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.

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.

• Authors: Chanchal Sharma, Sun Chul Kang
• Journal: Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association (Food Chem Toxicol) Vol. 138 Pg. 111246 (Apr 2020) ISSN: 1873-6351 [Electronic] England
• PMID: 32156567 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier Ltd. All rights reserved.

Chemical References

• Nerve Tissue Proteins
• Terpenes
• Acrylamide
• Cathepsin B
• garcinol

Topics

• Acrylamide (adverse effects)
• Animals
• Apoptosis (drug effects)
• Behavior, Animal
• Brain (metabolism)
• Cathepsin B (metabolism)
• Cognitive Dysfunction (chemically induced)
• Disease Models, Animal
• Inflammation (chemically induced)
• Larva (drug effects, metabolism)
• Mitochondria (drug effects)
• Molecular Docking Simulation
• Molecular Dynamics Simulation
• Nerve Tissue Proteins (metabolism)
• Neurons (drug effects)
• Terpenes (adverse effects)
• Zebrafish