Cordycepin alleviates ischaemic brain injury by suppressing microglia‐induced neuroinflammation via regulating the Notch1 signalling pathway

BACKGROUND AND PURPOSE: Microglia undergo rapid activation following ischaemic stroke, and this activation is correlated with patient prognosis. Cordycepin (3'-deoxyadenosine), a natural compound, possesses anti-inflammatory and neuroprotective properties. The specific impact of cordycepin on ischaemic stroke and its underlying mechanisms remain largely under investigated. Here, we explored the potential protective effects of cordycepin against ischaemic stroke through the modulation of microglial activation to elucidate the underlying mechanisms involved. EXPERIMENTAL APPROACH: In vivo, ischaemic stroke was induced in male mice using middle cerebral artery occlusion (MCAO). Sensorimotor and cognitive functions, neuroinflammation and microglia activation were examined. In vitro, a cell model of ischaemic brain injury was established by oxygen-glucose deprivation in primary cultured microglia. Cordycepin intervention was performed on the cell model to elucidate its effects and underlying mechanism. KEY RESULTS: MCAO mice receiving cordycepin therapy exhibited reduced brain oedema, improved morphological abnormalities, mitigated neurological deficit scores, and ameliorated sensorimotor and cognitive functions. We found that cordycepin suppressed microglial hyperactivation and reduced the expression of proinflammatory factors, thereby inhibiting neuroinflammation after ischaemic stroke. Mechanistically, cordycepin accelerated the lysosomal degradation of the Notch1 intracellular domain (NICD) and subsequently blocked the activation of the Notch1 signalling pathway in microglia. CONCLUSION AND IMPLICATIONS: Cordycepin prevents neuroinflammation in primary cultured microglia and reduces ischaemic brain injury in male mice. These findings elucidate a potential molecular mechanism underlying the action of cordycepin, indicating its potential as a therapeutic candidate for the treatment of ischaemic stroke and other neurological disorders characterised by excessive neuroinflammation.