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3.14.1 MICROGLIA AND NEUROINFLAMMATION IN PD
Wednesday, 14 December 2011 / Parkinsonism and Related Disorders 18S2 (2012) S161–S234
Parallel Session 16:00–17:30 Role of Neuroinflammation in the Pathogenesis of PD Chairperson: Jianqing Ding, China 3.14.1 MICROGLIA AND NEUROINFLAMMATION IN PD S. Przedborski. Departments of Neurology, Pathology, and Cell Biology, Columbia University, New York, NY, USA Parkinson’s disease (PD) is the second most frequent neurodegenerative disorder of the aging brain after Alzheimer’s dementia. It has been established that degenerative changes in PD involve morphological and functional changes in glial cells and in infiltrating T-cells. For decades, gliosis in PD has been regarded as a secondary and mechanistically insignificant alteration. However, recent human epidemiological studies have now suggested that inflammation increases the risk of developing PD, and investigations in experimental models of PD have shown that the inflammatory response can modulate the extent of dopamineregic neuron degeneration. How such an innate immune response is triggered in PD, and where it takes place in the sequence of events that ultimately lead to the demise of dopaminergic neurons will be discussed. We will illustrate that, among specific pro-inflammatory factors, inducible NOS and NADPH-oxidase do play a role in the neurodegenerative process in experimental models of PD, but others, such as myeloperoxidase, do not. We will also discuss the issue of cyclooxygenase-2, which is a known pro-inflammatory enzyme in the periphery, but appears to stimulate dopaminergic neurodegeneration by a process possibly unrelated to inflammation. To conclude on a therapeutic note, we will present pre-clinical data obtained by a paradigm of vaccination, in which we tested the concept of modifying the inflammatory phenotype as a more promising avenue for neuroprotection. 3.14.2 NEUROINFLAMMATION AND PD E.C. Hirsch. CRICM, Experimental Therapeutics of Neurodegeneration, INSERM, CNRS, UPMC, ICM, Paris, France Both epidemiological and genetic studies support a role of neuroinflammation in the pathophysiology of Parkinson’s disease (PD). Furthermore, post mortem studies confirm the involvement of both innate and adaptive immunity in the affected brain regions in patients with PD. Indeed, activated microglial cell and T lymphocytes have been detected in the substantia nigra of patients concomitantly with an increased expression of pro-inflammatory cytokines. Studies in animal models indicate that inflammation is instrumental in the degenerative process although it is unlikely to be a primary cause for neuronal death. Neuroinflammatory processes in PD a rather involved in self-perpetuating processes that lead to protracted neuronal degeneration. In line with this, Glucocorticoid Receptors are important in curtailing microglial reactivity, and their deregulation in PD could lead to sustained inflammation-mediated degeneration. Altogether, neuroinflammatory processes might represent a target for neuroprotection in PD. 3.14.3 INFLAMMATION-MEDIATED DEGENERATION OF DOPAMINERGIC NEURONS: MECHANISMS, INTERVENTIONS AND RELEVANCE TO PARKINSON’S DISEASE J.-S. Hong. Neuropharmacology Section, Laboratory of Pharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA 1. Creation of a new rodent PD model: We have developed a new mouse PD model by a systemic injection of LPS (lipopolysaccharide). Mice showed delayed and progressive loss of DA neurons in the substantia nigra (SN) and motor functions. Studies also showed a persistent activation of microglia and prolonged increase in
S167
various pro-inflammatory factors. This model mimics the delayed and progressive nature of the disease symptoms in PD patients. 2. Studies on the progressive nature of inflammation-mediated neuro-degeneration: We formulated a “self-propelling cycle” model for further mechanistic study and development of therapeutic interventions. The major findings from this series of studies include: 1. Microglia are essential for the formation of chronic neuroinflammation and progression of neuro-degeneration, 2. Continuing neuronal death/damage is crucial for the long-term microglial activation, 3. Reactive microgliosis (neuronal death-induced reactivation of microglia) is responsible for the maintenance of long-term microglial activation and subsequent progressive neuronal death. 3. Development of glia-based therapy for PD: We have developed a “dual therapy” intervention strategy by: 1. modulating microglial activity so that neuro-inflammation can be dampened to controllable levels and becomes beneficial for neuronal survival, and 2. enhancing release of neurotrophic factors from astroglia. We discovered potent neuroprotection exerted by several groups of small molecules, such as valproate and memantine. 