Neuroglial responses to the dopaminergic neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mouse striatum

doi:10.1016/0892-0362(94)00048-I

Neurotoxicology and Teratology

Volume 17, Issue 1, January–February 1995, Pages 7-12

https://doi.org/10.1016/0892-0362(94)00048-I Get rights and content

Abstract

We have studied the reactive responses of both astrocytes and microglia to dopaminergic denervation of the Striatum by MPTP. Following MPTP treatment, increased GFAP immunoreactivity reached a peak at 2 days and persisted for at least 6 weeks. Immunoreactivity to vimentin was also markedly increased in astrocytes 48 h after MPTP treatment. Striatal laminin immunoreactivity, however, appeared to be unaffected by drug treatment. GFAP protein levels increased to 196% and 321% of control 24 and 48 hours after MPTP treatment, respectively. Concomitantly, GFAP mRNA levels increased to 560% and 1620% of control, respectively. These reactive changes in Striatal astrocytes in response to MPTP treatment were also accompanied by a reactive microglial response as evidenced by increased immunohistochemical visualization of striatal microglia using antibodies to Mac-1. Our results and those reported previously by O'Callaghan et al., strongly suggest that MPTP-induced reactive gliosis in mouse striatum is associated with reactive microglia, albeit without increased interleukin-1β.

References (43)

H. Akiyama et al.
Microglial response to 6-hydroxydopamine-induced substantia nigra lesions
Brain Res.
(1989)
P.J. Coffey et al.
An investigation into the early stages of inflammatory response following ibotenic acid-induced neuronal degeneration
Neuroscience
(1990)
D. Dahl et al.
Filament proteins in rat optic nerves undergoing Wallerian degeneration: Localization of vimentin, the fibroblastic 100-A protein, in normal and reactive astrocytes
Exp. Neurol.
(1981)
L.F. Eng
Glial fibrillary acidic protein (GFAP): The major protein of glial intermediate filaments in differentiated astrocytes
J. Neuroimmunol.
(1985)
A.M. Fagan et al.
Cholinergic sprouting in the hippocampus: A proposed role for IL-1
Exp. Neurol.
(1990)
S.A. Frautschy et al.
Localization of fibroblast growth factor and its mRNA after CNS injury
Brain Res.
(1991)
I. Hozumi et al.
GFAP mRNA levels following stab wounds in rat brains
Brain Res.
(1990)
I. Hozumi et al.
Biochemical and immunocytochemical changes in glial fibrillary acidic protein after stab wounds
Brain Res.
(1990)
Y. Matsumoto et al.
Immunohistochemical study on neuroglia identified by the monoclonal antibody against a macrophage differentiation antigen (Mac-1)
J. Neuroimmunol.
(1985)
M. Mogi et al.
Effects of repeated systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine on striatal tyrosine hydroxylase activity in vitro and tyrosine hydroxylase content
Neurosci. Lett.
(1987)

J.P. O'Callaghan et al.

Characterization of the origins of astrocyte response to injury using the dopaminergic neurotoxicant, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

Brain Res.

(1990)

M. Ogawa et al.

Astroglial cell alteration caused by neurotoxins: Immunohistochemical observations with antibodies to glial fibrillary acidic protein, laminin, and tyrosine hydroxylase

Exp. Neurol.

(1989)

V.H. Perry et al.

Immunohistochemical localization of macrophages and microglia in the adult and developing mouse brain

Neuroscience

(1985)

S. Pixley et al.

Transition between immature radial glia and mature astrocytes studied with a monoclonal antibody to vimentin

Dev. Brain Res.

(1984)

J.F. Reinhard et al.

The neurotoxicant MPTP increases glial fibrillary acidic protein and decreases dopamine levels of the mouse striatum: evidence for glial response to injury

Neurosci. Lett.

(1988)

I. Stromberg et al.

Astrocytic responses to dopaminergic denervations by 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine as evidenced by glial fibrillary acidic protein immunohistochemistry

Brain Res. Bull.

(1986)

D.A. Aquino et al.

Glial fibrillary acidic protein increases in the spinal cord of Lewis rats with acute experimental autoimmune encephalomyelitis

J. Neurochem.

(1988)

D. Aquino et al.

Expression of glial fibrillary acidic protein and neurofilament mRNA in gliosis induced by experimental autoimmune encephalomyelitis

J. Neurochem.

(1990)

D.I. Beller et al.

Anti-Mac-1 selectively inhibits the mouse and human type three complement receptor

J. Exp. Med.

(1982)

R.S. Burns et al.

A primate model of parkinsonism: Selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

J.M. Chirgwin et al.

Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease

Biochemistry

(1979)

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ArticleNeuroglial responses to the dopaminergic neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mouse striatum

Abstract

Brain Res.

Neuroscience

Exp. Neurol.

J. Neuroimmunol.

Exp. Neurol.

Brain Res.

Brain Res.

Brain Res.

J. Neuroimmunol.

Neurosci. Lett.

Brain Res.

Exp. Neurol.

Neuroscience

Dev. Brain Res.

Neurosci. Lett.

Brain Res. Bull.

Glial fibrillary acidic protein increases in the spinal cord of Lewis rats with acute experimental autoimmune encephalomyelitis

J. Neurochem.

Expression of glial fibrillary acidic protein and neurofilament mRNA in gliosis induced by experimental autoimmune encephalomyelitis

J. Neurochem.

Anti-Mac-1 selectively inhibits the mouse and human type three complement receptor

J. Exp. Med.

A primate model of parkinsonism: Selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease

Biochemistry

Article
Neuroglial responses to the dopaminergic neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mouse striatum