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PK2/PKRs pathway is involved in the protective effect of artemisinin against trimethyltin chloride-induced hippocampal injury

Yuting Gao,Wenli Liao,Ruyi Zhang,Yining Lei,Tao Chen,Lingling Wu,Manqin Li,Xinran Liu,Fei Cai

Neuroinflammation is one of the important mechanisms of trimethyltin chloride (TMT) central neurotoxicity . Artemisinin (ARS) is a well-known antimalarial drug that also has significant anti-inflammatory effects. Prokineticin 2 (PK2) is a small molecule secreted protein that is widely expressed in the nervous system and plays a key role in the development of neuroinflammation. However, it remains unclear whether ARS can ameliorate neuroinflammation caused by TMT and whether PK2/PKRs signaling pathway plays a part in it. In this research, male Balb/c mice were administered TMT (2.8 mg/kg, i.p.) followed by immunohistochemistry to assess the expression of PK2, PKR1, and PKR2 proteins in the hippocampus. Network pharmacology was used to predict the intersection targets of ARS, central nervous system(CNS) injury and TMT. The neurobehavior of mice was evaluated by behavioral scores. Histopathological damage of the hippocampus was evaluated by HE, Nissl and Electron microscopy . Western blotting was used to identify the expression of synapse-related proteins (PSD95, SYN1, Synaptophysin), PK system-related proteins (PK2, PKR1, PKR2), and inflammation-related proteins (TNF-α, NF-κB p65). Immunohistochemistry showed that TMT resulted in elevated PK2 and PKR2 protein expression in the CA2 and CA3 regions of the hippocampus in mice, while PKR1 protein was not significantly altered. Network pharmacology showed that PK2 could interact with the intersectional targets of ARS, CNS injury, and TMT. ARS remarkably attenuated TMT-induced seizures and hippocampal histological damage. Further studies demonstrated that ARS treatment attenuated TMT-induced hippocampal ultrastructural damage, possibly by increasing the number of rough endoplasmic reticulum and mitochondria as well as upregulating the levels of synapse-associated proteins (PSD95, SYN1, Synaptophysin). Western blotting results revealed that ARS downregulated TMT-induced TNF-α and NF-κB p65 protein levels. In addition, ARS also decreased TMT-induced protein expression of PK2 and PKR2 in the mouse hippocampus, but had no significant effect on PKR1 protein expression. Our results suggested that ARS ameliorated TMT-induced abnormal neural behavior and hippocampal injury, which may be achieved by regulating PK2/PKRs inflammatory pathway and ameliorating synaptic injury. Therefore, we suggest that PK2/PKRs pathway may be involved in TMT neurotoxicity and ARS may be a promising drug that can relieve TMT neurotoxicity.