Metallothionein, neurotrophins and selegiline in providing neuroprotection in Parkinson's disease

M. Ebadi, M. V. Ramana Kumari, M. Hiramatsu, R. Hao, Ronald Pfeiffer, P. Rojas

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

The finding that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) elicits parkinsonism in human beings suggests that endogenous or xenobiotic neurotoxic compounds may be involved in the etiology of Parkinson's disease (PD). We have shown that cerebrospinal fluid (CSF) of newly diagnosed and drug untreated patients with PD contains a low molecular weight substance(s) which inhibits the growth and function of dopaminergic neurons in culture. In addition, selegiline in a dosage below the level that inhibits monoamine oxidase B (MAO-B), protects dopaminergic neurons in culture against toxic factor(s) present in the CSF of patients with PD, and the said effect is mediated via elaboration of brain-derived neurotrophic factor (BDNF). In view of the fact that 6-hydroxydopamine (6-OHDA) or MPTP causes parkinsonism by generating free radicals, and inducers of metallothionein (MT) isoforms avert the said neurotoxicity, we intended to learn whether MT isoforms were capable of scavenging free radicals. By employing electron spin resonance spectroscopy (ESR), we examined for the first time the free radical scavenging effects of MT-I and MT-II isoforms on four types of free radicals. Solutions of 0.15 mM of MT-I and 0.3 mM of MT-II scavenged the 1,1-diphenyl- 2-picrylhydrazyl radicals completely. Furthermore, they were able to scavenge hydroxyl radicals generated in a Fenton reaction. Moreover, MT-I scavenged almost 90% of the superoxide generated by the hypoxanthine and xanthine oxidase system, while MT-II could only scavenge 40%. By using 2,2,6,6- tetramethyl-4-piperidone as a 'spin-trap' for the reactive oxygen species (containing singlet oxygen, superoxide and hydroxyl radicals) generated by photosensitized oxidation of riboflavin, and measuring the relative signal intensities of the resulting stable nitroxide adduct, 2,2,6,6-tetramethyl-4- piperidone-1-oxyl, we observed that MT-II could scavenge 92%, while MT-I could completely scavenge all the reactive species generated. The results of this investigation are interpreted to suggest that selegiline by preventing the generation of free radicals, MT isoforms by scavenging free radicals, and neurotrophins by rescuing dopaminergic neurons are capable of attenuating oxidative stress and of providing neuroprotection in PD.

Original languageEnglish (US)
Pages (from-to)103-111
Number of pages9
JournalRestorative Neurology and Neuroscience
Volume12
Issue number2-3
StatePublished - Jun 1998
Externally publishedYes

Fingerprint

Selegiline
Metallothionein
Nerve Growth Factors
Parkinson Disease
Free Radicals
Dopaminergic Neurons
Protein Isoforms
Oxidopamine
Parkinsonian Disorders
Superoxides
Hydroxyl Radical
Cerebrospinal Fluid
Reactive Oxygen Species
Neuroprotection
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Singlet Oxygen
Riboflavin
Xanthine Oxidase
Poisons
Brain-Derived Neurotrophic Factor

Keywords

  • 6-hydroxydopamine
  • And oxygen free radicals
  • Brain-derived neurotrophic factor
  • Dopamine
  • Nerve growth factor
  • Selegiline

ASJC Scopus subject areas

  • Neuroscience(all)
  • Neuropsychology and Physiological Psychology

Cite this

Metallothionein, neurotrophins and selegiline in providing neuroprotection in Parkinson's disease. / Ebadi, M.; Ramana Kumari, M. V.; Hiramatsu, M.; Hao, R.; Pfeiffer, Ronald; Rojas, P.

In: Restorative Neurology and Neuroscience, Vol. 12, No. 2-3, 06.1998, p. 103-111.

