Curzerenone attenuates neuroinflammation and oxidative stress via MAPK signaling pathway modulation: Network pharmacology and in vivo insights in a scopolamine-induced model of Alzheimer's disease

Alzheimer's disease (AD) is a grave global health challenge characterized by progressive cognitive decline and neuronal degeneration. This study aims to evaluate the therapeutic potential of curzerenone, a sesquiterpene compound, against AD using integrated network pharmacology, molecular docking, and an in vivo pharmacological evaluation strategy. Network pharmacology analyzed key targets involved in neuroinflammation, neurotransmission, and amyloidogenesis, including SOD2, NOS2, PTGS2, NFKB1, BACE1, and MAPK signaling components (ERK, JNK, p38), predicting a multi-faceted therapeutic potential of curzerenone. Molecular docking, followed by protein deformability results, confirmed the binding with MAPK signaling targets. Curzerenone was extracted using standard chromatographic methods, and its integrity was confirmed using HPLC, 1 H NMR, and 13 C NMR analyses. In vivo , curzerenone (1, 5, 10 mg/kg, i.p.) markedly improved spatial memory in a scopolamine-induced amnesia model assessed by Y-maze and MWM behavioral tests. FTIR analysis detected decreased inflammatory markers, while ELISA confirmed reduced proinflammatory cytokines (TNF-α, IL-1β). AChE assay ascertained curzerenone's ability to suppress ACHE activity. Biochemical analysis confirmed decreased levels of Oxidative markers (NO, MDA) while significantly enhancing antioxidant levels (GSH, GST, CAT, SOD). Additionally, qRT-PCR confirmed the downregulation of gene expression of inflammatory proteins, including ERK, JNK, p38, iNOS, and AP-1. • Curzerenone improves memory in scopolamine-induced amnesic mice. • FTIR spectroscopy showed reduced inflammation markers in brain tissue. • Computational studies identified MAPK pathway targets modulated by Curzerenone. • Targets identified include ERK, JNK, p38 MAPK, and iNOS. • AChE and cytokine levels decreased significantly after treatment. • Biochemical and qPCR assays validated neuroprotective and anti-inflammatory effects.