Glutamoyl diester of the dietary polyphenol curcumin offers improved protection against peroxynitrite-mediated nitrosative stress and damage of brain mitochondria in vitro: implications for Parkinson’s disease

Abstract

Oxidative/nitrosative stress plays a crucial role in Parkinson's disease (PD) by triggering mitochondrial dysfunction. Nitrosative stress is mediated by reactive species such as peroxynitrite (PN) which could damage biomolecules thereby impinging on the cellular machinery. We observed that PN (0-1000 μM) inhibited brain mitochondrial complex I (CI) activity in a dose-dependent manner with concomitant tyrosine nitration of proteins. We also observed that exposure to PN at low concentrations (62.5-125 μM) significantly decreased the mitochondrial membrane potential and affected the mitochondrial integrity at higher doses (500-750 μM) as indicated by the mitochondrial swelling experiment. Therefore, it could be surmised that compounds that prevent such mitochondrial damage might have therapeutic value in neurological conditions such as PD. We previously showed that curcumin could detoxify PN and protect against CI inhibition and protein nitration. However, the therapeutic potential of curcumin is constrained by limited bioavailability. To address this issue and obtain improved antioxidants, three bioconjugates of curcumin (Di-demethylenated piperoyl, di-valinoyl and di-glutamoyl esters) were generated and tested against PN-mediated nitrosative stress and mitochondrial damage. We found that among the bioconjugates, the glutamoyl diester of curcumin showed improved protection against PN-dependent CI inhibition and protein nitration compared to other conjugates. Di-glutamoyl curcumin protected dopaminergic neurons against 1-methyl-4-phenylpyridinium (MPP(+))-mediated neuronal death. These effects were improved compared to curcumin alone suggesting that di-glutamoyl curcumin could be a better neuroprotective agent in neurodegenerative diseases such as PD.

Therapeutic Potential of Polyphenols in Parkinson’s Disease

“…This is consistent with earlier reports suggesting that curcumin contributes to neurogenesis (Kim, S. J. et al 2008, Xu, Y. et al 2007. Similarly, our laboratory also demonstrated that curcumin derivatives with improved bioavailability offers better defense against 1-methyl-4-phenylpyridinium (MPP + ) in dopaminergic neurons (Mythri et al 2011). Curcumin treatment attenuates 3-nitropropionic acid mediated oxidative stress in vivo (Kumar, A. et al, 2007).…”

“…In all these s t u d i e s , p r o t e c t i o n w a s a f f o r d e d o n l y b y p r e t r e a t m e n t w i t h c u r c u m i n p r i o r t o administration of the toxin. A recent study in our laboratory indicated that chronic dietary consumption of turmeric caused an increase in the tyrosine hydroxylase (TH) positive neurons in the SN (Mythri et al 2011). This is consistent with earlier reports suggesting that curcumin contributes to neurogenesis (Kim, S. J. et al 2008, Xu, Y. et al 2007.…”

“…It was also shown that curcumin protected against PN induced protein nitration and inhibition of enzyme activity of mitochondrial complex I with implications for PD (Mythri et al 2007). Recently, we demonstrated that curcumin protects against PN mediated loss of mitochondrial membrane potential and mitochondrial integrity and curcumin derivatives offered improved protection compared to curcumin (Mythri et al 2011). Mishra et al demonstrated that at low superoxide concentrations, curcumin effectively caused superoxide dismutation without itself undergoing any chemical change, but at higher www.intechopen.com concentrations of superoxide, curcumin inhibited superoxide activity by reacting with it (Mishra et al, 2004).…”

“…PN is a highly labile reactive nitrogen species which inflicts severe cellular damage by nitrosative protein modifications. However, PN mediated nitrosative stress and mitochondrial dysfunction were attenuated by pretreatment with curcumin in vitro (Mythri et al 2011). Curcumin mediated protection from PN toxicity is probably due to its direct interaction with and inactivation of PN in vitro (Iwunze & McEwan 2004, Mythri et al 2007 or indirectly by enhancing GSH levels in vivo ((Jagatha et al 2008, Mythri et al 2007).…”

Emerging Role of Curcumin in Parkinsons Disease

“…Furthermore, consequent to its anti-oxidant activity, curcumin offers mitochondrial protection in peroxynitrite-mediated nitrosative stress and damage of brain mitochondria in vitro with direct therapy [4]. Meanwhile, the most compelling and pivotal rationale for the continuing use of curcumin is its extremely good safety profile.…”