Neuroprotection from protein misfolding in cerebral hypoperfusion concurrent with metabolic syndrome. A translational perspective

The authors summarize preclinical findings from rodent models of CCH (BCCAO, 2VO, bilateral common carotid artery ligation) demonstrating that hypoperfusion disrupts protein quality-control mechanisms including the ubiquitin-proteasome system, chaperone-mediated autophagy, and macroautophagy. Multiple neuroprotective agents—gastrodin, Lipoxin A4 methyl ester, baclofen, FAAH inhibitor URB597, melatonin, and endocannabinoid analogs—have shown protective effects in these models by modulating autophagy or proteasomal degradation pathways. The review also highlights WFS1 gene deficiency as a factor linking ER stress, unfolded protein response activation, and tau pathology.