Invited Review Free radicals and the pathobiology of brain dopamine systems

doi:10.1016/S0197-0186(97)00031-4

Neurochemistry International

Volume 32, Issue 2, February 1998, Pages 117-131

https://doi.org/10.1016/S0197-0186(97)00031-4 Get rights and content

Abstract

Oxygen is an essential element for normal life. However, reactive oxygen species (ROS) can also participate in deleterious reactions that can affect lipid, protein, and nucleic acid. Normal physiological function thus depends on a balance between these ROS and the scavenging systems that aerobic organisms have developed over millennia. Tilting of that balance towards a pro-oxidant state might result from both endogenous and exogenous causes. In the present paper, we elaborate on the thesis that the neurodegenerative effects of two drugs, namely methamphetamine (METH, ICE) and methylenedioxymethamphetamine (MDMA, Ecstasy) are due to ROS overproduction in monoaminergic systems in the brain. We also discuss the role of oxygen-based species in 6-hydroxydopamine (6-OHDA)-induced nigrostriatal dopaminergic degeneration and in Parkinson's disease. Studies are underway to identify specific cellular and molecular mechanisms that are regulated by oxygen species. These studies promise to further clarify the role of oxidative stress in neurodegeneration and in plastic changes that occur during the administration of addictive agents that affect the brain.

Introduction

Recent progress in cellular and molecular neurobiology has identified an essential role for free radicals in brain function. Although many investigators initially wrote and talked about excitotoxicity as the main culprit in neurodegenerative diseases, it has become quite clear that free radicals are intimately involved in the cascade of events that cause cell death after exposure to glutamate agonists. Nevertheless, the pathways involved in this reactive cascade have yet to be completely understood. The recent cloning of a number of cell death-related genes promises to provide a strong boost towards the further elucidation of the role of oxidative stress in neurodegenerative disorders. Thus, the purpose of this review is to provide an introduction to oxyradicals and their role in the normal physiology of the brain with an eye towards assessing their participation in the protracted degeneration of central dopamine (DA) systems observed after the administration of some toxins and in Parkinson’s disease.

Section snippets

Free radicals in the brain

Free radicals are chemical species that contain unpaired electrons. They are highly reactive and can cause damage to nucleic acids, lipids and proteins. Damaging oxyradical species can be produced through both endogenous and exogenous sources. Exogenous sources include xenobiotics, radiation, and chemical toxins, while endogenous ones include mitochondrial respiration, cytochrome P-450 reactions, phagocytic oxidative bursts and peroximal leakage.

Aerobic organisms take up oxygen which is used by

Role of catecholamines in free radical production

In the central nervous system, catecholamines are an important source of free radical production (Fig. 1). For example, the step catalyzed by monoamine oxidase during the metabolic breakdown of DA, serotonin, and norepinephrine produces H₂O₂ (Cohen, 1987). In addition, catecholamines can autoxidize to form quinones in the following order: 6-hydroxy-dopamine>dopamine> norepinephrine>epinephrine (Graham, 1978).The rate of cyclization to less reactive leukochromes was in the reverse order. It is

Scavenging systems in the brain

Oxygen-based radicals have very short lives because of the existence of very well functioning scavenging systems. This antioxidant defense system includes the enzymes SOD, glutathione peroxidase (GSH-Px), and catalase (CAT). Nonenzymatic dietary antioxidants include: ascorbic acid (vitamin C), α-tocopherol (vitamin E), β-carotene, uric acid, ceruloplasmin, and ubiquinone. Other antioxidants include glutathione (GSH) and sulfydryl-containing proteins. Fig. 3 provides a simplistic version of the

Pathobiology of free radicals

The molecular events involved in the cytotoxic effects of free radicals have not been completely elucidated. Although the superoxide radical is less reactive than hydroxyl radicals, it can kill bacteria, damage cells in culture, and inactivate enzymes such as CAT. ROS can cause cellular demise through their actions on phospholipids, proteins, and nucleic acids. Attacks on cell membranes can lead to lipid peroxidation. This consists of an initiation, propagation, and termination step. The

Toxic effects of methamphetamine

Methamphetamine (METH) can cause neurotoxic damage to monoaminergic systems of rats (Ricaurte et al., 1980), mice (OCallaghan and Miller, 1994; Steranka and Sanders-Bush, 1980), and nonhuman primates (Preston et al., 1985).Several markers of DA and serotonin terminals are severely affected by these drugs. These include neostriatal DA levels (Cadet et al., 1994b; OCallaghan and Miller, 1994; Ricaurte et al., 1980; Wagner et al., 1980), striatal tyrosine hydroxylase activity (Hotchkiss and Gibb,

Role of free radicals in Parkinson’s Disease

Parkinson’s disease (PD) is a neurodegenerative syndrome which consists of tremor, hypokinesia, muscular rigidity and loss of postural reflexes (MDMA,Bernheimer et al., 1973;MDMA, Marsden, 1990). Exposure to a number of drugs and neurotoxins such as manganese can MDMA, also result in Parkinsonism (Fahn, 1977). The clinical course of PD is that of a progressive deterioration over several years. The motor phenomena are secondary to the degeneration of pigmented nuclei in the brain stem (MDMA,Agid

Conclusions

The purpose of this review was to present the data that support the possible role of free radicals in some models of neurotoxicity and neurodegeneration. Thus, we reviewed the observations that support a role for oxidative stress in the neurotoxic effects of METH and MDMA, the development of Parkinson’s disease as well as in the degeneration of DA system caused by some toxins. The accumulated evidence supports the involvement of catecholamine oxidation in the degeneration of monoaminergic

Acknowledgements

—This work is supported by the NIH\NIDA Intramural Research Program.Lafon-Cazal et al. 1993b

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Invited Review Free radicals and the pathobiology of brain dopamine systems

Abstract

Introduction

Section snippets

Free radicals in the brain

Role of catecholamines in free radical production

Scavenging systems in the brain

Pathobiology of free radicals

Toxic effects of methamphetamine

Role of free radicals in Parkinson’s Disease

Conclusions

Acknowledgements

Pharmacol. Biochem. Behav.

Brain Res.

Brain.

Brain Res. Bull.

Brain Res.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Psychiat. Res.

Neuropharmacol.

J. Neurol. Sci.

Arch. Biochem. Biophys.

Neurosci. Lett.

Brain Res.

Neurosci. Lett.

Immunol. Today

Neurosci. Lett.

Free Radical Biol. Med.

Neuropharmacol.

Eur. J. Pharmacol.

Free Rad. Biol. Med.

Eur. J. Pharmacol.

Brain Res.

Brain Res.

Brain Res.

J. Biol. Chem.

Mol. Chem. Neuropath

Movement Disorders

Synapse

Neurol.

Br. J. Pharmacol.

Glia

J. Pharmacol. Exp. Ther.

J. Dev. Physiol.

J. Neurochem.

J. Neurochem

Brain Res. Bull.

J. Neurol. Sci.

J. Pharmacol. Exp. Ther.

Medical Hypotheses

Synapse

Integr. Psychiatry

Ann. N.Y. Acad. Sci.

J. Neurochem.

Physiol. Rev.

Neurol.

Neurol.

J. Pharmacol. Exp. Ther.

J. Pharmacol. Exp. Ther.

J. Neurosci.

J. Neurosci.