulate such regulatory network to confer neuroprotection. Ischemia-associated danger signals activate Toll-like receptor-2 (TLR2) through di/tri-acylated lipopolysaccharides, engaging MyD88 and TRAF6 to stimulate protein kinase C (PKC). PKC activation promotes nuclear factor-κB (NF-κB) signaling, leading to interleukin-1β (IL-1β) production and priming of the NLRP3 inflammasome. Subsequent caspase-1 activation drives neuroinflammation and neuronal apoptosis, ultimately resulting in neuronal death. Compounds such as tannic acid, punicalagin, corilagin, pedunculagin, chebulagic acid, chebulinic acid, castalagin, and epigallocatechin gallate (EGCG) suppress NF-κB/IL-1β signaling, while tellimagrandin II, procyanidin C1/B2, paeoniflorin gallate, rosmarinic acid, and savinin directly inhibit NLRP3 activation. Additional phytochemicals, including baicalin and carnosic acid, attenuate upstream PKC signaling. Crucially, these effects are fine-tuned by ncRNAs: miR-146a and miR-155/lncRNA TUG1 regulate NF-κB activity, miR-124 and miR-223 constrain PKC and NLRP3 signaling, and lncRNA NEAT1 modulates caspase-1 activation. Collectively, the integrated suppression of PKC/NF-κB/NLRP3-ncRNA neuroinflammatory signaling by tannins limits inflammasome activation, reduces neuronal apoptosis, and mitigates ischemia-induced neuronal loss. This framework underscores tannins as promising multi-target neuroprotective agents for GCI.