The PDGFBB-PDGFRβ pathway and Laminins in pericytes are involved in the temporal change of AQP4 polarity during Epileptic Pathogenesis

Objective: To investigate the temporal changes in AQP4 polarity and pericyte vascularity during the pathological progression of epilepsy, with the goal of identifying potential drug targets or regulatory strategies to delay epilepsy progression and inhibit its onset. Methods: A rat model of chronic epilepsy was established via intraperitoneal injection of pilocarpine. The polarity of AQP4 and the vascular coverage of pericytes were assessed using immunofluorescence. The effects of pharmacological modulation of AQP4 polarity distribution on PTZ-induced seizures were observed. The molecular mechanisms mediating the polar distribution of AQP4 in pericytes were explored through Transwell co-culture and transcriptomics and validated at the cellular protein expression level. Immunofluorescence was employed to examine changes in the mediating molecules during the progression of epilepsy. Additionally, ELISA was used to measure the levels of PDGF-BB in serum and cerebrospinal fluid during the pathological process of epilepsy. Results: The polar distribution of AQP4 and the perivascular localization of pericytes increased rapidly after epileptic model establishment but gradually decreased, reaching their lowest levels in epileptic animals. Trifluoperazine inhibited the acute redistribution of AQP4 and reduced the latency and duration of PTZ-induced seizures, alleviated brain edema. Pericytes did not affect dystrophin-associated protein (DAP) complex components (e.g., α-syntrophin, β-dystroglycan, dystrophin, and agrin) in astrocytes compared to endothelial cells. However, astrocytes significantly enhanced pericyte-derived laminin expression. During epilepsy progression, LAMA1 and LAMA2 expression initially increased and then declined. The levels of PDGF-BB in serum and cerebrospinal fluid gradually decreased after model establishment, reaching their lowest point during epilepsy. Conclusion: The polar distribution of AQP4 plays a crucial role in the development of epilepsy. During the pathological process, AQP4 polarity is largely influenced by pericyte vascular coverage. Key regulators, such as laminins (e.g., LAMA1) and PDGF-BB, are critical for maintaining AQP4 polarity, delaying epileptic pathology, and inhibiting epileptogenesis.