Studies with Antioxidants, Polyphenolic Compounds and Nicotinamide in PD

In vitro studies with antioxidants and nicotinamide: Certain antioxidants such as vitamin A, beta-carotene and coenzyme Q10 inhibited formation of alpha-synuclein fibrils and destabilized preformed alpha-synuclein fibrils in a dose-dependent manner, whereas vitamin B2, vitamin B6, vitamin C and vitamin E were ineffective in vitro [120]. Melatonin, deprenyl and vitamin E inhibited auto-oxidation of DA in a dose-dependent manner, whereas vitamin C was ineffective [121]. Glutamate- induced degeneration of DA neurons was blocked by an analog of NAC (N-acetylcysteine amide) [122], vitamin E [17] and coenzyme Q10 [18]. Treatment of human neuroblastoma cells in culture with a relatively high dose of nicotinamide (vitamin B3) protected from MPP + -induced toxicity by decreasing the activities of complex I and alpha-ketoglutarate dehydrogenase, and the levels of reactive oxygen specie (ROS), and oxidation products of DNA and protein [123].

Studies with vitamin E in animal models of PD: Pre-treatment of rats with d-alpha tocopherol or dl-alpha-tocopherol significantly reduced 6-OHDA-induced behavior and biochemical abnormalities [124, 125]. Intramuscular administration of d-alpha- tocopheryl succinate, the most effective form of vitamin E [126], protected 6-OHDA-induced death of locus coeruleus neurons as well as behavioral and biochemical defects in rats [127, 128].

Studies with L-carnitine in animal models of PD: Quinolinic acid, an excitotoxin and free radical generator, and 3-nitropropionic acid and rotenone (mitochondrial toxins) induced oxidative damage to DA neurons, and behavioral alterations in animals similar to those observed in PD patients. Administration of L-carnitine, coenzyme Q10, vitamin E, alpha-lipoic acid or resveratrol reduced oxidative damage and behavior abnormalities in animal model of PD induced by these diverse groups of neurotoxins [129, 130].

Studies with N-acetylcysteine (NAC) in animal models of PD: Supplementation with NAC decreased the levels of alpha-synuclein in mice overexpressing wild-type human alpha-synuclein in the brain, and partially prevented the loss of dopaminergic terminals in these mice [131].

Studies with nicotinamide in animal models of PD: Nicotinamide, an inhibitor of histone deacetylase, preserves the activity of silent information regulator-1 (SIRT- 1), a regulator of mitochondrial biogenesis [132]. This vitamin inhibits oxidative damage and improves mitochondrial function and thus can protect neurodegeneration and improve motor functions. In addition, in Drosophila melanogaster model of PD (an alpha-synuclein transgenic fly), nicotinamide treatment significantly improved the motor function (climbing ability) [123].

Studies with fish oil, melatonin or vitamin E in animal models of PD: Pretreatment treatment of mice with fish oil, melatonin or vitamin E decreased the levels of MPTP-induced elevation of the activity of COX-2 and lipid peroxides in the homogenates of midbrain. Treatment with fish oil was more effective in reducing MPTP-induced rise in COX-2 activity than vitamin E or melatonin, whereas melatonin was more effective in reducing MPTP-induced rise in lipid peroxides than fish oil or vitamin E [133]. These results suggest that different antioxidants affect markers of increased oxidative stress and chronic inflammation differently.

Studies with omega-3-fatty acids in animal models of PD: Omega-3-fatty acids restricted diet increased the levels of NO in the striatum of young and adult rats but not in the substantia nigra; however, increased lipoperoxidation and decreased catalase activity were found in both regions of the brain, while total SOD activity was lowered in the striatum. In addition, fewer tyrosine hydroxylase- and brain- derived nerve growth factor-positive cells present in the substantia nigra compared to the controls

Studies with resveratrol in animal models of PD: Resveratrol is also an activator of SIRT1, and thus, stimulated mitochondrial biogenesis in mice and reduces production of reactive oxygen species [134]. Pretreatment of fibroblasts obtained from patients with early-onset PD carrying mutated Park2 gene with resveratrol enhanced mitochondrial oxidative function by activating Peroxisome proliferator-activated receptor-gamma coactivator-1a (PGC-1a) [135].

Studies with curcumin and a mixture of antioxidants in animal models of PD:

Both curcumin and a mixture of dietary and endogenous antioxidants (a gift from Premier Micronutrient Corporation, Nashville, TN) reduced the incidence of death and hypokinesia induced by MPTP treatment in mice. Although both curcumin and an antioxidant mixture markedly blocked MPTP-induced depletion of tyrosine hydroxylase (TH) activity, only the antioxidant mixture enhanced the TH activity [136]. This suggested that an antioxidant mixture treatment was more effective than the curcumin treatment in preventing MPTP-induced depletion of TH in mice.

Treatment of neuroblastoma cells (PC-12derived from the rat and SH-SY5Y derived from the human) with curcumin prevented mutated alpha-synuclein (A53T)-induced cell death, by inhibiting oxidative stress, mitochondrial depolarization, cytochrome c release, and caspase-9 and caspase-3 activation [137, 138]

Studies with quercetin and an iron chelator in animal models of PD: Pretreatment of rats with a flavonoid quercetin and a chelator of iron desferrioxamine reduced 6-OHDA-induced increase in the levels of protein carbonyl, glutathione, dopamine, and SOD in the striatum [139].

Studies with certain phytochemicals in animal models of PD: Treatment with some phytochemicals such as methanol extract of Garcinia indica fruits [140], sily- marin, derived from the seeds of the plant Silyburn marianum [141], and silibinin, a major constituent of silymarin [142] reduced MPTP- and 6-OHDA-induced toxicity on dopaminergic neurons in the substantia nigra of rats. These agents exhibit antioxidant and anti-inflammation activities.

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