Time-course of nigrostriatal neurodegeneration and neuroinflammation in the 6-hydroxydopamine-induced axonal and terminal lesion models of Parkinson's disease in the rat

doi:10.1016/j.neuroscience.2010.12.005

Neuroscience

Volume 175, 17 February 2011, Pages 251-261

https://doi.org/10.1016/j.neuroscience.2010.12.005 Get rights and content

Abstract

The pathogenesis of Parkinson's disease is thought to involve a self-sustaining cycle of neuroinflammation and neurodegeneration. In order to develop novel anti-inflammatory therapies to break this cycle, it is crucial that the temporal relationship between neurodegeneration and neuroinflammation is characterised in pre-clinical models to maximise their predictive validity. Thus, this study aimed to investigate the progression of neuroinflammation relative to nigrostriatal neurodegeneration in the two most commonly-used rat models of Parkinson's disease. Male Sprague–Dawley rats were lesioned by terminal or axonal administration of 6-hydroxydopamine, and were sacrificed for quantitative immunohistochemistry (to assess nigrostriatal integrity (anti-tyrosine hydroxylase), microgliosis (anti-OX42) and astrocytosis (anti-GFAP)) at 6 h 24 h 72 h or 2 weeks post-lesion. Following terminal lesion, dopaminergic deafferentation of the striatum was evident from 6 h post-lesion and was accompanied by microglial and astroglial activation. Dopamine neuron loss from the substantia nigra did not occur until 2 weeks after terminal lesion, and this was preceded by microglial, but not astroglial, activation. Following axonal lesion, retraction of nigrostriatal terminals from the striatum was not observed until the 72 h time-point, and this was associated with a slight astrocytosis, but not microgliosis. Degeneration of dopaminergic neurons from the substantia nigra was also evident from 72 h after axonal lesion, and was accompanied by nigral microgliosis and astrocytosis by 2 weeks. This study highlights the temporal relationship between neurodegeneration and neuroinflammation in models of Parkinson's disease, and should facilitate use of these models in the development of anti-inflammatory therapies for the human condition.

Research Highlights

▶Spatiotemporal pattern of neuroinflammation differs in the 6-hydroxydopamine-induced axonal and terminal lesion models of Parkinson's disease. ▶The terminal lesion is associated with rapid striatal microglial activation and dopaminergic deafferentation. ▶In both lesion models, activation of glial cells precedes or coincides with 6-hydroxydopamine-induced nigrostriatal degeneration.

Section snippets

Animals

Male Sprague–Dawley rats (Charles River, UK) were used in this study (n=82), weighing 225–250 g at the start of the experiment. They were housed under a 12 h light:dark cycle in a room maintained at 21±2 °C and had access to food and water ad libitum. All procedures were carried out under licence from the Irish Department of Health and Children, were approved by the Animal Care and Research Ethics Committee of the National University of Ireland, Galway and were in compliance with the European

Time-course of neurodegeneration following terminal and axonal lesion

Quantitative TH immunostaining was used to determine the time-course of nigrostriatal neurodegeneration induced by injection of 6-hydroxydopamine or vehicle into the nigrostriatal terminals or axons.

Discussion

This study sought to establish the temporal relationship between nigrostriatal neurodegeneration and neuroinflammation in the two most commonly used rat models of Parkinson's disease—those induced by terminal or axonal administration of the catecholaminergic neurotoxin 6-hydroxydopamine. Although a number of other studies have investigated the neuroinflammatory response in terminal and axonal 6-hydroxydopamine lesion models, to our knowledge, none have directly compared the time-course of

Acknowledgments

S. Walsh is a recipient of an EMBARK PhD studentship from the Irish Research Council for Science, Engineering and Technology.

References (44)

H. Akiyama et al.
Microglial response to 6-hydroxydopamine-induced substantia nigra lesions
Brain Res
(1989)
G. Ambrosi et al.
Effects of early and delayed treatment with an mGluR5 antagonist on motor impairment, nigrostriatal damage and neuroinflammation in a rodent model of Parkinson's disease
Brain Res Bull
(2010)
O. Butovsky et al.
Activation of microglia by aggregated beta-amyloid or lipopolysaccharide impairs MHC-II expression and renders them cytotoxic whereas IFN-gamma and IL-4 render them protective
Mol Cell Neurosci
(2005)
H.M. Gao et al.
Why neurodegenerative diseases are progressive: uncontrolled inflammation drives disease progression
Trends Immunol
(2008)
S. Grealish et al.
Unilateral axonal or terminal injection of 6-hydroxydopamine causes rapid-onset nigrostriatal degeneration and contralateral motor impairments in the rat
Brain Res Bull
(2008)
Y. He et al.
Minocycline inhibits microglial activation and protects nigral cells after 6-hydroxydopamine injection into mouse striatum
Brain Res
(2001)
J. Henning et al.
Differential astroglial activation in 6-hydroxydopamine models of Parkinson's disease
Neurosci Res
(2008)
E.C. Hirsch et al.
Neuroinflammation in Parkinson's disease: a target for neuroprotection?
Lancet Neurol
(2009)
J. Iczkiewicz et al.
Osteopontin expression in activated glial cells following mechanical- or toxin-induced nigral dopaminergic cell loss
Exp Neurol
(2007)
C. Rosenblad et al.
Sequential administration of GDNF into the substantia nigra and striatum promotes dopamine neuron survival and axonal sprouting but not striatal reinnervation or functional recovery in the partial 6-OHDA lesion model
Exp Neurol
(2000)

