Elsevier

Brain Research Reviews

Volume 30, Issue 2, August 1999, Pages 153-163
Brain Research Reviews

Full-length review
Neurodegenerative disorders: the role of peroxynitrite

https://doi.org/10.1016/S0165-0173(99)00014-4Get rights and content

Abstract

Inflammatory reaction is thought to be an important contributor to neuronal damage in neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and the parkinsonism dementia complex of Guam. Among the toxic agents released in brain tissues by activated cells, we focus attention in this review on peroxynitrite, the product of the reaction between nitric oxide (NO) and superoxide. Peroxynitrite is a strong oxidizing and nitrating agent which can react with all classes of biomolecules. In the CNS it can be generated by microglial cells activated by pro-inflammatory cytokines or β-amyloid peptide (β-A) and by neurons in three different situations: hyperactivity of glutamate neurotransmission, mitochondrial dysfunction and depletion of l-arginine or tetrahydrobiopterin. The first two situations correspond to cellular responses to an initial neuronal injury and the peroxynitrite formed only exacerbates the inflammatory process, whereas in the third situation the peroxynitrite generated directly contributes to the initiation of the neurodegenerative process.

Introduction

The association of many proteins known to be involved in inflammatory processes with senile plaques and microfibrillary tangles in chronic neurodegenerative disorders like Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and the parkinsonism dementia complex of Guam is consistent with the autotoxic loop hypothesis developed by McGeer and McGeer 56, 57(Fig. 1).

These authors assume that in a first step, an initial insult promotes neuronal damage with the deposit of debris that activates the microglial cells leading to the release of cytotoxic agents and initiation of the classical complement cascade [80]. The toxic products thus produced cause neuronal death which in turn spurs an inflammatory reaction. This reaction can be a self-sustaining autodestructive force in which cell response injures bystander neurons and produces further lesions. Thus, a vicious cycle of damage can be generated and sustained.

Accumulating evidence has implicated not only reactive oxygen radicals but also nitric oxide (NO) in the inflammatory process. Here we provide a brief account of present knowledge regarding the product of the reaction between NO and superoxide (O2−), namely, peroxynitrite, which is thought to mediate the toxic action of these species [6]and play an important role in sustaining as well as initiating the inflammatory autotoxic loop in the pathogenesis of neurodegenerative disorders.

Section snippets

Formation of peroxynitrite and reactions with biological compounds

Radicals like NO and O2− have little propensity to react with non-radical biomolecules because such reactions are electronically unbalanced and do not result in additional bond formation which favors such reactions. However, the reaction rate for combination between NO and O2− occurs at the near diffusion-limited rate of 4.3 to 6.7×109 M−1 s−1 generating peroxynitrite 36, 60, 68, a potent oxidant and nitrating agent capable of attacking and modifying proteins, lipids and DNA as well as

The formation of peroxynitrite in the CNS

Because the concentrations of SOD and O2− in a given tissue are relatively constant, the primary driving force for peroxynitrite formation is the NO concentration. In the CNS, three NO-synthase isoforms, neuronal Type-I NOS, inducible Type-II NOS and endothelial Type-III NOS, can generate NO. They catalyze the formation of NO and citrulline from l-arginine via the intermediate Nω-hydroxyarginine (Fig. 3). (This review will not include a great deal of detail about the biochemistry and

Relevance of peroxynitrite to neurodegenerative disorders

Toxicity of peroxynitrite has been reported for cultured cells such as rat thymocytes 69, 70, neurons (peroxynitrite acting as an inhibitor of glutamate uptake) 85, 86and PC12 cells (large doses of peroxynitrite resulted in cell necrosis, whereas lower concentrations induced apoptosis) [22].

Peroxynitrite has also been suggested to contribute to tissue damage in AD, PD, MS, ALS and the parkinsonism dementia complex of Guam.

Peroxynitrite as a mediator of neuronal damage

The association of many inflammatory mediators with the lesions detected in the brain of patients with neurodegenerative disorders such as AD, PD, ALS and MS has led Mc Geer and Mc Geer 56, 57to assume that the neuronal damage observed in these diseases is caused by a chronic innate immune reaction in brain. In the autotoxic loop model proposed by these authors, the inflammatory reaction is not believed to be the primary cause of the neuronal damage but only the autotoxic response to an unknown

Acknowledgements

The authors thank Dr. Sharon Lynn Salhi for critical comments and help in preparing the manuscript.

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    Present address: Faculté des Sciences III — Tripoli nord-Liban BP: 826, Lebanon.

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