According to the latest research, stroke is the second leading cause of death worldwide (Feigin et al., 2022). Approximately 80% of strokes are ischemic, caused by arterial thrombosis or embolism (Fluri et al., 2015). The current dominant approach to treating ischemic stroke involves either intravenous administration of recombinant tissue plasminogen activator to dissolve the clot or the use of mechanical thrombectomy to restore cerebral blood flow (Jin et al., 2018). Despite significant advances in reperfusion strategies, patients remain at risk of cerebral ischemia/reperfusion injury due to the narrow therapeutic window. The pathogenesis of CIRI is extremely complex and includes factors such as oxidative stress, neuroinflammation, blood-brain barrier (BBB) disruption, glutamate/neurotoxin release, and calcium overload. Current therapeutic approaches focus primarily on neuroprotection, anti-inflammation, and vascular protection (Zhang et al., 2023). The efficacy of these treatments is limited, highlighting the urgent need for the development of innovative therapeutic interventions.

Astrocytes, characterized by their star-shaped morphology, are a type of neural cell derived from the ectodermal neuroepithelium, accounting for about half of all brain cells. Each astrocyte occupies a unique spatial domain, covering the central nervous system (CNS) continuously and non-overlapping (Mahmoud et al., 2019). In the mammalian brain, astrocytes are differentiated into distinct subpopulations, such as the radial astrocytes surrounding the ventricles, protoplasmic astrocytes located within the gray matter, and fibrous astrocytes present in the white matter (Bihlmaier et al., 2023). The roles of astrocytes in the CNS are multifaceted and essential for neural function. They supply neurons with nutrients, remove metabolic waste via dual connections to neurons and blood vessels, regulate cerebral blood flow, and form the BBB. They also maintain the water-electrolyte balance in brain tissue through their ion channels and aquaporin-4 (AQP4). Furthermore, they manage the concentration of neurotransmitters surrounding synapses, vital for synaptic transmission and preventing the neuronal damage caused by excitotoxicity. In essence, astrocytes are responsible for all CNS physiological processes except for electron conduction, making them indispensable for neural health and function (Cooper et al., 2018).

Under physiological conditions, astrocytes maintain a quiescent state to preserve CNS homeostasis (Allen and Lyons, 2018). However, in response to injury, they switch from a resting to a reactive state. Activated astrocyte presence is heightened in ischemic brains, contrasting with healthy ones (Datta et al., 2013), highlighting the potential involvement of activated astrocytes in the pathogenesis of CIRI. Therefore, targeting astrocytes through various pathways is pivotal for advancing CIRI therapies. In summary, this review aims to investigate potential therapeutic strategies based on the mechanisms of astrocytes in CIRI, aiming to stimulate further research in this field.

To comprehensively review the major pathological processes, signaling pathways, and anti-inflammatory effects of drugs and inhibitors targeting astrocytes in CIRI, we performed an extensive search of the PubMed database from 2012 to 2023, using specific keywords such as “astrocytes”, “cerebral ischemia-reperfusion injury”, “excitotoxicity”, “inflammation”, “oxidative stress”, “edema”, “blood-brain barrier”, and “autophagy”. From the initial pool of 306 articles, 39 were excluded due to their classification as reviews, commentaries, retracted publications, or unavailable online. Furthermore, 183 studies that lacked relevance to astrocytes, cerebral ischemia-reperfusion injury, or signaling pathways were excluded from the analysis. Ultimately, a total of 84 references were considered appropriate for inclusion in our analysis.