Garcinol pacifies acrylamide induced cognitive impairments, neuroinflammation and neuronal apoptosis by modulating GSK signaling and activation of pCREB by regulating cathepsin B in the brain of zebrafish larvae. (April 2020)

• Record Type: Journal Article
• Authors: Sharma, Chanchal; Kang, Sun Chul
• Is Part Of: Food and chemical toxicology. Volume 138(2020)
• Publication Date: 2020-04
• Subjects: Acrylamide -- Neuro-inflammation -- Garcinol -- Cathepsin-B -- APP -- Tau; Toxicology -- Periodicals; Food poisoning -- Periodicals; Food Poisoning -- Periodicals; Toxicology -- Periodicals; Toxicologie -- Périodiques; Intoxications alimentaires -- Périodiques; Food poisoning; Toxicology; Periodicals; Electronic journals; 615.9
• DOI: 10.1016/j.fct.2020.111246
• Languages: English
• ISSNs: 0278-6915

Abstract

Abstract: The presence of acrylamide (ACR) in food results in evident cognitive decline, accumulation of misfolded proteins, neurotoxicity, neuroinflammation, and neuronal apoptosis leading to progressive neurodegeneration. Here, we used 4 dpf zebrafish larvae exposed to ACR (1mM/3days) as our model, and neuronal proteins were analyzed. Next, we tested the effect of garcinol (GAR), a natural histone-acetylation inhibitor, whose neuroprotection mechanism of action remains to be fully elucidated. Our result revealed that ACR exposure significantly impaired cognitive behavior, downregulated oxidative repair machinery, and enhanced microglia-induced neuronal apoptosis. Moreover, ACR mediated cathepsin-B (CAT-B) translocation acted as the intracellular secretase for the processing of amyloid precursor protein (APP) and served as an additional risk factor for tau hyper-phosphorylation. Here, GAR suppresses ACR mediated CATB translocation as similar with standard inhibitor CA-074. And, this pharmacological repression helped in inhibiting amyloidogenic APP processing and downstream tau hyper-phosphorylation. GAR neuroprotection was accompanied by CREB, ATF1, and BDNF activation promoting neuronal survival. At the same time, GAR subdued cdk5 and GSK3β, the link between APP processing and tau hyper-phosphorylation. Taken together, our findings indicate that GAR rescued from ACR mediated behavioral defects, oxidative injury, neuroinflammation, undesirable APP processing, tau hyper-phosphorylation which in turn found to be CATB dependent. Graphical abstract: Image 1 Highlights: GAR repaired ACR induced cognitive behavior impairments and defects in neurocranium of zebrafish larvae. ACR induced oxidative injury resulted in translocation of CATB in the cytosol and corresponding mitochondrial damage. GAR inhibited ACR induced CATB mediated irregular processing of APP and downstream phosphorylation of tau. GAR attenuated CATB mediated glial activation and ensured redox balance by stimulation of CREB and BDNF. GAR act as a compelling neuroprotection agent against ACR-neurotoxicity by repressing CATB secretase activity.