Acetaminophen and aspirin inhibit superoxide anion generation and lipid peroxidation, and protect against 1-methyl-4-phenyl pyridinium-induced dopaminergic neurotoxicity in rats

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Abstract

We assessed the antioxidant activity of non-narcotic analgesics, acetaminophen and aspirin in rat brain homogenates and neuroprotective effects in vivo in rats intranigrally treated with 1-methyl-4-phenyl pyridinium (MPP+). Both drugs inhibited cyanide-induced superoxide anion generation, as well as lipid peroxidation in rat brain homogenates, the combination of the agents resulting in a potentiation of this effect. Acetaminophen or aspirin when administered alone or in combination, did not alter dopamine (DA) levels in the forebrain or in the striatum. Intranigral infusion of MPP+ in rats caused severe depletion of striatal DA levels in the ipsilateral striatum in rats by the third day. Systemic post-treatment of acetaminophen afforded partial protection, whereas similar treatment of aspirin resulted in complete blockade of MPP+-induced striatal DA depletion. While these findings suggest usefulness of non-narcotic analgesics in neuroprotective therapy in neurodegenerative diseases, aspirin appears to be a potential candidate in prophylactic as well as in adjuvant therapy in Parkinson’s disease.

Introduction

The brain is a primary target organ in cyanide toxicity (Gunasekar et al., 1996). Acute toxicity of cyanide produces tonic and clonic seizures, convulsions (Way, 1984) and in some individuals a Parkinson-like condition may develop as a post toxicity sequel (Utti et al., 1985). Cyanide produces dopaminergic toxicity, characterized by loss of dopaminergic neurons in the basal ganglia, which is accompanied by impaired motor function (Gunasekar et al., 1996). Due to the number of antioxidant enzymes being inhibited by cyanide, it is also believed that oxidative stress plays an important role in cyanide induced neurotoxicity (Ardelt et al., 1989). Johnson et al. (1987) proposed that increased intracellular calcium after cyanide treatment generates reactive oxygen species leading to peroxidation of lipids and subsequent neuronal damage.

Parkinson’s disease (PD) is a debilitating disorder characterized by tremor, rigidity, and immobility. The biochemical basis of the disorder is a deficiency in the neurotransmitter, dopamine (DA) in the nigro-striatal pathway in the brain due to destruction of dopaminergic neurons (Piggott et al., 1999). The clinical symptoms of this disorder only manifest after about 80% of the neurons are lost. A persistent increase in free radical generation is believed to be the cause of neuronal death, which reaches more than 80% by middle age (Koutsilieri et al., 2002). Thus, neuroprotective strategies employing antioxidants is one approach to protect neurons and to curtail the progression of this disorder. There is thus a dire need to search for neuroprotective agents with novel mechanisms and to assess their potential benefit in such disorders. It has recently been shown that acetaminophen administration in rats induces a rise in brain serotonin and norepinephrine levels (Courade et al., 2000). Since this agent is often combined with aspirin, a drug known to exhibit antioxidant effects in the brain (Daya et al., 2000), we decided to investigate firstly, the antioxidant effects of these drugs alone and in combination using rat brain homogenates and secondly, to determine the effects of these agents alone and in combination on rat forebrain DA and 3,5-dihydroxyphenyl acetic acid (DOPAC) levels. Since the metabolite of aspirin, salicylic acid is known to protect against nigrostriatal DA toxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (Mohanakumar et al., 2000, Sairam et al., 2003), we finally tested these two non-narcotic anti-inflammatory drugs in 1-methyl-4-phenyl pyridinium (MPP+)-induced DA neurotoxicity in rats. Finally, we tested whether either of these drugs are capable of reviving MPP+-induced dopaminergic neurotoxicity.

Section snippets

Chemicals

Aspirin, acetaminophen, potassium cyanide (KCN), 2-thiobarbituric acid (TBA), 1,1,3,3-tetramethoxypropane (98%) and butylated hydroxytoluene (BHT), DA, DOPAC, heptane sulfonic acid, MPP+, nitroblue diformazan (NBD) and nitroblue tetrazolium (NBT) were purchased from Sigma Chemical Co., St. Louis, Mo. Trichloroacetic acid (TCA), butanol and glacial acetic acid were purchased from SAARCHEM (PTY) Ltd., Krugersdorp, South Africa. All other bench reagents were purchased from Merck, Darmstadt,

Lipid peroxidation

Exposure of the rat brain homogenate to 1 mM KCN caused a significant and marked rise in lipid peroxidation in comparison to the control (Fig. 1). However, this rise in MDA concentration was significantly reduced by 37% for acetaminophen, 21% for aspirin and by 65% for the combination of acetaminophen and aspirin (1 mM). In data not shown, 0.25 and 0.5 mM of acetaminophen and the combination of acetaminophen with aspirin significantly reduced the rise in lipid peroxidation caused by 1 mM KCN. A

Discussion

The search for neuroprotective agents in neurodegenerative diseases such as PD involves a number of screening methods to detect their ability to quench dangerous free radicals, to reduce lipid peroxidation and ultimately prevent neuronal death. In PD it is the free radicals, which ultimately bring about neuronal death of the dopaminergic neurons in the substantia nigra (Koutsilieri et al., 2002). An agent that could provide these neuroprotective effects and restore striatal DA levels would have

Acknowledgements

This study was made possible by a grant from the South African Medical Research Council and National Research Council to Dr. S. Daya. D.S. Maharaj thanks the Andrew Mellon Foundation and Medical Research Council (South Africa) for her Ph.D. scholarship. KSS is a Senior Research Fellow of the Council of Scientific & Industrial Research. Partially funded by the National Bioscience Award to KPM from Department of Biotechnology, Government of India. The authors would like to thank Sally and Dave

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