Exploring the Therapeutic Potential of Aquaporin-4 Modulation in Sepsis: Inhibitors and Facilitators.

Sepsis is a life-threatening syndrome driven by a dysregulated host response to infection and is frequently complicated by sepsis-associated encephalopathy (SAE), which contributes to long-term cognitive and neuropsychiatric sequelae. Despite advances in critical care, effective targeted therapies for SAE remain limited. Aquaporin-4 (AQP4), the predominant astrocytic water channel, plays a central role in cerebral water homeostasis, neuroinflammatory signaling, and blood-brain barrier integrity, suggesting its potential involvement in sepsis-induced cerebral dysfunction and neurorepair processes. Polymicrobial sepsis was induced in C57BL/6J mice using the cecal ligation and puncture (CLP) model. AQP4 activity was pharmacologically modulated through either inhibition or facilitation following sepsis induction. Disease severity was assessed using physiological parameters and a modified murine sepsis score. Neurological outcomes were evaluated through standardized behavioral tests assessing locomotor activity, motor coordination, cognitive performance, and depressive-like behavior. Neuroinflammatory and neuronal changes were examined by immunohistochemical analyses of microglial activation (Iba1), astroglial reactivity (GFAP), neuronal integrity (NeuN), and AQP4 expression. Compared with AQP4 facilitation, pharmacological inhibition of AQP4 was associated with a more favorable clinical recovery profile, reflected by lower sepsis severity scores and a more favorable body weight trajectory during the recovery phase. Behavioral analyses demonstrated preserved cognitive function, enhanced motor coordination, and reduced depressive-like behavior in AQP4 inhibitor-treated mice compared with animals receiving AQP4 facilitation. At the histological level, the inhibitor-treated group showed lower microglial and astroglial activation and better preservation of neuronal markers than the facilitator-treated group, whereas AQP4 facilitation exacerbated neuroinflammatory responses and neuronal alterations. These findings highlight a dual, context-dependent role of AQP4 in sepsis-associated cerebral dysfunction. These findings suggest that AQP4 modulation influences sepsis-associated cerebral dysfunction in a context-dependent manner. Within our experimental design, AQP4 facilitation was associated with worse outcomes, whereas AQP4 inhibition was associated with a comparatively more favorable neurobehavioral and histological profile.