Inhibiting PI3K/Akt-Signaling Pathway Improves Neurobehavior Changes in Anti-NMDAR Encephalitis Mice by Ameliorating Blood-Brain Barrier Disruption and Neuronal Damage
The disruption of the blood-brain barrier (BBB) is believed to play a role in the progression of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, though the underlying mechanisms remain unclear. Recent studies have implicated the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in the regulation of the BBB in various diseases. This study aimed to investigate the mechanism of BBB damage and associated neurobehavioral changes in anti-NMDAR encephalitis mice. Female C57BL/6J mice were actively immunized to create an anti-NMDAR encephalitis model, allowing for the assessment of neurobehavioral deficits. To explore the potential mechanisms involved, the PI3K inhibitor LY294002 (8 mg/kg) and the PI3K agonist Recilisib (10 mg/kg) were administered via intraperitoneal injection.
Mice with anti-NMDAR encephalitis exhibited neurological impairments, increased BBB permeability, disrupted endothelial tight junctions (TJs), and decreased expression of TJ-related proteins zonula occludens-1 (ZO-1) and Claudin-5. However, treatment with the PI3K inhibitor significantly reduced the levels of phosphorylated PI3K (p-PI3K) and Akt (p-Akt), improved neurobehavioral function, restored BBB integrity, and upregulated the expression of ZO-1 and Claudin-5. Furthermore, PI3K inhibition reversed the reduction of NMDAR NR1 subunits in hippocampal neuron membranes, which mitigated the loss of neuron-specific nucleoprotein (NeuN) and microtubule-associated protein 2 (MAP2). In contrast, administration of the PI3K agonist Recilisib tended to worsen BBB disruption and neurological deficits.
These findings suggest that the activation of the PI3K/Akt pathway, along with alterations in TJ-related proteins like ZO-1 and Claudin-5, is closely linked to BBB disruption and neurobehavioral changes in anti-NMDAR encephalitis mice. PI3K inhibition appears to attenuate BBB damage and neuronal injury, thereby improving neurobehavioral outcomes.