pNaktide mitigates inflammation-induced neuronal damage and behavioral deficits through the oxidative stress pathway.

Neuroinflammation is closely related to the etiology and progression of neurodegenerative diseases such as Parkinson disease and Alzheimer disease. pNaktide, an Src inhibitor, exerts antioxidant effects by mimicking Na/K-ATPase. It has been verified that its anti-inflammation and anti-oxidation ability could be embodied in obesity, steatohepatitis, uremic cardiomyopathy, aging, and prostate cancer. This study aimed to investigate the effects and mechanisms of pNaktide in lipopolysaccharide (LPS)-induced behavioral damage, neuroinflammation, and neuronal damage. We found that pNaktide improved anxiety, memory, and motor deficits. pNaktide inhibited MAPK and NF-κB pathways induced by TLR4 activation, inhibited the NLRP3 inflammasome complex, and reduced the expression of inflammatory factors, complement factors, and chemokines. pNaktide inhibited the activation of Nrf2 and HO-1 antioxidant stress pathways by LPS and reduced the level of oxidative stress. Inhibition of autophagy and enhancement of apoptosis induced by LPS were also alleviated by pNaktide, which restored LPS-induced injury to newborn neurons in the hippocampus region. In summary, pNaktide attenuates neuroinflammation, reduces the level of oxidative stress, has neuroprotective effects, and may be used for the treatment of neuroinflammation-related diseases.