Astrocytes: Therapeutic targets for stroke.

Abstract

Stroke is the leading cause of mortality globally, ultimately leading to severe, lifelong neurological impairments. Patients often suffer from a secondary cascade of damage, including neuroinflammation, cytotoxicity, oxidative stress, and mitochondrial dysfunction. Regrettably, there is a paucity of clinically available therapeutics to address these issues. Emerging evidence underscores the pivotal roles of astrocytes, the most abundant glial cells in the brain, throughout the various stages of ischemic stroke. In this comprehensive review, we initially provide an overview of the fundamental physiological functions of astrocytes in the brain, emphasizing their critical role in modulating neuronal homeostasis, synaptic activity, and blood-brain barrier integrity. We then delve into the growing body of evidence that highlights the functional diversity and heterogeneity of astrocytes in the context of ischemic stroke. Their well-established contributions to energy provision, metabolic regulation, and neurotransmitter homeostasis, as well as their emerging roles in mitochondrial recovery, neuroinflammation regulation, and oxidative stress modulation following ischemic injury, are discussed in detail. We also explore the cellular and molecular mechanisms underpinning these functions, with particular emphasis on recently identified targets within astrocytes that offer promising prospects for therapeutic intervention. In the final section of this review, we offer a detailed overview of the current therapeutic strategies targeting astrocytes in the treatment of ischemic stroke. These astrocyte-targeting strategies are categorized into traditional small-molecule drugs, microRNAs (miRNAs), stem cell-based therapies, cellular reprogramming, hydrogels, and extracellular vesicles. By summarizing the current understanding of astrocyte functions and therapeutic targeting approaches, we aim to highlight the critical roles of astrocytes during and after stroke, particularly in the pathophysiological development in ischemic stroke. We also emphasize promising avenues for novel, astrocyte-targeted therapeutics that could become clinically available options, ultimately improving outcomes for patients with stroke.