3.14.4 IMMUNIZATION STRATEGIES IN PD H. Gendelman, R.L. Mosley. Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA Parkinson’s disease is amongst the most devastating movement disorders. Currently, no curative treatments or treatments that interdict disease progression are available. Over the past decade, immunization strategies were developed in our laboratories to combat disease progression. These strategies were developed in laboratory and animal models of human disease. Induction of humoral immune responses were seen against misfolded protein aggregates. Robust adaptive immunity against nitrated misfolded protein(s) accelerated disease progression through specific effector T cell responses that facilitated neuronal death. Our works proposed that shifting the balance between effector and regulatory T cell activity can attenuate neurotoxic inflammatory events. This lecture will summarize our works for immune regulation in PD with an aim towards restoring homeostatic glial responses for therapeutic gain. New means to optimize immunization schemes and measure their clinical efficacy will be discussed. Parallel Session 16:00–17:30 Pain and Fatigue in PD Chairperson: Christian Baumann, Zurich, Switzerland 3.15.1 EPIDEMIOLOGY AND PHENOMENOLOGY Z. Zhang. Peking Union Medical College Hospital, Beijing, China We conducted a cross-sectional analysis with 901 Parkinson’s disease (PD) patients in China to understand the epidemiological characteristics of PD-pain among Chinese patients. In addition, we searched PubMed and CHKD for epidemiological studies of pain and fatigue among PD patients from 1999 to 2011 to understand the prevalence of these symptoms around the world and associated clinical features. The 901 PD cases were recruited from 42 university affiliated hospitals randomly selected from seven provincial capitals across four economic-regions of China. We documented motor and non-motor symptoms via clinical examinations and questionnaire surveys. Using logistic regression models, we evaluated factors that were associated with PD-pain among these Chinese patients. Of the 901 Chinese patients, 269 (29.9%) had PD-related pain. After adjusting for confounders, only dyskinesias (OR = 2.66) and depression (OR = 2.88) were independently associated with PD-pain.
Parallel Session 16:00–17:30 Role of Neuroinflammation in the Pathogenesis of PD Chairperson: Jianqing Ding, China 3.14.1 MICROGLIA AND NEUROINFLAMMATION IN PD S. Przedborski. Departments of Neurology, Pathology, and Cell Biology, Columbia University, New York, NY, USA Parkinson’s disease (PD) is the second most frequent neurodegenerative disorder of the aging brain after Alzheimer’s dementia. It has been established that degenerative changes in PD involve morphological and functional changes in glial cells and in infiltrating T-cells. For decades, gliosis in PD has been regarded as a secondary and mechanistically insignificant alteration. However, recent human epidemiological studies have now suggested that inflammation increases the risk of developing PD, and investigations in experimental models of PD have shown that the inflammatory response can modulate the extent of dopamineregic neuron degeneration. How such an innate immune response is triggered in PD, and where it takes place in the sequence of events that ultimately lead to the demise of dopaminergic neurons will be discussed. We will illustrate that, among specific pro-inflammatory factors, inducible NOS and NADPH-oxidase do play a role in the neurodegenerative process in experimental models of PD, but others, such as myeloperoxidase, do not. We will also discuss the issue of cyclooxygenase-2, which is a known pro-inflammatory enzyme in the periphery, but appears to stimulate dopaminergic neurodegeneration by a process possibly unrelated to inflammation. To conclude on a therapeutic note, we will present pre-clinical data obtained by a paradigm of vaccination, in which we tested the concept of modifying the inflammatory phenotype as a more promising avenue for neuroprotection. 