Central neuropeptides as key modulators of astrocyte function in neurodegenerative and neuropsychiatric disorders

Abstract

Central neuropeptides are small proteins or peptides primarily produced and released by neurons. They act as neurotransmitters, neuromodulators, and neuroregulators within the central nervous system (CNS). Numerous studies have demonstrated that these neuropeptides play a role in both normal neurophysiological processes and pathological conditions. Astrocytes, the most abundant glial cells in the CNS, are crucial for maintaining brain function and health, and they contribute significantly to the development of CNS disorders-especially neurodegenerative and neuropsychiatric diseases. Previous research suggests that central neuropeptides influence astrocyte activity by regulating their proliferation, morphology, and secretory functions, among other aspects, thereby impacting the pathogenesis of these disorders. Based on preclinical evidence, both central neuropeptides and their receptors are emerging as promising targets for treating CNS disorders. In this review, we examine the effects of select central neuropeptides-including neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), pituitary adenylate cyclase-activating polypeptide (PACAP), cholecystokinin (CCK), corticotropin-releasing hormone (CRH), angiotensin (Ang), oxytocin (OXT), orexin (OX)/hypocretin (HCRT), and glucagon-like peptide-1 (GLP-1)-on astrocyte state transitions. Our aim is to provide novel insights that could inform the clinical treatment of neurodegenerative and neuropsychiatric disorders.

Keywords: Astrocyte; Central nervous system; Neurodegenerative disorders; Neuropeptide; Neuropsychiatric disorders.

Fig. 1

Central neuropeptides regulate astrocyte state transitions in neurodegenerative and neuropsychiatric disorders. The pathogenesis of neurodegenerative and neuropsychiatric disorders is multifaceted, involving factors such as abnormal microglial activation, neurotransmitter dysregulation, neurodegeneration, demyelination, plaque aggregation and fibrillary tangles, vascular pathology, and chronic stress. These factors ultimately alter astrocyte morphology, leading to a cascade of pathological changes. Central neuropeptides are small proteins or peptides primarily synthesized and secreted by neurons within the CNS. By binding to specific G protein-coupled receptors (GPCRs), they modulate neuronal activity and participate in a wide range of physiological processes. Numerous studies have demonstrated that several central neuropeptides—including neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), pituitary adenylate cyclase-activating polypeptide (PACAP), cholecystokinin (CCK), corticotropin-releasing hormone (CRH), angiotensin (Ang), oxytocin (OXT), orexin (OX)/hypocretin (HCRT), and glucagon-like peptide-1 (GLP-1)—influence the onset and progression of these disorders by regulating the state transitions of astrocytes. [Created with BioRender.com]

Fig. 2

Diverse effects of central neuropeptides on astrocytes via specific GPCRs. Astrocytes express a wide array of neuropeptide receptors, enabling central neuropeptides to finely regulate their function. For example, NPY, acting through Y1R, inhibits the release of iNOS and NO and reduces ROS production, while also stimulating its own secretion via mGluR activation. VIP and PACAP, through PAC1 receptors, promote the synthesis and release of NT-3, glutathione (GSH), ADNP, ADNF, and MIP, thereby providing neuroprotection; additionally, PACAP enhances ERK1/2 phosphorylation in a cAMP-dependent manner, leading to astrocyte proliferation and activation of GFAP gene expression. In contrast, Ang II, via AT1R, induces the release of inflammatory factors, suppresses GSH production, increases ROS generation, and triggers ferroptosis, while also promoting astrocyte growth through the activation of Src, Pyk2, and ERK1/2, and contributing to neuropsychiatric disorders via the β-arrestin2 pathway. ACE2 converts Ang II into Ang (1–7), which activates MasR to exert neuroprotective effects by downregulating p38MAPK-mediated inflammation, reducing inflammatory factor levels, and modulating astrocyte-mediated neuroinflammation through the lncRNA SNHG14/miR-223-3p/NLRP3 pathway. Moreover, orexin, acting through OXR, increases cAMP production and ERK1/2 phosphorylation while inhibiting NF-κB and MAPK pathways, thereby reducing astrocyte activation and apoptosis and alleviating neuroinflammation. GLP-1, via GLP-1R, suppresses the secretion of MMP, MCP-1, and CXCL-1, and lowers VEGF-A levels by inhibiting JAK2/STAT3 signaling to maintain BBB integrity. CCK, through CCKBR and mGluR5, elevates intracellular Ca²⁺ and ATP release, which regulates synaptic plasticity. OXT, via OXTR, inhibits the release of the NLRP3 inflammasome, thus modulating neuroinflammation, while CRH, acting through CRHR1, suppresses CXCL5 secretion by astrocytes, inhibiting synapse formation in hippocampal neurons. Finally, UCN2 promotes hippocampal synapse formation by inducing astrocytes to secrete NGF. [Created with BioRender.com]