Vascular dementia (VaD) is the second most common form of dementia after Alzheimer's disease (AD) and is unique in that its progression can be slowed through prevention and treatment (Morgan and Mc Auley, 2024). Globally, over 15 million people suffer from impairments in orientation, memory, or cognitive function due to VaD (Rundek et al., 2022). The etiology of VaD is complex, often involving a combination of vascular pathological changes and cerebral hemodynamic abnormalities. Existing evidence suggests that chronic cerebral hypoperfusion (CCH) is one of the key drivers of VaD onset and progression (Rajeev et al., 2023). CCH promotes neurodegenerative changes and the development of AD-like pathology through multiple mechanisms, including oxidative stress, synaptic dysfunction, neuronal loss, and neuroinflammation (Tian et al., 2022; Rajeev et al., 2022). The impact of these pathological changes extends beyond severely impairing patients' quality of life, also creating a major economic and healthcare burden for society. However, conventional therapeutic interventions for VaD remain limited in their efficacy. Therefore, a deeper understanding of the molecular biology underlying VaD holds promise for providing new therapeutic strategies for its recovery.

As the primary innate immune cells in the central nervous system (CNS), microglia play a crucial role in continuously monitoring changes in the brain microenvironment under physiological conditions and rapidly responding under pathological conditions (Lepiarz-Raba et al., 2023; Lima et al., 2022). In neurodegenerative diseases such as Parkinson's disease and AD, the overactivation of microglia, especially the classical activation phenotype (M1 type), has been confirmed as a key driver of disease progression (Thiankhaw et al., 2022; Munro et al., 2024). Similarly, after CCH, microglia exhibited significant functional changes, namely, the sustained activation of M1-type microglia (Pang et al., 2023). This activation triggers a series of homeostatic disturbances, including chronic neuroinflammation, reduced synaptic plasticity, and neuronal degeneration and death (Yang et al., 2022). However, during the recovery phase, M1 microglia can transition into M2 microglia (alternative activated phenotype), which suppress neuroinflammation and promote neuronal repair by releasing IL-10 and TGF-β (Poh et al., 2021). Recent studies have shown that the nucleotide oligomerization domain (NOD)-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome plays a critical role in various neurological diseases and is closely linked to the activation of M1-type microglia and pyroptosis (Poh et al., 2022; Li et al., 2020). In contrast, pharmacological interventions that inhibit the NLRP3 inflammasome can restore the M1/M2 microglial balance and alleviate neuroinflammation and neurological deficits (Su et al., 2020; Ma et al., 2020). However, most of these drugs are associated with toxicity or lack specificity. Therefore, developing a safe and effective drug to inhibit NLRP3 inflammasome activation may provide a promising therapeutic strategy for cognitive recovery following CCH.

Extensive research has shown that CNS regulates immune-inflammatory responses and learning and memory processes through the secretion of neuropeptides (Wang et al., 2022; Guo et al., 2024a; Guo et al., 2024b). Among these, Orexin A is a neuropeptide produced in the lateral hypothalamus, capable of crossing the blood-brain barrier (BBB) via simple diffusion. It binds to Orexin receptors −1 (OXR1) and − 2 (OXR2) and participates in various physiological activities, particularly playing a crucial role in regulating the sleep-wake cycle, cellular metabolism, and stress responses. Recent studies have revealed the significant neuroprotective effects of Orexin A in neuroinflammation and neuronal injury. For instance, in AD and sepsis-associated encephalopathy, Orexin A alleviates motor and cognitive dysfunction by inhibiting oxidative stress and neuroinflammation (Guo et al., 2024b). Additionally, reduced levels of Orexin A and its receptors in cerebrospinal fluid are closely linked to BBB damage and elevated neurodegenerative biomarkers, which may accelerate the progression of AD (Guo et al., 2023; Nehra et al., 2025). Notably, Orexin A can also enhance the anti-inflammatory, antioxidant, and sleep-regulating effects of melatonin, maintaining BBB integrity and preventing age-related cognitive decline (Liu et al., 2017). These findings offer new perspectives on the potential use of Orexin A as a therapeutic strategy for neurodegenerative diseases. Recent research suggests that in diabetes-related vascular injury models, Orexin A reduces high glucose-induced ROS accumulation and NLRP3 inflammasome activation (Zhang et al., 2019), although the underlying mechanisms and functional correlations remain to be further clarified. Building on these findings, we propose that Orexin A alleviates neuroinflammation and cognitive dysfunction caused by CCH by inhibiting NLRP3 inflammasome activation and promoting the transition of M1-type microglia to M2-type microglia.

This study seeks to comprehensively explore the role of Orexin A and its underlying mechanisms in cognitive dysfunction in CCH rats, utilizing both in vitro and in vivo approaches. We aim to provide preclinical evidence supporting Orexin A as a potential therapeutic candidate for VaD.