Research output: Contribution to journalArticle

Ebadi, M, Ramana Kumari, MV, Hiramatsu, M, Hao, R, Pfeiffer, R & Rojas, P 1998, 'Metallothionein, neurotrophins and selegiline in providing neuroprotection in Parkinson's disease', Restorative Neurology and Neuroscience, vol. 12, no. 2-3, pp. 103-111.
Ebadi, M. ; Ramana Kumari, M. V. ; Hiramatsu, M. ; Hao, R. ; Pfeiffer, Ronald ; Rojas, P. / Metallothionein, neurotrophins and selegiline in providing neuroprotection in Parkinson's disease. In: Restorative Neurology and Neuroscience. 1998 ; Vol. 12, No. 2-3. pp. 103-111.
@article{ea97559833dc4547bd99cd29ee1079f8,
title = "Metallothionein, neurotrophins and selegiline in providing neuroprotection in Parkinson's disease",
abstract = "The finding that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) elicits parkinsonism in human beings suggests that endogenous or xenobiotic neurotoxic compounds may be involved in the etiology of Parkinson's disease (PD). We have shown that cerebrospinal fluid (CSF) of newly diagnosed and drug untreated patients with PD contains a low molecular weight substance(s) which inhibits the growth and function of dopaminergic neurons in culture. In addition, selegiline in a dosage below the level that inhibits monoamine oxidase B (MAO-B), protects dopaminergic neurons in culture against toxic factor(s) present in the CSF of patients with PD, and the said effect is mediated via elaboration of brain-derived neurotrophic factor (BDNF). In view of the fact that 6-hydroxydopamine (6-OHDA) or MPTP causes parkinsonism by generating free radicals, and inducers of metallothionein (MT) isoforms avert the said neurotoxicity, we intended to learn whether MT isoforms were capable of scavenging free radicals. By employing electron spin resonance spectroscopy (ESR), we examined for the first time the free radical scavenging effects of MT-I and MT-II isoforms on four types of free radicals. Solutions of 0.15 mM of MT-I and 0.3 mM of MT-II scavenged the 1,1-diphenyl- 2-picrylhydrazyl radicals completely. Furthermore, they were able to scavenge hydroxyl radicals generated in a Fenton reaction. Moreover, MT-I scavenged almost 90{\%} of the superoxide generated by the hypoxanthine and xanthine oxidase system, while MT-II could only scavenge 40{\%}. By using 2,2,6,6- tetramethyl-4-piperidone as a 'spin-trap' for the reactive oxygen species (containing singlet oxygen, superoxide and hydroxyl radicals) generated by photosensitized oxidation of riboflavin, and measuring the relative signal intensities of the resulting stable nitroxide adduct, 2,2,6,6-tetramethyl-4- piperidone-1-oxyl, we observed that MT-II could scavenge 92{\%}, while MT-I could completely scavenge all the reactive species generated. The results of this investigation are interpreted to suggest that selegiline by preventing the generation of free radicals, MT isoforms by scavenging free radicals, and neurotrophins by rescuing dopaminergic neurons are capable of attenuating oxidative stress and of providing neuroprotection in PD.",
keywords = "6-hydroxydopamine, And oxygen free radicals, Brain-derived neurotrophic factor, Dopamine, Nerve growth factor, Selegiline",
author = "M. Ebadi and {Ramana Kumari}, {M. V.} and M. Hiramatsu and R. Hao and Ronald Pfeiffer and P. Rojas",
year = "1998",
month = "6",
language = "English (US)",
volume = "12",
pages = "103--111",
journal = "Restorative Neurology and Neuroscience",
issn = "0922-6028",
publisher = "IOS Press",
number = "2-3",

}

TY - JOUR

T1 - Metallothionein, neurotrophins and selegiline in providing neuroprotection in Parkinson's disease

AU - Ebadi, M.

AU - Ramana Kumari, M. V.

AU - Hiramatsu, M.

AU - Hao, R.

AU - Pfeiffer, Ronald

AU - Rojas, P.

