The therapeutic effects and mechanisms of glucagon-like peptide-1 receptor agonists in neurocognitive disorders
Junchen Si, Kai Yu, Jiheng Hao, Jiyue Wang, Liyong Zhang
Abstract
Chronic cerebral hypoperfusion (CCH) represents a key pathogenic contributor to neurocognitive disorders. It can lead to multifaceted pathological alterations including neuroinflammation, neuronal apoptosis, blood-brain barrier disruption, synaptic plasticity deficits, and mitochondrial dysfunction. The glucagon-like peptide-1 receptor (GLP-1R), ubiquitously expressed across multiple organ systems, exerts neuroprotective effects by maintaining intracellular homeostasis and mitigating neuronal damage triggered by oxidative stress, inflammatory cascades, apoptotic signaling, and ischemic insults. Furthermore, GLP-1R activity is modulated by gut microbiota composition and short-chain fatty acid abundance, implicating the gut-brain axis in its regulatory influence on neurological function. This review systematically examines the pathophysiological mechanisms underlying CCH and highlights the therapeutic potential of GLP-1R activation. Specifically, GLP-1R-targeted interventions attenuate hypoperfusion-induced damage through pleiotropic pathways and gut-brain crosstalk, thereby offering novel perspectives for advancing both fundamental research and clinical management of neurocognitive disorders.