6-Paradol mitigates rotenone-induced Parkinson’s disease via shutting TNFR-1/RIPK1/RIPK3/MLKL cascade and enhancement of PPARγ/PGC-1α/TFAM axis

Abstract

Abstract Background Zingiber officinale rhizomes (Ginger, Zingiberaceae) are used traditionally in treating various ailments, including neurodegenerative diseases. Therefore, its constituents like 6-paradol may be useful in the management of Parkinson's disease (PD). Moreover, promising molecular docking scores of 6-paradol targeting PARKIN1, cAMP-response-element binding protein (CREB), PTEN-induced kinase 1 (PINK1), and tyrosine kinase B (TrKB) proteins associated with PD prompted in vivo investigations to assess its therapeutic potential on rotenone-induced PD in rats. Results 6-Paradol-treated rats showed improved muscular coordination in grip-strength, rotarod, and open-field tests and reduced histopathological damage. 6-Paradol increased tyrosine hydroxylase immunoreactivity and rescued dopaminergic neurons in the nigrostriatal pathway. It suppressed neuroinflammation by downregulating high-mobility group box 1 (HMGB-1) and Toll-like receptor 4 (TLR4) mRNA expressions and decreasing nuclear factor kappa-B (pS536-NFκB) p65 and tumor necrosis factor-alpha (TNF-α) protein levels. Additionally, 6-paradol inhibited necroptosis by reducing TNFR1 gene expression and RIPK1, RIPK3, and MLKL protein contents. It also enhanced mitochondrial biogenesis, increasing mitochondrial transcription factor-A (TFAM) peroxisome proliferative-activated receptor-gamma (PPARγ), and PPARγ coactivator 1 alpha (PGC-1α) protein levels, thereby reducing malondialdehyde and increasing glutathione levels. These effects of 6-paradol were comparable to L-dopa/carbidopa. Conclusion The neuroprotection potential of 6-paradol is related to suppression of neuroinflammation, inhibition of necroptosis, enhancement of mitochondrial biogenesis, and alleviation of oxidative stress. These findings further supported the traditional uses of ginger for neurodegenerative disorders. Graphical abstract

Keywords

• Ginger
• Parkinson’s disease
• 6-paradol
• Necroptosis
• Neuroinflammation
• PGC-1α