PY - 1998/6

Y1 - 1998/6

N2 - The finding that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) elicits parkinsonism in human beings suggests that endogenous or xenobiotic neurotoxic compounds may be involved in the etiology of Parkinson's disease (PD). We have shown that cerebrospinal fluid (CSF) of newly diagnosed and drug untreated patients with PD contains a low molecular weight substance(s) which inhibits the growth and function of dopaminergic neurons in culture. In addition, selegiline in a dosage below the level that inhibits monoamine oxidase B (MAO-B), protects dopaminergic neurons in culture against toxic factor(s) present in the CSF of patients with PD, and the said effect is mediated via elaboration of brain-derived neurotrophic factor (BDNF). In view of the fact that 6-hydroxydopamine (6-OHDA) or MPTP causes parkinsonism by generating free radicals, and inducers of metallothionein (MT) isoforms avert the said neurotoxicity, we intended to learn whether MT isoforms were capable of scavenging free radicals. By employing electron spin resonance spectroscopy (ESR), we examined for the first time the free radical scavenging effects of MT-I and MT-II isoforms on four types of free radicals. Solutions of 0.15 mM of MT-I and 0.3 mM of MT-II scavenged the 1,1-diphenyl- 2-picrylhydrazyl radicals completely. Furthermore, they were able to scavenge hydroxyl radicals generated in a Fenton reaction. Moreover, MT-I scavenged almost 90% of the superoxide generated by the hypoxanthine and xanthine oxidase system, while MT-II could only scavenge 40%. By using 2,2,6,6- tetramethyl-4-piperidone as a 'spin-trap' for the reactive oxygen species (containing singlet oxygen, superoxide and hydroxyl radicals) generated by photosensitized oxidation of riboflavin, and measuring the relative signal intensities of the resulting stable nitroxide adduct, 2,2,6,6-tetramethyl-4- piperidone-1-oxyl, we observed that MT-II could scavenge 92%, while MT-I could completely scavenge all the reactive species generated. The results of this investigation are interpreted to suggest that selegiline by preventing the generation of free radicals, MT isoforms by scavenging free radicals, and neurotrophins by rescuing dopaminergic neurons are capable of attenuating oxidative stress and of providing neuroprotection in PD.

AB - The finding that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) elicits parkinsonism in human beings suggests that endogenous or xenobiotic neurotoxic compounds may be involved in the etiology of Parkinson's disease (PD). We have shown that cerebrospinal fluid (CSF) of newly diagnosed and drug untreated patients with PD contains a low molecular weight substance(s) which inhibits the growth and function of dopaminergic neurons in culture. In addition, selegiline in a dosage below the level that inhibits monoamine oxidase B (MAO-B), protects dopaminergic neurons in culture against toxic factor(s) present in the CSF of patients with PD, and the said effect is mediated via elaboration of brain-derived neurotrophic factor (BDNF). In view of the fact that 6-hydroxydopamine (6-OHDA) or MPTP causes parkinsonism by generating free radicals, and inducers of metallothionein (MT) isoforms avert the said neurotoxicity, we intended to learn whether MT isoforms were capable of scavenging free radicals. By employing electron spin resonance spectroscopy (ESR), we examined for the first time the free radical scavenging effects of MT-I and MT-II isoforms on four types of free radicals. Solutions of 0.15 mM of MT-I and 0.3 mM of MT-II scavenged the 1,1-diphenyl- 2-picrylhydrazyl radicals completely. Furthermore, they were able to scavenge hydroxyl radicals generated in a Fenton reaction. Moreover, MT-I scavenged almost 90% of the superoxide generated by the hypoxanthine and xanthine oxidase system, while MT-II could only scavenge 40%. By using 2,2,6,6- tetramethyl-4-piperidone as a 'spin-trap' for the reactive oxygen species (containing singlet oxygen, superoxide and hydroxyl radicals) generated by photosensitized oxidation of riboflavin, and measuring the relative signal intensities of the resulting stable nitroxide adduct, 2,2,6,6-tetramethyl-4- piperidone-1-oxyl, we observed that MT-II could scavenge 92%, while MT-I could completely scavenge all the reactive species generated. The results of this investigation are interpreted to suggest that selegiline by preventing the generation of free radicals, MT isoforms by scavenging free radicals, and neurotrophins by rescuing dopaminergic neurons are capable of attenuating oxidative stress and of providing neuroprotection in PD.

KW - 6-hydroxydopamine

KW - And oxygen free radicals

KW - Brain-derived neurotrophic factor

KW - Dopamine

KW - Nerve growth factor

KW - Selegiline

UR - http://www.scopus.com/inward/record.url?scp=0031846893&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0031846893&partnerID=8YFLogxK

M3 - Article

C2 - 12671304

AN - SCOPUS:0031846893

VL - 12

SP - 103

EP - 111

JO - Restorative Neurology and Neuroscience

JF - Restorative Neurology and Neuroscience

SN - 0922-6028

IS - 2-3

ER -