The P38MAPK Pathway Mediates the Destruction of the Blood-Brain Barrier in Anti-NMDAR Encephalitis Mice
Dayuan Lao1, Zhuowei Gong1, Taiyan Li1
1Department of Neurology, The First Affiliated Hospital of Guangxi Medical University, #22 Shuangyong Road, Guangxi, Nanning, 530021, China.
Abstract:
The clinical manifestations of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis may be closely related to the integrity of the blood-brain barrier (BBB). The P38 mitogen-activated protein kinase (P38MAPK) pathway plays a protective role in neurodegenerative diseases. However, whether the P38MAPK pathway is involved in the underlying mechanism of tight junction (TJ) protein disruption and neuronal damage has not been elucidated. Therefore, in this study, a mouse model of anti-NMDAR encephalitis was established by active immunization with NMDAR NR1356-385 peptides. The critical pathways of P38MAPK were screened by interaction network and co-enrichment analysis. The role of P38MAPK pathways was investigated by the injection of P38MAPK inhibitor SB203580 (10 mg/kg, i.p.). Compared with the control group, the expression of occludin and zonula occludens (ZO)-1 in NMDAR NR1356-385 group mice was downregulated, and the structure and function of BBB were damaged. However, after the intervention of SB203580, the activation of the P38MAPK was inhibited, the expression of matrix metalloproteinase 9 (MMP9) was reduced, and the function of BBB was improved. Meanwhile, inhibiting the P38MAPK pathway reversed the degradation of NMDAR NR1, while reducing the expression of the glial fibrillary acidic protein (GFAP) and pro-inflammatory factor tumor necrosis factor (TNF-α). It also relieved the damage of neuron-specific nucleus (NeuN), thus alleviating psychobehavioral symptoms. In conclusion, our results suggested that the P38MAPK pathway is involved in BBB destruction and neurobehavioral change in mice with anti-NMDAR encephalitis. Targeting the P38MAPK pathway may be a promising option for the treatment of anti-NMDAR encephalitis.
Insights
The P38 mitogen-activated protein kinase (P38MAPK) pathway contributes to blood-brain barrier damage in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. Inhibiting this pathway improves neurological function and offers a potential treatment strategy.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is associated with blood-brain barrier (BBB) dysfunction.
- The P38 mitogen-activated protein kinase (P38MAPK) pathway is implicated in neuroprotection but its role in NMDAR encephalitis is unclear.
Purpose of the Study:
- To investigate the role of the P38MAPK pathway in BBB disruption and neuronal damage in a mouse model of anti-NMDAR encephalitis.
- To evaluate the therapeutic potential of targeting the P38MAPK pathway.
Main Methods:
- Established a mouse model of anti-NMDAR encephalitis via immunization with NMDAR peptides.
- Utilized interaction network and co-enrichment analysis to identify critical P38MAPK pathways.
- Administered P38MAPK inhibitor SB203580 to assess its effects on BBB integrity, neuronal damage, and behavioral symptoms.
Main Results:
- Anti-NMDAR encephalitis induced BBB damage, evidenced by downregulated tight junction proteins (occludin, ZO-1) and impaired BBB function.
- SB203580 treatment inhibited P38MAPK activation, reduced matrix metalloproteinase 9 (MMP9) expression, and improved BBB function.
- Inhibition of P38MAPK reversed NMDAR degradation, decreased GFAP and TNF-α expression, preserved NeuN, and alleviated psychobehavioral deficits.
Conclusions:
- The P38MAPK pathway is a key mediator of BBB destruction and neurobehavioral changes in anti-NMDAR encephalitis.
- Targeting the P38MAPK pathway presents a promising therapeutic strategy for managing anti-NMDAR encephalitis.