L. Zecca et al.

Neuromelanin of the substantia nigra: a neuronal black hole with protective and toxic characteristics

Trends Neurosci

(2003)

F. Blandini et al.

Time-course of nigrostriatal damage, basal ganglia metabolic changes and behavioural alterations following intrastriatal injection of 6-hydroxydopamine in the rat: new clues from an old model

Eur J Neurosci

(2007)

Y.C. Chung et al.

The role of neuroinflammation on the pathogenesis of Parkinson's disease

BMB Reproduction

(2010)

F. Cicchetti et al.

Neuroinflammation of the nigrostriatal pathway during progressive 6-OHDA dopamine degeneration in rats monitored by immunohistochemistry and PET imaging

Eur J Neurosci

(2002)

G.J. Counelis et al.

Bilateral subthalamic nucleus deep brain stimulation for advanced PD: correlation of intraoperative MER and postoperative MRI with neuropathological findings

Mov Disord

(2003)

S. Crotty et al.

Neuroprotective effects of novel phosphatidylglycerol-based phospholipids in the 6-hydroxydopamine model of Parkinson's disease

Eur J Neurosci

(2008)

A.M. Depino et al.

Microglial activation with atypical proinflammatory cytokine expression in a rat model of Parkinson's disease

Eur J Neurosci

(2003)

D.J. DiLorenzo et al.

Long-term deep brain stimulation for essential tremor: 12-year clinicopathologic follow-up

Mov Disord

(2010)

A.M. Floden et al.

Beta-amyloid-stimulated microglia induce neuron death via synergistic stimulation of tumor necrosis factor alpha and NMDA receptors

J Neurosci

(2005)

C. Gaig et al.

When does Parkinson's disease begin?

Mov Disord

(2009)

H.M. Gao et al.

Microglial activation-mediated delayed and progressive degeneration of rat nigral dopaminergic neurons: relevance to Parkinson's disease

J Neurochem

(2002)

G.A. Garden et al.

Microglia biology in health and disease

J Neuroimmune Pharmacol

(2006)

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Neurodegeneration, Neuroprotection, and Disease-Oriented NeuroscienceResearch PaperTime-course of nigrostriatal neurodegeneration and neuroinflammation in the 6-hydroxydopamine-induced axonal and terminal lesion models of Parkinson's disease in the rat

Abstract

Research Highlights

Section snippets

Animals

Time-course of neurodegeneration following terminal and axonal lesion

Discussion

Acknowledgments

Brain Res

Brain Res Bull

Mol Cell Neurosci

Trends Immunol

Brain Res Bull

Brain Res

Neurosci Res

Lancet Neurol

Exp Neurol

Exp Neurol

Trends Neurosci

Time-course of nigrostriatal damage, basal ganglia metabolic changes and behavioural alterations following intrastriatal injection of 6-hydroxydopamine in the rat: new clues from an old model

Eur J Neurosci

The role of neuroinflammation on the pathogenesis of Parkinson's disease

BMB Reproduction

Neuroinflammation of the nigrostriatal pathway during progressive 6-OHDA dopamine degeneration in rats monitored by immunohistochemistry and PET imaging

Eur J Neurosci

Bilateral subthalamic nucleus deep brain stimulation for advanced PD: correlation of intraoperative MER and postoperative MRI with neuropathological findings

Mov Disord

Neuroprotective effects of novel phosphatidylglycerol-based phospholipids in the 6-hydroxydopamine model of Parkinson's disease

Eur J Neurosci

Microglial activation with atypical proinflammatory cytokine expression in a rat model of Parkinson's disease

Eur J Neurosci

Long-term deep brain stimulation for essential tremor: 12-year clinicopathologic follow-up

Mov Disord

Beta-amyloid-stimulated microglia induce neuron death via synergistic stimulation of tumor necrosis factor alpha and NMDA receptors

J Neurosci

When does Parkinson's disease begin?

Mov Disord

Microglial activation-mediated delayed and progressive degeneration of rat nigral dopaminergic neurons: relevance to Parkinson's disease

J Neurochem

Microglia biology in health and disease

J Neuroimmune Pharmacol

Neurodegeneration, Neuroprotection, and Disease-Oriented Neuroscience
Research Paper
Time-course of nigrostriatal neurodegeneration and neuroinflammation in the 6-hydroxydopamine-induced axonal and terminal lesion models of Parkinson's disease in the rat