Neurokinin-1 receptor inhibition reverses ischaemic brain injury and dementia in bilateral common carotid artery occluded rats: possible mechanisms.

PMID 27380492


Increase in SP release as a function of hypoxia of the rat carotid body is a tissue response to ischemia that leads to neurogenic inflammation and cognitive deficits. Substance P-mediated inflammation is reported to attenuate the neuroprotective PPAR-γ. This study was undertaken to investigate the effect of aprepitant, a substance P-NK1 receptor antagonist in bilateral carotid artery occlusion (BCCAO)-induced ischaemic brain injury and vascular dementia. Bilateral carotid artery occlusion was performed in Wistar rats to produce hypoperfusion and ischaemic injury. Dementia was noted by an increase in brain acetylcholinesterase (AChE) activity, and attenuation of learning ability (escape latency time) and memory retention (time spent in target quadrant) using Morris water maze. Oxidative stress was estimated by an increase in thiobarbituric acid reactive substances (TBARS) level and a decrease in reduced glutathione level. Vascular dysfunction was measured by attenuation of acetylcholine-induced endothelium-dependent relaxation (isolated carotid ring preparation), and increased in carotid artery TBARS level. Neurodegeneration was assessed in the hippocampus by H&E staining. Aprepitant and donepezil (positive control) were administered to rats from day 28 to day 42 after BCCAO. Aprepitant (20 and 40 mg/kg) and donepezil (2 mg/kg) significantly improved vascular function, learning and memory ability, and decreases the neuronal cell death, oxidative stress, and ache in BCCAO rats. Donepezil effect was more significant than the low dose of aprepitant on disease markers. However, BADGE (30 mg/kg a, PPAR-γ antagonist) prevented the ameliorative effect of aprepitant. Thus, it may be concluded that aprepitant attenuates vascular dysfunction and dementia in BCCAO rats by activating downstream PPAR-γ.

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D.E.R. 332, used as embedding medium