3.14.2 NEUROINFLAMMATION AND PD E.C. Hirsch. CRICM, Experimental Therapeutics of Neurodegeneration, INSERM, CNRS, UPMC, ICM, Paris, France Both epidemiological and genetic studies support a role of neuroinflammation in the pathophysiology of Parkinson’s disease (PD). Furthermore, post mortem studies confirm the involvement of both innate and adaptive immunity in the affected brain regions in patients with PD. Indeed, activated microglial cell and T lymphocytes have been detected in the substantia nigra of patients concomitantly with an increased expression of pro-inflammatory cytokines. Studies in animal models indicate that inflammation is instrumental in the degenerative process although it is unlikely to be a primary cause for neuronal death. Neuroinflammatory processes in PD a rather involved in self-perpetuating processes that lead to protracted neuronal degeneration. In line with this, Glucocorticoid Receptors are important in curtailing microglial reactivity, and their deregulation in PD could lead to sustained inflammation-mediated degeneration. Altogether, neuroinflammatory processes might represent a target for neuroprotection in PD. 3.14.3 INFLAMMATION-MEDIATED DEGENERATION OF DOPAMINERGIC NEURONS: MECHANISMS, INTERVENTIONS AND RELEVANCE TO PARKINSON’S DISEASE J.-S. Hong. Neuropharmacology Section, Laboratory of Pharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA 1. Creation of a new rodent PD model: We have developed a new mouse PD model by a systemic injection of LPS (lipopolysaccharide). Mice showed delayed and progressive loss of DA neurons in the substantia nigra (SN) and motor functions. Studies also showed a persistent activation of microglia and prolonged increase in
S167
various pro-inflammatory factors. This model mimics the delayed and progressive nature of the disease symptoms in PD patients. 2. Studies on the progressive nature of inflammation-mediated neuro-degeneration: We formulated a “self-propelling cycle” model for further mechanistic study and development of therapeutic interventions. The major findings from this series of studies include: 1. Microglia are essential for the formation of chronic neuroinflammation and progression of neuro-degeneration, 2. Continuing neuronal death/damage is crucial for the long-term microglial activation, 3. Reactive microgliosis (neuronal death-induced reactivation of microglia) is responsible for the maintenance of long-term microglial activation and subsequent progressive neuronal death. 3. Development of glia-based therapy for PD: We have developed a “dual therapy” intervention strategy by: 1. modulating microglial activity so that neuro-inflammation can be dampened to controllable levels and becomes beneficial for neuronal survival, and 2. enhancing release of neurotrophic factors from astroglia. We discovered potent neuroprotection exerted by several groups of small molecules, such as valproate and memantine. 3.14.4 IMMUNIZATION STRATEGIES IN PD H. Gendelman, R.L. Mosley. Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA Parkinson’s disease is amongst the most devastating movement disorders. Currently, no curative treatments or treatments that interdict disease progression are available. Over the past decade, immunization strategies were developed in our laboratories to combat disease progression. These strategies were developed in laboratory and animal models of human disease. Induction of humoral immune responses were seen against misfolded protein aggregates. Robust adaptive immunity against nitrated misfolded protein(s) accelerated disease progression through specific effector T cell responses that facilitated neuronal death. Our works proposed that shifting the balance between effector and regulatory T cell activity can attenuate neurotoxic inflammatory events. This lecture will summarize our works for immune regulation in PD with an aim towards restoring homeostatic glial responses for therapeutic gain. New means to optimize immunization schemes and measure their clinical efficacy will be discussed. Parallel Session 16:00–17:30 Pain and Fatigue in PD Chairperson: Christian Baumann, Zurich, Switzerland 3.15.1 EPIDEMIOLOGY AND PHENOMENOLOGY Z. Zhang. Peking Union Medical College Hospital, Beijing, China We conducted a cross-sectional analysis with 901 Parkinson’s disease (PD) patients in China to understand the epidemiological characteristics of PD-pain among Chinese patients. In addition, we searched PubMed and CHKD for epidemiological studies of pain and fatigue among PD patients from 1999 to 2011 to understand the prevalence of these symptoms around the world and associated clinical features. The 901 PD cases were recruited from 42 university affiliated hospitals randomly selected from seven provincial capitals across four economic-regions of China. We documented motor and non-motor symptoms via clinical examinations and questionnaire surveys. Using logistic regression models, we evaluated factors that were associated with PD-pain among these Chinese patients. Of the 901 Chinese patients, 269 (29.9%) had PD-related pain. After adjusting for confounders, only dyskinesias (OR = 2.66) and depression (OR = 2.88) were independently associated with PD-pain.