Discovery of Vinyl Sulfones as a Novel Class of Neuroprotective Agents toward Parkinson’s Disease Therapy

Abstract

Although the etiology of Parkinson's disease (PD) remains elusive, recent studies suggest that oxidative stress contributes to the cascade leading to dopaminergic (DAergic) neurodegeneration. The Nrf2 signaling is the main pathway responsible for cellular defense system against oxidative stress. Nrf2 is a transcription factor that regulates environmental stress response by inducing expression of antioxidant enzyme genes. We have synthesized novel vinyl sulfone derivatives. They exhibited a broad range of activities in inducing HO-1, whose gene expression is under the control of Nrf2. Among them, compound 12g was confirmed to activate Nrf2 and induce expression of the Nrf2-dependent antioxidant enzymes NQO1, GCLC, GLCM, and HO-1, at both mRNA and protein levels in DAergic neuronal cells. This was accompanied by protection of DAergic neurons in both in vitro and MPTP-induced in vivo models of PD. In addition, compound 12g effectively resulted in attenuation of the PD-associated behavioral deficits in the mouse model.

A Novel Compound ITC-3 Activates the Nrf2 Signaling and Provides Neuroprotection in Parkinson’s Disease Models

“…Mouse DAergic CATH.a neuronal cells (Suri et al 1993) and microglial BV-2 cells (Blasi et al 1990) were grown in respective culture media as previously reported (Woo et al 2014;Lee et al 2015).…”

“…Cell viability was assessed by determining the intracellular level of ATP using CellTiter-Glo Ò kit as described before (Woo et al 2014). …”

“…Sandwich ELISA for HO-1 was carried out using both capture and detection HO-1 antibodies as described (Woo et al 2014). …”

“…Studies in humans also indicate that the Nrf2 system is dysregulated in brains of PD patients (Imaizumi et al 2012;Matigian et al 2010;Cook et al 2011) and that variation in Nrf2 gene may be related to the pathogenesis of idiopathic PD (von Otter et al 2010(von Otter et al , 2014. We have previously reported that a novel vinyl sulfoxide compound that activates the Nrf2 signaling protected the nigral neurons (Woo et al 2014;Lee et al 2015).…”

“…Therefore, induction of enzymes that remove the quinone and/or ROS would be highly beneficial. Indeed, induction of NAD(P)H:quinone reductase (NQO1), the enzyme that catalyzes reduction of the quinone, heme oxygenase (HO)-1, the biliverdin-producing enzyme with antioxidant properties, and glutamylcysteinyl ligase (GCL), the enzyme responsible for GSH synthesis, have all been shown to protect the DAergic cells (Han et al 2007;Choi et al 2003;Woo et al 2014).…”