Protection from 1-methyl-4-phenylpyridinium (MPP+) toxicity and stimulation of regrowth of MPP+-damaged dopaminergic fibers by treatment of mesencephalic cultures with EGF and basic FGF

doi:10.1016/0006-8993(92)90855-4

Brain Research

Volume 599, Issue 1, 18 December 1992, Pages 83-97

https://doi.org/10.1016/0006-8993(92)90855-4 Get rights and content

Abstract

Several peptide growth factors can maintain survival or promote recovery of injured central neurons. In the present study, the effects of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) on the toxicity produced by the dopaminergic neurotoxin, 1-methyl-4-phenylpyridinium (MPP⁺), were investigated in rat mesencephalic dopaminergic neurons in culture. High affinity [³H]DA uptake and morphometric analyses of tyrosine hydroxylase immunostained neurons were used to assess the extent of MPP⁺ toxicity, dopaminergic neuronal survival and growth of neurites. Consistent with previous reports, EGF and bFGF treatments stimulated neuritic outgrowth in dopaminergic neurons, increased DA uptake and enhanced their long-term survival in vitro. These growth factors also stimulated proliferation of astrocytes. The time course of EGF and bFGF effects on dopaminergic neurons coincided with the increase in glial cell density, suggesting that proliferation of glia mediates their trophic effects. Several findings from our study support this possibility. When MPP⁺ was applied to cultures at 4 days in vitro, before glial cells had proliferated, the damage to dopaminergic neurons was not affected by EGF or bFGF pretreatments. However, when cultures maintained in the presence of the growth factors for 10 days were exposed to MPP⁺, after they had become confluent with dividing glial cells, the MPP⁺-induced decreases in DA uptake and cell survival were significantly attenuated. Furthermore, when glial cell proliferation was inhibited by 5-fluoro-2′-deoxyuridine, the protective effects of EGF and bFGF against MPP⁺ toxicity were abolished. Continuous treatment of MPP⁺-exposed cultures with EGF or bFGF resulted in the stimulation of process regrowth of damaged dopaminergic neurons with concomitant recovery of DA uptake, suggesting that the injured neurons are able to respond to the trophic effects of EGF and bFGF. In summary, our study shows that the trophic effects of EGF and bFGF on mesencephalic dopaminergic neurons include protection from the toxicity produced by MPP⁺ and promotion of recovery of MPP⁺-damaged neurons. Stimulation of glial cell proliferation is necessary for these effects.

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Protection from 1-methyl-4-phenylpyridinium (MPP+) toxicity and stimulation of regrowth of MPP+-damaged dopaminergic fibers by treatment of mesencephalic cultures with EGF and basic FGF

Abstract

Biochem. Biophys. Res. Commun.

Eur. J. Pharmacol.

Neuroscience

Neuron

Trends Neurosci.

Brain Res.

Dev. Biol.

Exp. Neurol.

Dev. Biol.

Neuroscience

Neuroscience

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Int. J. Dev. Neurosci.

Neurosci. Lett.

Life Sci.

Exp. Neurol.

Neurosci. Lett.

Neurosci. Lett.

FEBS Lett.

Brain Res.

Dev. Brain Res.

Neurosci. Lett.

Neuroscience

Brain Res. Bull.

Neurosci. Lett.

Dev. Brain Res.

Neuroscience

Brain Res.

Influences of the glial environment on the elongation of axons after injury

J. Exp. Biol.

Basic fibroblast growth factor prevents death of lesioned cholinergic neurons in vivo

Nature

Trophic interactions between astroglial cells and hippocampal neurons in culture

Science

Pretreatment of dopaminergic neurons in culture with brain-derived neurotrophic factor attenuates toxicity of 1-methyl-4-pheynylpyridinium

Neurodegeneration

Extensive elongation of axons from rat brain into peripheral nerve grafts

Nature

Regeneration of monoaminergic and cholinergic neurons in the mammalian central nervous system

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Adrenal medulla grafts enhance recovery of striatal dopaminergic fibers

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Protection from 1-methyl-4-phenylpyridinium (MPP⁺) toxicity and stimulation of regrowth of MPP⁺-damaged dopaminergic fibers by treatment of mesencephalic cultures with EGF and basic FGF