Cerebral ischemia injury, the leading cause of morbidity and mortality worldwide, initiates sequential molecular and cellular pathologies that underlie ischemic encephalopathy (IE), such as ischemic stroke, Alzheimer disease (AD), Parkinson’s disease (PD), epilepsy, etc. Targeted therapeutic treatments are urgently needed to tackle the pathological processes implicated in these neurological diseases. Recently, accumulating studies demonstrate that microRNA-124 (miR-124), the most abundant miRNA in brain tissue, is aberrant in peripheral blood and brain vascular endothelial cells following cerebral ischemia. Importantly, miR-124 regulates a variety of pathophysiological processes that are involved in the pathogenesis of age-related IE. However, the role of miR-124 has not been systematically illustrated. Paradoxically, miR-124 exerts beneficial effects in the age-related IE via regulating autophagy, neuroinflammation, oxidative stress, neuronal excitability, neurodifferentiation, Aβ deposition, and hyperphosphorylation of tau protein, while it may play a dual role via regulating apoptosis and exerts detrimental effects on synaptic plasticity and axonal growth. In the present review, we thus focus on the paradoxical roles of miR-124 in age-related IE, as well as the underlying mechanisms. A great understanding of the effects of miR-124 on the hypoxic–ischemic brain will open new avenues for therapeutic approaches to protect against cerebral ischemia injury.

Objective: NOD-like receptor protein 3 (NLRP3)-mediated pyroptosis is pivotal in the pathological development of cerebral ischemia/reperfusion injury (CIRI). Although previous research has shown that electroacupuncture (EA) can alleviate CIRI through sirtuin-1 (SIRT1), the mechanism has not been well elucidated. Our study aimed to clarify whether the neuroprotective functions of EA are related to the reduction in NLRP3-mediated pyroptosis through the SIRT1 pathway. Materials and Methods: Rats received daily pretreatment with EA for 5 consecutive days before undergoing middle cerebral artery occlusion surgery. The Longa score was used to assess neurologic function. Infarct volume and morphological alterations were analyzed using 2,3,5-triphenyltetrazolium chloride and hematoxylin and eosin staining. In addition, neuronal pyroptosis was identified by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling/caspase-1 and neuronal nuclear antigen/caspase-1 immunofluorescence double staining. Levels of expression of pyroptosis markers were assessed by Western blotting and enzyme-linked immunosorbent assay. Results: EA improved deficits in neurologic function and minimized cerebral infarct volume. Mechanistically, a number of neuronal pyroptotic cells and protein levels of NLRP3, apoptosis-associated speck-like protein containing a CARD, and gasdermin D in the cerebral cortex were markedly reduced by EA treatment, and conversely, SIRT1 levels were increased. Notably, the specific SIRT1 inhibitor, EX527, reversed the effects of EA. Conclusions: EA potentially exerts a neuroprotective effect against CIRI through the SIRT1 pathway in NLRP3-mediated pyroptosis.