Upregulated SHP‐2 expression in the epileptogenic zone of temporal lobe epilepsy and various effects of SHP099 treatment on a pilocarpine model

Temporal lobe epilepsy (TLE) is defined as the sporadic occurrence of spontaneous recurrent seizures, and its pathogenesis is complex. SHP‐2 (Src homology 2‐containing protein tyrosine phosphatase 2) is a widely expressed cytosolic tyrosine phosphatase protein that participates in the regulation of inflammation, angiogenesis, gliosis, neurogenesis and apoptosis, suggesting a potential role of SHP‐2 in TLE. Therefore, we investigated the expression patterns of SHP‐2 in the epileptogenic brain tissue of intractable TLE patients and the various effects of treatment with the SHP‐2‐specific inhibitor SHP099 on a pilocarpine model. Western blotting and immunohistochemistry results confirmed that SHP‐2 expression was upregulated in the temporal neocortex of patients with TLE. Double‐labeling experiments revealed that SHP‐2 was highly expressed in neurons, astrocytes, microglia and vascular endothelial cells in the epileptic foci of TLE patients. In the pilocarpine‐induced C57BL/6 mouse model, SHP‐2 upregulation in the hippocampus began one day after status epilepticus, reached a peak at 21 days and then maintained a significantly high level until day 60. Similarly, we found a remarkable increase in SHP‐2 expression at 1, 7, 21 and 60 days post‐SE in the temporal neocortex. In addition, we also showed that SHP099 increased reactive gliosis, the release of IL‐1β, neuronal apoptosis and neuronal loss, while reduced neurogenesis and albumin leakage. Taken together, the increased expression of SHP‐2 in the epileptic zone may be involved in the process of TLE.