Naringin Alleviates Autistic‐Like Behaviors in BTBR Mice Through Cannabinoid Receptor Type 1‐Mediated Restoration of Hippocampal Neurogenesis

ABSTRACT Background Naringin, a flavanone glycoside (naringenin 7‐O‐neohesperidose), exhibits a broad range of pharmacological activities, including neuroprotection. However, its effects on autistic‐like behavior have not been extensively studied. Methods In this investigation, we utilized the autistic BTBR T + tf/J (BTBR) mice to conduct behavioral tests assessing autistic‐like phenotypes. We evaluated hippocampal neurogenesis through immunofluorescence and employed molecular biological techniques, along with RNA sequencing, to elucidate the underlying molecular mechanisms. Results Our findings revealed that the administration of naringin alleviated autism‐associated behaviors in BTBR mice. RNA sequencing analysis indicated that naringin facilitated the recovery of impaired hippocampal neurogenesis in these mice, as evidenced by an increase in doublecortin (DCX)‐positive cells and neuronal progenitor cells (NPCs) in the dentate gyrus (DG). Furthermore, we confirmed that the cannabinoid receptor type‐1 (CB1) plays a role in the therapeutic effects of naringin. Conclusions This research highlights the potential of naringin as a promising treatment option for autism spectrum disorder (ASD) and suggests that targeting hippocampal neurogenesis through the CB1 receptor may be an effective strategy.