Antiparkinson potential of khellin on rotenone-induced Parkinson's disease in a zebrafish model: targeting MAO, inflammatory, and oxidative stress markers with molecular docking, MD simulations, and histopathology evidence.

Autor: Hemanth Babu A; Raghavendra Institute of Pharmaceutical Education and Research, JNTUA, Anantapuramu, Andhra Pradesh 515721, India., Prasanth DSNBK; School of Pharmacy & Technology Management, SVKM's Narsee Monjee Institute of Management Studies (NMIMS), Polepally SEZ, TSIIC, Jadcherla, Mahbubnagar, Hyderabad 509301, India., Yaraguppi DA; Department of Biotechnology, KLE Technological University, Hubli, Karnataka 580031, India., Panda SP; Department of Pharmacology, Institute of Pharmaceutical Research, GLA University, Mathura, Uttarpradesh, India., Ahmad SF; Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia., Al-Mazroua HA; Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia., Sai AR; Raghavendra Institute of Pharmaceutical Education and Research, JNTUA, Anantapuramu, Andhra Pradesh 515721, India., Praveen Kumar P; Raghavendra Institute of Pharmaceutical Education and Research, JNTUA, Anantapuramu, Andhra Pradesh 515721, India. Electronic address: praveenpharmaco@gmail.com.
Jazyk: angličtina
Zdroj: Comparative biochemistry and physiology. Toxicology & pharmacology : CBP [Comp Biochem Physiol C Toxicol Pharmacol] 2024 Oct; Vol. 284, pp. 109997. Date of Electronic Publication: 2024 Aug 03.
DOI: 10.1016/j.cbpc.2024.109997
Abstrakt: In this study, the antiparkinson effect of khellin (KL) on rotenone-induced Parkinson's disease (PD) was examined in zebrafish. Initially, In silico evaluations, such as drug likeness and ADME/T analysis, confirmed the pharmacological viability of KL. Molecular docking and molecular dynamics (MD) analysis revealed stable binding interactions between KL and monamine oxidase B (MAO-B). Molecular docking results for KL and pioglitazone (CCl) revealed binding energies of -6.5 and -10.4 kcal/mol, respectively. Later, molecular dynamics (MD) studies were performed to assess the stability of these complexes, which yielded binding energies of -36.04 ± 55.21 and -56.2 ± 80.63 kJ/mol for KL and CCl, respectively. These results suggest that KL exhibits considerable binding affinity for MAO-B. In In vitro studies, according to the DPPH free radical scavenging assay, KL exhibited significant antioxidant effects, indicating that it can promote redox balance with an IC 50 value of 22.68 ± 0.5 μg/ml. In vivo studies and evaluation of locomotor activity, social interaction, histopathology and biochemical parameters were conducted in KL-treated zebrafish to measure SOD and GSH antioxidant activity, the oxidative stress marker malondialdehyde (MDA), the inflammatory marker myeloperoxidase (MPO) and MAO-B. However, while the locomotor and social interaction abilities of the rotenone-treated zebrafish were significantly reduced, KL treatment significantly improved locomotor activity (p < 0.001) and social interaction (p < 0.001). KL alleviated PD symptoms, as indicated by significant increases in SOD (p < 0.01), GSH (p < 0.001), MDA (p < 0.001), MAO-B (p < 0.001) and MPO (p < 0.001) in rotenone-induced PD fish (p<0.001) significantly reduced activities. Histopathological studies revealed that rotenone-induced brain hyperintensity and abnormal cellularity of the periventricular gray matter in the optic tectum were significantly reduced by KL treatment. This study provides a strong basis for developing KL as a new candidate for the treatment of Parkinson's disease, with the prospect of improved safety profiles and efficacy.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Sheikh Fayaz Ahmad reports financial support was provided by King Saud University. Sheikh Fayaz Ahmad reports a relationship with King Saud University that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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