PNaktide Alleviates Inflammatory Response-induced Neuronal Damage And Behavioral Deficits Via Oxidative Stress Pathwa

Neuroinflammation and oxidative stress are closely related to the etiology and progression of Parkinson’s disease(PD),Alzheimer’s disease(AD)and other neurodegenerative diseases,and are important parts of their pathogenesis.They are inseparable.Neuroinflammation induces the production of reactive oxygen species(ROS),which in turn produces oxidative stress,and ROS is the secondary messenger of inflammatory response and promotes the exacerbation of inflammatory response.Sodium potassium adenosine triphosphatase(Na/K-ATPase),from the P-type ATPase family,is involved in oxidative stress signal amplification.Src,a member of the Src tyrosine kinase family,is involved in various physiological signals of cells,promoting inflammation and oxidative stress.Na/K-ATPase can regulate Src activity by binding to Src and participate in Src cascade activation.PNaktide is a Src kinase inhibitor designed based on the N domain of the binding site of sodium potassium ATPase and Src kinase.It can specifically inhibit the activation of Src kinase by binding to its kinase domain,achieving antioxidant effects.Prior to this,studies have confirmed that its antioxidant capacity can play a role in the inhibition of diseases such as obesity,steatohepatitis,uremic cardiomyopathy,aging,and prostate cancer.However,the role of pNaktide in neurodegenerative diseases and the mechanisms that trigger it are not yet known.In order to explore the role and mechanism of pNaktide in inhibiting a series of pathological processes induced by neuroinflammation and oxidative stress,this study established an animal model of neuroinflammation by intraperitoneal injection of LPS in mice for subsequent research.Randomly grouping mice into CON group,LPS group,pNaktide+LPS group,open field test,rotarod test,O maze,and Y maze behavioral results showed that pNaktide can improve learning and memory disorders,increased anxiety,and motor disorders induced by LPS.Further research results such as oxidative stress detection,Western blot,and RT-PCR indicate that PNaktide can inhibite the activated NFκB and MAPK pathways induced by the binding of LPS to TLR4,reducing the production of inflammasome complexes and their effectors,thereby reducing the expression of inflammatory factors,complement factors,and chemokines,inhibiting the activation of Nrf2/HO-1 antioxidant stress pathway by LPS,and reducing oxidative stress levels.At the same time,pNaktide can also reduce LPS induced autophagy inhibition and enhanced apoptosis,and the damage caused by LPS to newborn neurons and synapses in the hippocampus can also be recovered.In summary,pNaktide can alleviate LPS induced neuroinflammation by inhibiting the NFκB and MAPK pathways,thereby reducing oxidative stress levels and exerting neuroprotective effects.It is a potential approach for treating neuroinflammation related diseases.