Evidence from postmortem analysis implicates the involvement of microglia in the neurodegenerative process of several degenerative neurological diseases, including Alzheimer's disease and Parkinson's disease. It remains to be determined, however, whether microglial activation plays a role in the initiation stage of disease progression or occurs merely as a response to neuronal death. Activated microglia secrete a variety of proinflammatory and neurotoxic factors that are believed to induce and/or exacerbate neurodegeneration. In this article, we summarize recent advances on the study of the role of microglia based on findings from animal and cell culture models in the pathogenesis of neurodegenerative diseases, with particular emphasis on Parkinson's disease. In addition, we also discuss novel approaches to potential therapeutic strategies.

Role of Microglia in Inflammation-Mediated Neurodegenerative Diseases: Mechanisms and Strategies for Therapeutic Intervention

Current concepts of the pathogenesis of Parkinson's disease (PD) center on the formation of reactive oxygen species and the onset of oxidative stress leading to oxidative damage to substantia nigra pars compacta. Extensive postmortem studies have provided evidence to support the involvement of oxidative stress in the pathogenesis of PD; in particular, these include alterations in brain iron content, impaired mitochondrial function, alterations in the antioxidant protective systems (most notably superoxide dismutase [SOD] and reduced glutathione [GSH]), and evidence of oxidative damage to lipids, proteins, and DNA. Iron can induce oxidative stress, and intranigral injections have been shown to induce a model of progressive parkinsonism. A loss of GSH is associated with incidental Lewy body disease and may represent the earliest biochemical marker of nigral cell loss. GSH depletion alone may not result in damage to nigral neurons but may increase susceptibility to subsequent toxic or free radical exposure. The nature of the free radical species responsible for cell death in PD remains unknown, but there is evidence of involvement of hydroxyl radical (OH.), peroxynitrite, and nitric oxide. Indeed, OH. and peroxynitrite formation may be critically dependent on nitric oxide formation. Central to many of the processes involved in oxidative stress and oxidative damage in PD are the actions of monoamine oxidase-B (MAO-B). MAO-B is essential for the activation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine to 1-methyl-4-phenylpyridinium ion, for a component of the enzymatic conversion of dopamine to hydrogen peroxide (H2O2), and for the activation of other potential toxins such as isoquinolines and beta-carbolines. Thus, the inhibition of MAO-B by drugs such as selegiline may protect against activation of some toxins and free radicals formed from the MAO-B oxidation of dopamine. In addition, selegiline may act through a mechanism unrelated to MAO-B to increase neurotrophic factor activity and upregulate molecules such as glutathione, SOD, catalase, and BCL-2 protein, which protect against oxidant stress and apoptosis. Consequently, selegiline may be advantageous in the long-term treatment of PD.

Oxidative stress and the pathogenesis of Parkinson's disease

Neuroinflammation in Parkinson's disease: its role in neuronal death and implications for therapeutic intervention.

Parkinson disease (PD) is an age-related neurodegenerative disorder that affects as many as 1-2% of persons aged 60 years and older. With the aging of the population, the frequency of PD is expected to increase dramatically in the coming decades. Current therapy is largely based on a dopamine replacement strategy, primarily using the dopamine precursor levodopa. However, chronic treatment is associated with the development of motor complications, and the disease is inexorably progressive. Further, advancing disease is associated with the emergence of features such as freezing, falling, and dementia which are not adequately controlled with dopaminergic therapies. Indeed, it is now appreciated that these nondopaminergic features are common and the major source of disability for patients with advanced disease. Many different therapeutic agents and treatment strategies have been evaluated over the past several years to try and address these unmet medical needs, and many promising approaches are currently being tested in the laboratory and in the clinic. As a result, there are now many new therapies and strategic approaches available for the treatment of the different stages of PD, with which the treating physician must be familiar in order to provide patients with optimal care. This monograph provides an overview of the management of PD patients, with an emphasis on pathophysiology, and the results of recent clinical trials. It is intended to provide physicians with an understanding of the different treatment options that are available for managing the different stages of the disease and the scientific rationale of the different approaches.

