Pyrazolone-nicotinic acid derivative (4Z)-4-(2-hydroxybenzylidine)-5-methyl-2-(pyridine-3-ylcarbonyl)-2, 4-dihydro-3H-pyrazole-3-one (IIc) as multitarget inhibitor of neurodegeneration and behavioural impairment in Dementia.

Autor:	Kanwal M; Department of Pharmaceutical Chemistry, Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad 44000, Pakistan., Sarwar S; Cell Culture Lab, Department of Pharmacognosy, Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad 44000, Pakistan., Nadeem H; Department of Pharmaceutical Chemistry, Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad 44000, Pakistan., Alghamdi SA; Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia., Alamro AA; Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi Arabia., Malik S; Department of Pharmacology, Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad 44000, Pakistan., Maqsood S; Department of Pharmacology, Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad 44000, Pakistan., Alghamdi AA; Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi Arabia., Tariq MJ; Department of Pharmacology, Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad 44000, Pakistan., Malik I; Department of Pharmaceutical Chemistry, Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad 44000, Pakistan., Khan AU; Department of Pharmacology, Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad 44000, Pakistan., Muskan A; Department of Pharmacology, Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad 44000, Pakistan.
Jazyk:	angličtina
Zdroj:	The Journal of pharmacy and pharmacology [J Pharm Pharmacol] 2024 Oct 14. Date of Electronic Publication: 2024 Oct 14.
DOI:	10.1093/jpp/rgae075
Abstrakt:	Objective: The study was aimed at the synthesis and pharmacological investigation of (4Z)-4-(2-hydroxybenzylidine)-5-methyl-2-(pyridine-3-ylcarbonyl)-2, 4-dihydro-3H-pyrazole-3-one (IIc) in mice model of scopolamine-induced neurodegeneration and cognition impairment. Methods: The behavioural studies included Y-Maze Test, Water Morris Test, and Novel Object Recognition Test in Albino mice (20-25 g). Scopalamine was used as an inducing agent. The acetylcholinesterase (AChE) inhibitory assay was used to assess the role of the test compounds in vitro. The Crystal Violet Staining (Nissl staining) was used to assess the neuroprotective and antiapoptotic effect through quantifying the number of neurons and viability. The expression of the anti-inflammatory enzyme cyclooxygenase-2 (COX-2), cytokine tumour necrotic factor (TNF-α), key transcription factor producing pro-inflammatory signals nuclear factor kappa B (P-NFkB), and apoptosis marker p-JNK was validated through enzyme-linked immunosorbent assay (ELISA) and immunohistochemical (IHC) analysis. The tested compound reverted cognitive and behavioural impairment through inhibiting scopolamine-induced inflammation and oxidative stress. Key Findings: We found that the compound IIc improved the short-term memory and learning behaviour of the experimental animals. Further investigation into molecular mechanisms showed that this effect was the manifestation of immunomodulatory, antioxidant, and consequently, of downsizing of inflammatory cytokines. These results were further validated through docking analysis. Conclusion: Finally, we conclude that the pyrazolone-nicotinic acid derivative IIc reversed the scopolamine-induced cognitive and behavioural deficits, attributed to acetylcholinesterase inhibition, neuronal recovery, antioxidant potential, and through downregulating the neuroinflammatory mediators p-NF-kB, cytokine TNF-α, and anti-inflammatory enzyme COX-2. (© The Author(s) 2024. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
Databáze:	MEDLINE
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