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

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder accompanied by a selective loss of the dopamine(DA)ergic neurons residing in the substantia nigra. There is ample evidence that neuroinflammation and oxidative stress are involved in the pathogenesis of PD. In the present study, we aimed at protecting the DAergic neurons by suppressing these cellular events and generated a novel synthetic isothiocyanate ITC-3. The compound led to elevation of nuclear and total levels of the transcription factor Nrf2 and interacted with its binding protein Keap1 with high affinity, suggesting Nrf2 activation. ITC-3 was able to suppress production of the proinflammatory mediators in lipopolysaccharide-activated BV-2 microglial cells. It also increased mRNA and protein levels of the Nrf2-dependent antioxidant enzymes NAD(P)H quinone oxidoreductase, heme oxygenase-1, and glutamylcysteine ligase in both BV-2 and DAergic neuronal CATH.a cells. The compound protected the DAergic cells against oxidative stress. In vivo, ITC-3 attenuated the loss of tyrosine hydroxylase-immunopositive nigrostriatal DAergic neurons, suppressed microglial activation, and abolished PD-associated motor deficits in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-elicited animal model of PD. Taken together, ITC-3 may be useful toward development of neuroprotective therapy for PD.

Protective effects of irigenin against 1‐methyl‐4‐phenylpyridinium‐induced neurotoxicity through regulating the Keap1/Nrf2 pathway

“…For example, MPTP‐treated Nrf2 knockout mice exhibited increased levels of inflammatory markers such as cyclooxygenase‐2, inducible NO synthase, IL‐6, and TNF‐α, and are prone to neuroinflammation (Rojo et al, 2010). Activation of Nrf2 signaling by a novel compound ITC‐3 inhibited oxidative stress and inflammation, abolished motor deficits and provided neuroprotection in a MPTP‐elicited animal model of PD (Lee et al, 2015). Hydralazine and protocatechuic aldehyde exerted neuroprotection in MPTP‐ or MPP + ‐induced PD models at least partially by activation of Nrf2 pathway (Guo et al, 2019; Guo et al, 2019).…”

Safranal prevents rotenone-induced oxidative stress and apoptosis in an in vitro model of Parkinson's disease through regulating Keap1/Nrf2 signaling pathway

“…Additionally, knockdown of Keap1 increases the resistance to rotenone in cortical cultures (52). A recent study demonstrated that the activation of Nrf2 signaling by a novel compound ITC-3 inhibits oxidative stress and abolishes PD-associated motor deficits in an animal model of PD (13). In this study, we found that safranal could inhibit Keap1 expression induced by rotenone and promoted Nrf2 nuclear accumulation that led to transcription of antioxidant gene expression, by which safranal alleviated rotenone-induced neurotoxicity in dopaminergic neurons.…”

“…A recent study has suggested that the Keap1/Nrf2 signaling plays an important role in neurodegenerative diseases including PD (12). The activation of Nrf2 signaling shows a protective effect against PD (13).…”

Neuroprotective Effects of Glucosinolates

“…These promising results obtained with natural ITCs in different model of PD led to the production of synthetic ITCs to be investigated in this context of neurodegeneration. Lee et al [149] reported the synthesis of three novel ITCs (ITC-1, ITC-2, and ITC-3) and investigated their protective effects both in vitro, using CATH.a neuronal cells and microglial BV-2 cells, and in vivo in an animal model of PD. ITC-3 demonstrated the highest performance thanks to its low cytotoxicity compared to ITC-1, ITC-2, and SF.…”