Gurram_2025_Neuropeptides_113_102551

Neuroinflammation contributes to cognitive decline in Alzheimer's disease (AD), and the neurokinin pathway has been implicated in the pathophysiology of AD. Although Substance P (SP), an endogenous ligand to the neurokinin 1 receptor (NK1R), is primarily known as a neurotransmitter, but emerging evidence indicates it has shown both pro and anti-inflammatory actions. However, the dose-dependent nature of the SP-NK1R axis's functional role remains to be fully elucidated. In this study, we examined the effects of SP in a rat model of AD induced by lipopolysaccharide (LPS). A dose of 150 microg/10 microl of LPS was administered through intracerebroventricular injection to induce cognitive impairment in the rats. Two doses of SP, 50 microg/kg and 500 microg/kg were administered intraperitoneally once a day for 21 days. Behavioral assessments included the Morris water maze test and novel object recognition test to investigate cognitive defects, and the open field test evaluated locomotion. Tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), amyloid-beta (Abeta), acetylcholinesterase (AChE), lipid peroxidation, and catalase were estimated in the frontal cortex and hippocampus. The cAMP-responsive element-binding (CREB) protein levels in the whole brain were estimated by western blot. The LPS treatment significantly impaired cognition, increased levels of cytokines, Abeta, oxidative stress, and AChE, while decreasing CREB levels. Notably, the lower dose of SP (50 microg/kg) restored cognitive performance and markers of AD. In contrast, the higher dose of SP (500 microg/kg) failed to reverse spatial memory impairment and neuroinflammation. Thus, our data propose the dose-dependent effect of SP on neuroinflammation-induced cognitive deficits in AD.