Resveratrol Improves Memory and Reduces Neuroinflammation in an MPS IIIB Mouse Model

Mucopolysaccharidosis type IIIB (Sanfilippo syndrome type B) is a neurodegenerative lysosomal storage disorder characterized by cognitive decline, behavioral abnormalities, and neuroinflammation, for which no effective central nervous system (CNS)-targeted therapy currently exists. Increasing evidence indicates that inflammatory processes contribute substantially to disease progression. In this study, we evaluated the effects of resveratrol on behavioral outcomes and neuroinflammatory markers in an MPS IIIB mouse model, including both sexes. Behavioral analyses demonstrated anxiety-like behavior and memory impairment in MPS IIIB mice. Resveratrol treatment improved cognitive performance, reduced anxiety-related behavior, and normalized exploratory activity. Premature deaths occurred only in untreated MPS IIIB mice. Hematological and biochemical analyses revealed systemic inflammation, erythropoietic stress, metabolic dysregulation, and altered liver-associated parameters. Diseased mice exhibited leukocytosis, elevated pro-inflammatory immune cell populations, increased globulin concentrations, disturbed glucose and lipid metabolism, and sex-dependent alterations in liver and renal markers. Resveratrol partially normalized these abnormalities and reduced inflammatory and hematological disorders. Peripheral and central inflammatory responses were assessed by measurement of IL-1β, IL-6, and c-Fos levels. MPS IIIB mice displayed widespread neuroinflammation in the hippocampus, cortex, and amygdala, with pronounced sex- and region-dependent differences. Females exhibited stronger inflammatory changes in CA1, CA2, and retrosplenial cortical regions, whereas males showed predominant involvement of CA3, dentate gyrus, and motor cortical areas. Resveratrol reduced pro-inflammatory cytokine production and normalized neuronal hyperactivity, particularly in males. Overall, resveratrol modulated neuroinflammatory markers and improved selected behavioral outcomes in MPS IIIB mice, suggesting its potential to ameliorate CNS-related manifestations of Sanfilippo syndrome.