Die Effekte des α7-nikotinergen Acetylcholin-Agonisten PNU-282987 und des nikotinergen Acetylcholin-Antagonisten Mecamylamin auf Neuroinflammation und Neurodegeneration im akuten MPTP-Mausmodell des Morbus Parkinson

Das idiopathische Parkinson-Syndrom (IPS) zählt zu den häufigsten neurodegenerativen Erkrankungen. Es ist pathogenetisch durch die Degeneration dopaminerger Neurone und eine begleitende Neuroinflammation in der Substantia nigra pars compacta (SNpc) gekennzeichnet. Die Ätiologie der Erkrankung ist tr...

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Bibliographic Details
Main Author: Stuckenholz, Vanessa
Contributors: Dodel, Richard (Prof. Dr. med.) (Thesis advisor)
Format: Dissertation
Published: Philipps-Universität Marburg 2013
Online Access:PDF Full Text
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Table of Contents: Parkinson’s disease (PD) is one of the most common neurodegenerative disorders. Its pathogenetic hallmarks are the degeneration of dopaminergic neurons and an accompanying neuroinflammation in the substantia nigra pars compacta (SNpc). Despite intensive research, the aetiology of PD remains still unknown and there is no causal treatment yet available. Increasing evidence suggests that neuroinflammation in the SNpc caused by activated microglia is not only a result of dopaminergic neurodegeneration but also contributing to the cell loss. Damage of dopaminergic neurons in the SNpc results in an activation of microglial cells. Activated microglia produce a range of pro-inflammatory and potentially neurotoxic factors, e.g. the cytokines IL-1β, IL-6 and TNF-α, that can harm dopaminergic neurons in turn. This vicious circle – also known as reactive microgliosis – describes a self-propelling neurotoxicity which leads to a progressive neurodegeneration. During severe infections, the body has the potential to adjust the magnitude of inflammation by means of the inflammatory reflex by the autonomic nervous system. The efferent arm of this inflammatory reflex is termed the cholinergic anti-inflammatory signaling pathway. A major component of this pathway is the α7 nicotinic acetylcholine (α7 nACh) receptor which is expressed on immune cells like microglia. Its activation results in an inhibition of NFκB nuclear translocation, an activation of the Jak2/STAT3 signaling pathway and accordingly a decreased production of pro-inflammatory cytokines. Experimental models of several inflammatory diseases have shown that activation of the cholinergic anti-inflammatory signaling pathway can dampen inflammation and improve survival. Whether neuroinflammation caused by activated microglia in the SNpc can be affected by activation of the cholinergic anti-inflammatory signaling pathway and whether this could be a putative therapy approach of PD was to be examined in this study. Using the acute MPTP mouse model, the effects of the selective α7 nACh agonist PNU-282987 and the nACh antagonist mecamylamine have been investigated. The MPTP mouse model is the most commonly used animal model of Parkinson’s disease. As a neurotoxin MPTP selectively destroys dopaminergic neurons in the SNpc and induces PD. The relatively high dosing of the acute MPTP intoxication applied in this study (4x 20mg/kg body weight intraperitoneal at intervals of 2 hours) produces a distinct neuroinflammation and activation of microglia. To evaluate the extent of neuroinflammation the striatal concentrations of the pro-inflammatory cytokines IL-1β, IL-6 and TNF-α as well as of the anti-inflammatory cytokine IL-10 were quantified using an ELISA. The amount of activated microglia in the SNpc was assessed using immunohistochemistry. The impact of the treatment on dopaminergic neurodegeneration was assessed by means of the number of dopaminergic neurons in the SNpc. In addition, striatal levels of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid as well as the dopamine turnover were determined. Possible effects on motor performance were investigated using the rotarod test. Treatment with PNU-282987 resulted in an attenuation of neuroinflammation in the MPTP-lesioned SNpc. PNU-282987 was able to dampen activation of microglia in the SNpc and to diminish the MPTP-induced increase of striatal IL-1β and TNF-α. Furthermore, PNU-282987 attenuated the MPTP-induced dopaminergic cell loss in the SNpc and reduced striatal dopamine depletion. The concentration of DOPAC was increased as well. This neuroprotective effect of PNU-282987 is likely due to its anti-inflammatory potential, but may also be partly explained by its possible modulating effect on neurotransmitter release, as the α7 nACh receptor is also found presynaptically on neurons where it acts as a ligand-gated ion channel. Application of the nACh antagonist mecamylamine led to an attenuation of neuroinflammation against one’s expectations. It did not act neuroprotective though. This is probably due to its properties as an unselective nACh antagonist. The findings of this study strongly support the idea of a central cholinergic anti-inflammatory signaling pathway and demonstrate that activation of the α7 nACh receptor may provide a putative therapeutic target in the treatment of PD.