A novel thiol antioxidant that crosses the blood brain barrier protects dopaminergic neurons in experimental models of Parkinson's disease

Authors

  • Merav Bahat-Stroomza,

    1. Laboratory of Neurosciences, Felsenstein Medical Research Center and Department of Neurology, Rabin Medical Center, Beilinson Campus Tel Aviv University, Sackler School of Medicine, Petah-Tikva 49100, Israel
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  • Yossi Gilgun-Sherki,

    1. Laboratory of Neurosciences, Felsenstein Medical Research Center and Department of Neurology, Rabin Medical Center, Beilinson Campus Tel Aviv University, Sackler School of Medicine, Petah-Tikva 49100, Israel
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  • Daniel Offen,

    1. Laboratory of Neurosciences, Felsenstein Medical Research Center and Department of Neurology, Rabin Medical Center, Beilinson Campus Tel Aviv University, Sackler School of Medicine, Petah-Tikva 49100, Israel
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  • Hana Panet,

    1. Laboratory of Neurosciences, Felsenstein Medical Research Center and Department of Neurology, Rabin Medical Center, Beilinson Campus Tel Aviv University, Sackler School of Medicine, Petah-Tikva 49100, Israel
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  • Ann Saada,

    1. Metabolic Disease Unit, Shaare-Zedek Medical Center, Jerusalem, Israel
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  • Nili Krool-Galron,

    1. Department of Neurobiochemistry, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
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  • Aari Barzilai,

    1. Department of Neurobiochemistry, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
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  • Daphne Atlas,

    1. Department of Biological Chemistry, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
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  • Eldad Melamed

    1. Laboratory of Neurosciences, Felsenstein Medical Research Center and Department of Neurology, Rabin Medical Center, Beilinson Campus Tel Aviv University, Sackler School of Medicine, Petah-Tikva 49100, Israel
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Dr Daniel Offen, as above.
E-mail: doffen@post.tau.ac.il

Abstract

It is believed that oxidative stress (OS) plays an important role in the loss of dopaminergic nigrostriatal neurons in Parkinson's disease (PD) and that treatment with antioxidants might be neuroprotective. However, most currently available antioxidants cannot readily penetrate the blood brain barrier after systemic administration. We now report that AD4, the novel low molecular weight thiol antioxidant and the N-acytel cysteine (NAC) related compound, is capable of penetrating the brain and protects neurons in general and especially dopaminergic cells against various OS-generating neurotoxins in tissue cultures. Moreover, we found that treatment with AD4 markedly decreased the damage of dopaminergic neurons in three experimental models of PD. AD4 suppressed amphetamine-induced rotational behaviour in rats with unilateral 6-OHDA-induced nigral lesion. It attenuated the reduction in striatal dopamine levels in mice treated with 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP). It also reduced the dopaminergic neuronal loss following chronic intrajugular administration of rotenone in rats. Our findings suggest that AD4 is a novel potential new neuroprotective drug that might be effective at slowing down nigral neuronal degeneration and illness progression in patients with PD.

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