ABSTRACT
D-galactose (D-gal) induced senescence in rodents is a widely used model for assessment of molecules affecting brain ageing. Chronic administration of D-gal causes neuroinflammation leading to cognitive deficit and memory impairment which represent Alzheimer's dementia. In present study, we investigated the neuroprotective effects of the natural phenol, p-Coumaric acid (PCA) and its underlying mechanism in the chronic D-gal treated mice. Subcutaneous administration of D-gal (150 mg/kg) to Swiss albino mice for 42 consecutive days resulted in cognitive impairment as observed in Morris water maize (MWM) and Y maze test, which was ameliorated by concurrent treatment with PCA (80 mg/kg, and 100 mg/kg, p.o.). Importantly, PCA treatment attenuated the D-gal induced oxidative stress and significantly inhibited acetylcholinesterase (AChE) activity in mice brain. Furthermore, PCA treatment significantly lowered levels of inflammatory marker nuclear factor kappa B (NFκB) and reduced levels of proapoptotic enzyme caspase3. We also observed that PCA treatment exhibited ß-secretase enzyme (BACE1) inhibitory effect. However, our results revealed that PCA treatment failed to decrease the level of advanced glycation end products both in vitro and in vivo. Taken together, current study demonstrated the significant neuroprotective effect of PCA against D-gal induced oxidative stress, neuroinflammation, cognitive impairment and apoptosis.
Subject(s)
Coumaric Acids , Neuroprotective Agents , Neurotoxicity Syndromes , Animals , Mice , Acetylcholinesterase/metabolism , Amyloid Precursor Protein Secretases , Apoptosis , Aspartic Acid Endopeptidases , Brain/metabolism , Galactose/toxicity , Glycation End Products, Advanced/metabolism , Maze Learning , Neuroinflammatory Diseases , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , NF-kappa B/metabolism , Oxidative Stress , Phenols/pharmacology , Coumaric Acids/pharmacologyABSTRACT
OBJECTIVES: Systemic administration of lipopolysaccharide induces neuroinflammation leading to cognitive deficit and memory impairment. Herein, we investigated the effects of p-Coumaric acid (PCA) in LPS induced neuroinflammation in mice. PCA is reported to possess free radicle scavenging and neuroprotective action. METHODS: Mice received treatment with PCA (80 mg/kg, and 100 mg/kg, p.o.) for 28 days. LPS (0.25 mg/kg) was administered intraperitoneally from Day 15 to 21, to all groups. Memory impairment and cognitive deficit were assessed by MWM and Y maze test, followed by estimation of ROS, TNF-α, IL-6, caspase-3 and c-Jun in the brain homogenate by ELISA. Histopathological changes were investigated using Nissl and H&E staining. KEY FINDINGS: PCA attenuated increased oxidative stress, significantly increasing SOD, GSH levels and decreasing MDA level and AChE activity in mice brain, lowered the levels of TNF-α and IL-6 indicating protection against neuroinflammatory reaction. PCA also suppressed neuronal apoptosis, as indicated by decreased levels of caspase-3 and c-Jun. Further, histopathological findings revealed that PCA attenuated neuronal loss and pathological abnormalities in the hippocampus. CONCLUSIONS: Our findings give compulsive evidence suggesting a protective effect of PCA in neuroinflammation, cognitive impairment and neuronal apoptosis induced by LPS, through its antioxidant, AChE inhibitory, anti-inflammatory and antiapoptotic activity determined by behavioural, biochemical and histopathological measures.