The scientific and clinical basis for the treatment of Parkinson disease (2009)

The etiology of sporadic Parkinson's disease (PD) remains unknown. Increasing evidence has suggested a role for inflammation in the brain in the pathogenesis of PD. However, it has not been clearly demonstrated whether microglial activation, the most integral part of the brain inflammatory process, will result in a delayed and progressive degeneration of dopaminergic neurons in substantia nigra, a hallmark of PD. We report here that chronic infusion of an inflammagen lipopolysaccharide at 5 ng/h for 2 weeks into rat brain triggered a rapid activation of microglia that reached a plateau in 2 weeks, followed by a delayed and gradual loss of nigral dopaminergic neurons that began at between 4 and 6 weeks and reached 70% by 10 weeks. Further investigation of the underlying mechanism of action of microglia-mediated neurotoxicity using rat mesencephalic neuron-glia cultures demonstrated that low concentrations of lipopolysaccharide (0.1-10 ng/mL)-induced microglial activation and production of neurotoxic factors preceded the progressive and selective degeneration of dopaminergic neurons. Among the factors produced by activated microglia, the NADPH oxidase-mediated release of superoxide appeared to be a predominant effector of neurodegeneration, consistent with the notion that dopaminergic neurons are particularly vulnerable to oxidative insults. This is the first report that microglial activation induced by chronic exposure to inflammagen was capable of inducing a delayed and selective degeneration of nigral dopaminergic neurons and that microglia-originated free radicals play a pivotal role in dopaminergic neurotoxicity in this inflammation-mediated model of PD.

https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1471-4159.2002.00928.x

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

Pargyline and deprenyl prevent the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in monkeys.

The pandemic of von Economo's disease which began in January 1917 preceded that of influenza of 1918-1919 by more than a year. Though it has been customary to link the two it seems unlikely that the latter was responsible for the former as has been proposed. It has been assumed that von Economo's disease (ED) was caused by a virus; but in fact the etiology is in question as no virus has yet been transmitted to experimental animals or cells in culture. However, the presence of oligoclonal IgG bands in the CSF of suspected cases and the finding of chronic active lesions in the brain tissue at autopsy suggests a viral etiology. Occasional, sporadic presumed cases of the disease have been reported within the last 25 years. Encephalitides due to established neurotropic viruses or to other viruses that may on occasion invade the CNS only rarely produce parkinsonism, and when they do it differs from that seen in ED. The present report reviews the overall concept of a viral etiology of Parkinson's disease with particular reference to von Economo's disease.

/pdf/postencephalitic-parkinsonism-a-review-4qz4q7grl0.pdf

Postencephalitic parkinsonism – a review

Antineurofilament antibodies in postencephalitic and idiopathic Parkinson's disease

— There are at present numerous pharmacological agents available for the control of parkinson symptoms. None are ideal; all have their limitations. The most potent is levodopa administered with a peripheral decarboxylase inhibitor. However, because its effectiveness declines after long-term use and side effects increase in severity, it should be reserved for individuals with established symptoms which are functionally impairing. In patients with minimal symptoms, anticholinergic agents, or agents which facilitate dopaminergic mechanisms normally operative in the nervous system, should be used. In a limited trial, deprenyl has produced promising results during this phase of parkinsonism. Deprenyl's major usefulness however, has been demonstrated in patients under treatment with levodopa which has become complicated by fluctuating responses – particularly those of the end-start-dose variety. In such patients, it is possible to achieve an increase in “on” time and a decrease in the severity of parkinsonism. In most patients, such a response can maintained for a period of two years or longer.

Treatment of Parkinson's disease in early and late phases. Use of pharmacological agents with special reference to deprenyl (selegiline).

Abnormal involuntary eye movements were found in 8 of 27 patients with Parkinson's disease who were receiving levodopa and dopa decarboxylase inhibitors. The dyskinetic eye movements were smooth, slow, “to-and-fro” ocular deviations of large amplitude. They were suppressed by visual fixation and were prominent only in darkness or behind closed lids when patients were alert. They generally appeared in conjunction with involuntary body and limb movements but could occur alone. Many of the patients with ocular dyskinesias had prominent “on-off” responses to levodopa. Ocular dyskinesias were present in 8 of 10 patients with bodily dyskinesias. This suggests that if recording conditions are appropriate, these eye movements will commonly be found in patients with Parkinson's disease who develop abnormal involuntary bodily movements while they are receiving levodopa therapy.

Melvin D. Yahr

Papers

Pargyline and deprenyl prevent the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in monkeys.

Postencephalitic parkinsonism – a review

Antineurofilament antibodies in postencephalitic and idiopathic Parkinson's disease

Treatment of Parkinson's disease in early and late phases. Use of pharmacological agents with special reference to deprenyl (selegiline).

Ocular dyskinesias in patients with Parkinson's disease treated with levodopa.