Novel anti-inflammatory therapy for Parkinson's disease

https://doi.org/10.1016/S0165-6147(03)00176-7Get rights and content

Abstract

Parkinson's disease (PD) is a movement disorder that is characterized by progressive degeneration of the nigrostriatal dopamine system. Although dopamine replacement can alleviate symptoms of the disorder, there is no proven therapy to halt the underlying progressive degeneration of dopamine-containing neurons. Recently, increasing evidence from human and animal studies has suggested that neuroinflammation is an important contributor to the neuronal loss in PD. Moreover, the pro-inflammatory agent lipopolysaccharide itself can directly initiate degeneration of dopamine-containing neurons or combine with other environmental factor(s), such as the pesticide rotenone, to exacerbate such neurodegeneration. These effects provide strong support for the involvement of inflammation in the pathogenesis of PD. Furthermore, growing experimental evidence demonstrates that inhibition of the inflammatory response can, in part, prevent degeneration of nigrostriatal dopamine-containing neurons in several animal models of PD, suggesting that inhibition of inflammation might become a promising therapeutic intervention for PD.

Section snippets

The deleterious role of neuroinflammation in PD

Inflammation is the first line of defence against injury and infection; however, an excessive inflammatory response can also be a source of additional injury to host cells [16]. The brain has a relatively low adaptive immune response but is vulnerable to innate immune reactions. Neurons, as a result of a lack of ability to divide and little ability to recover from injury, are extremely vulnerable to autodestructive immune and inflammatory processes 17, 18, 19. This might hinder the recovery of

The protective effect of glial cells in PD

As described above, an inflammatory response might contribute to neuronal degeneration in PD. However, some aspects of inflammation might actually be beneficial in combating the disease [16]. Different populations of glia can influence the fate of the injured neurons by complicated and perhaps conflicting actions. For example, it is believed that microglia secrete primarily neurotoxic factors whereas astroglia are a primary source of neurotrophic factors, although activated microglia and

Glial reaction in PD patients and experimental models

A glial response has been observed in the vicinity of dying dopamine-containing neurons in human postmortem SN from PD patients [2] and MPTP-intoxicated patients [1]. Markers of elevated accumulation of NO, ROS and pro-inflammatory cytokines such as TNF-α, IL-1β and interferon γ (IFN-γ) in the SN of PD patients have been demonstrated [21], indicating a state of chronic inflammation in the PD brain. Inflammation has also been implicated in the neurodegenerative process in animal models of PD

Protective effect of inhibition of microglial activation

Given that neuroinflammation is an important contributor to the chronic neurodegenerative process in PD models, and perhaps in PD itself, we propose that inhibition of inflammation could be a promising neuroprotective strategy (Table 1, Fig. 2). Indeed, emerging experimental evidence demonstrates that inhibition of the inflammatory response can attenuate the degeneration of dopamine-containing neurons in several models of PD, which lends strong support to our hypothesis. For example,

Inhibition of inflammation is a promising disease-modifying therapy for PD

The progressive nature of PD presents opportunities for therapeutic intervention aimed at halting the degenerative process. In idiopathic PD, symptoms become apparent when up to 70–80% of striatal dopamine and ∼50% of nigral dopamine-containing neurons are lost. Before reaching the clinically symptomatic stage, there is a preclinical period of 5–7 years. Both positron emission tomography (PET) and single-photon emission computed tomography (SPECT) imaging seem to be able to detect a decline in

Concluding remarks

The activation of microglia and astroglia observed in the nigrostriatal system of PD patients and animal models of PD suggests the involvement of neuroinflammation in the progression of PD. The observations that the inflammatory process, induced by pro-inflammatory agents, can result in the degeneration of dopamine-containing neurons further indicates that neuroinflammation is an important contributor to the neuronal loss in PD. Moreover, the experimental evidence that inhibition of the

Acknowledgements

We thank Michelle Block for reading this manuscript.

References (66)

  • E. Rousselet

    Role of TNF-alpha receptors in mice intoxicated with the parkinsonian toxin MPTP

    Exp. Neurol.

    (2002)
  • Z.H. Feng

    Cyclooxygenase-2-deficient mice are resistant to 1-methyl-4-phenyl1, 2, 3, 6-tetrahydropyridine-induced damage of dopaminergic neurons in the substantia nigra

    Neurosci. Lett.

    (2002)
  • T.B. Sherer

    Selective microglial activation in the rat rotenone model of Parkinson's disease

    Neurosci. Lett.

    (2003)
  • M. Mogi

    Increase in level of tumor necrosis factor (TNF)-alpha in 6-hydroxydopamine-lesioned striatum in rats without influence of systemic L-DOPA on the TNF-alpha induction

    Neurosci. Lett.

    (1999)
  • I. Kurkowska-Jastrzebska

    The inflammatory reaction following 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine intoxication in mouse

    Exp. Neurol.

    (1999)
  • K. Sairam

    Non-steroidal anti-inflammatory drug sodium salicylate, but not diclofenac or celecoxib, protects against 1-methyl-4-phenyl pyridinium-induced dopaminergic neurotoxicity in rats

    Brain Res.

    (2003)
  • A. Klegeris et al.

    Cyclooxygenase and 5-lipoxygenase inhibitors protect against mononuclear phagocyte neurotoxicity

    Neurobiol. Aging

    (2002)
  • P.L. McGeer et al.

    Inflammation, autotoxicity and Alzheimer disease

    Neurobiol. Aging

    (2001)
  • X. Lu

    Naloxone prevents microglia-induced degeneration of dopaminergic substantia nigra neurons in adult rats

    Neuroscience

    (2000)
  • J.W. Langston

    Evidence of active nerve cell degeneration in the substantia nigra of humans years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure

    Ann. Neurol.

    (1999)
  • P.L. McGeer

    Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson's and Alzheimer's disease brains

    Neurology

    (1988)
  • G.T. Liberatore

    Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease

    Nat. Med.

    (1999)
  • K. Sriram

    Mice deficient in TNF receptors are protected against dopaminergic neurotoxicity: implications for Parkinson's disease

    FASEB J.

    (2002)
  • H.M. Gao

    Distinct role for microglia in rotenone-induced degeneration of dopaminergic neurons

    J. Neurosci.

    (2002)
  • F. Cicchetti

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

    Eur. J. Neurosci.

    (2002)
  • A. Castano

    Lipopolysaccharide intranigral injection induces inflammatory reaction and damage in nigrostriatal dopaminergic system

    J. Neurochem.

    (1998)
  • W.G. Kim

    Regional difference in susceptibility to lipopolysaccharide-induced neurotoxicity in the rat brain: role of microglia

    J. Neurosci.

    (2000)
  • B. Liu

    Systemic infusion of naloxone reduces degeneration of rat substantia nigral dopaminergic neurons induced by intranigral injection of lipopolysaccharide

    J. Pharmacol. Exp. Ther.

    (2000)
  • D.C. Wu

    Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease

    J. Neurosci.

    (2002)
  • Y. Du

    Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson's disease

    Proc. Natl. Acad. Sci. U. S. A.

    (2001)
  • P. Teismann et al.

    Inhibition of the cyclooxygenase isoenzymes COX-1 and COX-2 provide neuroprotection in the MPTP-mouse model of Parkinson's disease

    Synapse

    (2001)
  • A. Compston

    Brain repair

    J. Intern. Med.

    (1995)
  • M.J. Carson et al.

    Balancing function versus self defense: the CNS as an active regulator of immune responses

    J. Neurosci. Res.

    (1999)
  • Cited by (302)

    View all citing articles on Scopus
    View full text