Melatonin protects against oxidative stress caused by 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine in the mouse nigrostriatum

Bobby Thomas, Kochupurackal P. Mohanakumar

Research output: Contribution to journalArticle

87 Citations (Scopus)

Abstract

We tested the hypothesis that melatonin acts as a powerful hydroxyl radical (OH) scavenger in vivo in the brain, and interferes with oxidative stress caused by the parkinsonian neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We investigated the effect of melatonin on in vitro OH production employing a Fenton-like reaction in test tubes, and ex vivo OH generation in isolated mitochondria induced by 1-methyl-4-phenyl pyridinium (MPP+), as well as on in vivo OH formation in the mouse striatum following systemic administration of MPTP. We also measured reduced glutathione (GSH) levels, and superoxide dismutase (SOD) activity in the nucleus caudatus putamen (NCP) and substantia nigra (SN), 7 days following MPTP and/or melatonin administration. Melatonin caused a significant and dose-dependent inhibition of the production of OH in the in vitro, ex vivo and in vivo experimental conditions. Melatonin caused no changes in monoamine oxidase-B activity, in vitro in mitochondrial P2 fractions or in vivo following systemic administration. MPTP treatment in mice caused a significant depletion of GSH, and increased the specific activity of SOD both in SN and NCP on the seventh day. MPTP-induced GSH depletion was dose-dependently blocked in SN and NCP by melatonin. Higher doses of melatonin exhibited a synergistic effect on MPTP-induced increase in the SOD activity in the SN. These results suggest that while GSH inhibition is a direct consequence of OH generation following neurotoxin administration, the increase in SOD activity is a compensatory mechanism for removing superoxide radicals generated as the result of MPTP. Our results not only point to the potency of melatonin in blocking the primary insults caused by MPTP, but also provide evidence for triggering secondary neuroprotective mechanisms, suggesting its use as a therapeutic agent in neurodegenerative disorders, such as Parkinson's disease.

Original languageEnglish (US)
Pages (from-to)25-32
Number of pages8
JournalJournal of Pineal Research
Volume36
Issue number1
DOIs
StatePublished - Jan 1 2004

Fingerprint

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Melatonin
Oxidative Stress
Substantia Nigra
Superoxide Dismutase
Caudate Nucleus
Putamen
Neurotoxins
1-Methyl-4-phenylpyridinium
Monoamine Oxidase
Superoxides
Neurodegenerative Diseases
Hydroxyl Radical
Glutathione
Parkinson Disease
Mitochondria
Brain

Keywords

  • Endogenous antioxidant molecules and enzymes
  • Experimental Parkinson's disease
  • Fenton-like reaction
  • Glutathione
  • MPP-induced OH generation in mitochondria
  • Neuroprotective therapy
  • Superoxide dismutase

ASJC Scopus subject areas

  • Endocrinology

Cite this

Melatonin protects against oxidative stress caused by 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine in the mouse nigrostriatum. / Thomas, Bobby; Mohanakumar, Kochupurackal P.

In: Journal of Pineal Research, Vol. 36, No. 1, 01.01.2004, p. 25-32.

Research output: Contribution to journalArticle

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