Neuropharmacological Insights into Glutamate Homeostasis in Post-stroke Depression Regulated by Astrocytes

Abstract: Stroke patients often experience multiple functional impairments, including difficulties with swallowing, speech, cognition, and motor skills, which can lead to symptoms such as emotional distress and cognitive deficits. Approximately one-third of post-stroke patients may develop poststroke depression (PSD), significantly hindering recovery and increasing the burden on families and healthcare systems. This review focuses on the underlying mechanisms of PSD, emphasizing the glutamatergic hypothesis. As the primary excitatory neurotransmitter, glutamate plays a central role in neural-signaling. However, excessive glutamate accumulation can cause neuronal damage, making it a key mechanism in the development of PSD. Astrocytes are crucial for maintaining glutamate homeostasis by clearing excess glutamate and regulating its synthesis and transport, thereby preventing excitotoxicity. Following a stroke, astrocytic dysfunction—characterized by overactivation and inflammatory responses—can exacerbate neuronal injury and further contribute to the emergence of depressive symptoms. This article also highlights potential therapeutic approaches targeting the glutamatergic system, such as NMDA receptor antagonists, AMPA receptor antagonists, and modulators of glutamate transporters, as well as other types (e.g., Chinese medicine, herbal medicine, and targeted pathways acting on neurons). These strategies offer promising avenues for PSD treatment. Future studies should delve deeper into the molecular mechanisms by which astrocytes regulate glutamate homeostasis, providing a robust foundation for the precision treatment of post-stroke depression.