Hydralazine Protects Nigrostriatal Dopaminergic Neurons From MPP+ and MPTP Induced Neurotoxicity: Roles of Nrf2-ARE Signaling Pathway

Abstract

Although the pathogenic mechanisms of Parkinson's disease (PD) remain unclear, ample empirical evidence suggests that oxidative stress is involved in the pathogenesis of this disease. The nuclear factor E2-related factor 2 (Nrf2) is known to activate several antioxidant response element (ARE)-driven antioxidative genes that prevents oxidative stress in vitro and in vivo. Moreover, it was documented that hydralazine is a potent Nrf2 activator. In this study, we tested whether hydralazine can attenuate 1-Methyl-4-phenylpyridinium (MPP+) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)- induced neurotoxicity in vitro and in vivo by activating Nrf2 and its downstream network of antioxidative genes. We found that treatment with hydralazine attenuated MPP+ or H2O2-induced loss of cell viability in human neuroblastoma cell line (SH-SY5Y). In addition, hydralazine significantly promoted the nuclear translocation of Nrf2, and upregulated the expression of its downstream antioxidative genes. Further, knockout of Nrf2 abolished the protection conferred by hydralazine on MPP+ -induced cell death. Similar findings were observed in vivo. Before, during, and after MPTP 30 mg/kg (i.p.) administration for 7 days, the mice were given hydralazine (Hyd) 51.7 mg/kg per day by oral gavage for 3 weeks. Oral administration of hydralazine ameliorated oxidative stress, MPTP-induced behavioral disorder, and loss of neurons of dopaminergic system in the substantia nigra (SN) and striatum, all of which were attributed to its ability to activate the Nrf2-ARE pathway. Hydralazine increased the migration of Nrf2 to the nucleus in dopaminergic neurons, enhanced the expression of its downstream antioxidative genes. Together, these datasets show that the Nrf2-ARE pathway mediates the protective effects of hydralazine on Parkinson's disease.

Hydralazine targets cAMP-dependent protein kinase leading to sirtuin1/5 activation and lifespan extension in C. elegans

“…In streptozotocin-induced diabetic rats, hydralazine significantly reduced serum levels of triglycerides, phospholipids, free fatty acids, and cholesterol by an obscure mechanism 60 . Administration of hydralazine for three weeks has been reported to be beneficial in protecting dopaminergic neurons and recovering the locomotor performance in an MPTP-induced Parkinson’s mouse model as well 19 . Altogether, these reports support our findings and indicate conserved health benefits for hydralazine therapy across evolutionary boundaries.…”

“…The anti-aging benefits of hydralazine have also been demonstrated in rotifers in a screen for identification of life-extending FDA approved drugs 15,16 . Hydralazine ameliorates behavioral disorders and prevents loss of dopaminergic neurons in the substantia nigra (SN) and striatum by the activation of Nrf2-ARE pathway in an MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced mouse model of Parkinson’s disease 19 . Despite numerous studies, the fundamental mechanism of hydralazine’s action is poorly understood.…”

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

“…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). Indole derivative NC001‐8 showed a neuroprotective effect through activation of the Nrf2 antioxidative pathway in PD cell models (Wei et al, 2019).…”

Redox Effects of Molecular Hydrogen and Its Therapeutic Efficacy in the Treatment of Neurodegenerative Diseases

“…The nuclear factor erythroid 2-related factor 2 (Nrf2) pathway act as a vital role in protecting cells against different stressors and its dysfunction is correlated with decreased tolerance to OS [37]. Nrf2 is an important defense mechanism of the brain against toxins in both, glial and neuronal cells [38,39]. The Nrf2 pathway targets various genes for instance heme oxygenase-1 (HO-1), glutathione S-transferase, SOD, CAT, NAD(P)H dehydrogenase(quinone)1, and others, thus, protecting the neurons of the CNS against OS [40,41].…”