The α7 nAChR agonist PNU-282987 reduces inflammation and MPTP-induced nigral dopaminergic cell loss in mice.
BACKGROUND
Parkinson's disease (PD) is associated with neurodegeneration of dopaminergic neurons and an accompanying neuroinflammatory process in the substantia nigra (SN). The cholinergic anti-inflammatory signalling pathway allows the autonomic nervous system to modulate immunologic stimuli and inflammatory processes. A major component of this pathway is the α7 nicotinic acetylcholine receptor (α7 nACh receptor), which is expressed on immune cells such as microglia.


OBJECTIVE
To determine the role of this cholinergic anti-inflammatory signalling pathway, we investigated the effects of the selective α7 nACh agonist PNU-282987 and of the non-competitive nACh antagonist mecamylamine on microglia-induced neuroinflammation and toxin-induced degeneration of dopaminergic neurons in a mouse model of PD.


METHODS
PNU-282987, mecamylamine or placebo administration was started one day before MPTP intoxication and repeated daily until sacrifice after MPTP intoxication. C57Bl/6 mice were injected intraperitoneally four times at 2 h intervals with either 20 mg/kg MPTP-HCl or a corresponding volume of saline. Two or seven days after the end of the MPTP intoxication, the animals were killed and their brains were processed for further analysis.


RESULTS
Treatment with PNU-282987 resulted in an attenuation of neuroinflammation in the MPTP-lesioned SN. Furthermore, PNU-282987 attenuated MPTP-induced dopaminergic cell loss in the SN and reduced striatal dopamine depletion. Unexpectedly, mecamylamine lowered neuroinflammation as well, though it did not show a neuroprotective potential at the nigral level.


CONCLUSIONS
Our results demonstrate the therapeutic potential of the selective α7 nicotinic acetylcholine agonist PNU-282987 in attenuating neuroinflammation and toxin-induced loss of dopaminergic neurons in the acute MPTP mouse model of PD.
Department of Neurology, Philipps-University of Marburg, Baldingerstrasse, Marburg, Germany.
Vanessa
V
Stuckenholz
Michael
M
Bacher
Monika
M
Balzer-Geldsetzer
Daniel
D
Alvarez-Fischer
Wolfgang H
WH
Oertel
Richard C
RC
Dodel
Carmen
C
Noelker
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000627:therapeutic use*; D001643:Bridged Bicyclo Compounds / Q000627:therapeutic use*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects; D004660:Encephalitis / Q000188:drug therapy* / Q000209:etiology*; D004797:Enzyme-Linked Immunosorbent Assay; D006719:Homovanillic Acid / Q000378:metabolism; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism; D018722:Nicotinic Agonists / Q000494:pharmacology; D020734:Parkinsonian Disorders / Q000150:complications*
C491049:Aif1 protein, mouse; D001549:Benzamides; D001643:Bridged Bicyclo Compounds; D002135:Calcium-Binding Proteins; D016207:Cytokines; D008840:Microfilament Proteins; D018722:Nicotinic Agonists; C498513:PNU-282987; D015102:3,4-Dihydroxyphenylacetic Acid; D008464:Mecamylamine; D004298:Dopamine; D006719:Homovanillic Acid