A Novel Synthetic Precursor of Styryl Sulfone Neuroprotective Agents Inhibits Neuroinflammatory Responses and Oxidative Stress Damage through the P38 Signaling Pathway in the Cell and Animal Model of Parkinson’s Disease

Abstract

A novel class of styryl sulfones were designed and synthesized as CAPE derivatives by our work team, which showed a multi-target neuroprotective effect, including antioxidative and anti-neuroinflammatory properties. However, the underlying mechanisms remain unclear. In the present study, the anti-Parkinson’s disease (PD) activity of 10 novel styryl sulfone compounds was screened by the cell viability test and the NO inhibition test in vitro. It was found that 4d exhibited the highest activity against PD among them. In a MPTP-induced mouse model of PD, the biological activity of 4d was validated through suppressing dopamine neurotoxicity, microglial activation, and astrocytes activation. With compound 4d, we conducted the mechanistic studies about anti-inflammatory responses through inhibition of p38 phosphorylation to protect dopaminergic neurons, and antioxidant effects through promoting nuclear factor erythroid 2-related factor 2 (Nrf2). The results revealed that 4d could significantly inhibit 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/1-methyl-4-phenylpyridinium (MPTP/MPP+)-induced p38 mitogen-activated protein kinase (MAPK) activation in both in vitro and in vivo PD models, thus inhibiting the NF-κB-mediated neuroinflammation-related apoptosis pathway. Simultaneously, it could promote Nrf2 nuclear transfer, and upregulate the expression of antioxidant phase II detoxification enzymes HO-1 and GCLC, and then reduce oxidative damage.

Targeting the Nrf2-dependent mechanism of b-Ecdysterone in attenuating the motor dysfunction in the MPTP/Pro-induced Parkinson’s disease mice model

“…HO-1 and GCLc are important endogenous phase II antioxidant enzymes, which play protective roles against free-radical damage. In the MPTP-induced PD mouse model, the Nrf2/ARE-driven genes, such as GCLc and HO-1, were up-regulated after caffeic acid phenethyl ester derivative intervention [19]. In this study, we evaluated whether β-Ecd enhances the expression of GCLc, GCLm, HO-1, and NQO1 in the SN.…”

Antioxidant Therapy in Oxidative Stress-Induced Neurodegenerative Diseases: Role of Nanoparticle-Based Drug Delivery Systems in Clinical Translation

“…Similarly, the synthetic pyrazole derivative of curcumin (CNB-001) was demonstrated to suppress RNS generation with anti-inflammatory effect [ 167 ]. Synthetic derivatives of a natural phenolic compound such as caffeic acid phenethyl ester (CAPE) [ 168 ] or coumarin [ 169 ] also demonstrated to protect dopaminergic neurons by inhibiting p38 phosphorylation, increasing cell viability, and promoting antioxidant response.…”

Deconvoluting the Complexity of Reactive Oxygen Species (ROS) in Neurodegenerative Diseases

“…A novel synthetic styryl sulfone and a novel chalcone compound have been published to prove this statement. These compounds activate Nrf2 to produce HO-1, which inhibits the production of ROS and the p38 MAPK and NF-κB mediated neuroinflammation and in PD models, rescues the dopamine neurotoxicity (Lee et al, 2019 ; Guo et al, 2021 ).…”