Abstract
Parkinson’s disease (PD) is characterized by the degeneration of the dopaminergic neurons in the substantia nigra pars compacta (SNpc). Clinical and experimental evidence suggest that the activation of the nicotinic acetylcholine receptor (nAChR) could be protective for PD. In this study, we investigated the neuroprotective capacity of nicotine in a rat PD model. Considering that iron metabolism has been implicated in PD pathophysiology and nicotine has been described to chelate this metal, we also studied the effect of nicotine on the cellular labile iron pool (LIP) levels. Rotenone (1 μg) was unilaterally injected into the median forebrain bundle to induce the degeneration of the nigrostriatal pathway. Nicotine administration (1 mg/K, s.c. daily injection, starting 5 days before rotenone and continuing for 30 days) attenuated the dopaminergic cell loss in the SNpc and the degeneration of the dopaminergic terminals provoked by rotenone, as assessed by immunohistochemistry. Furthermore, nicotine partially prevented the reduction on dopamine levels in the striatum and improved the motor deficits, as determined by HPLC-ED and the forelimb use asymmetry test, respectively. Studies in primary mesencephalic cultures showed that pretreatment with nicotine (50 μM) improved the survival of tyrosine hydroxylase-positive neurons after rotenone (20 nM) exposure. Besides, nicotine induced a reduction in the LIP levels assessed by the calcein dequenching method only at the neuroprotective dose. These effects were prevented by addition of the nAChRs antagonist mecamylamine (100 μM). Overall, we demonstrate a neuroprotective effect of nicotine in a model of PD in rats and that a reduction in iron availability could be an underlying mechanism.
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Acknowledgments
We thank to Prof. Prem Ponka for providing us with the iron quelator salicylaldehyde isonicotinoyl hydrazone. We also thank Prof. Cecilia Scorza and MSc. José P Prieto for helping with the behavioral experiments, Andrés Di Paolo for his technical assistance with the confocal microscopy, and Dr. Federico Dajas-Bailador for revising the manuscript.
Funding
This work was partially supported by the Agencia Nacional de Investigación e Innovación (ANII), Uruguay (FCE2007-517) and Programa de Desarrollo de las Ciencias Básicas (PEDECIBA), Uruguay.
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Mouhape, C., Costa, G., Ferreira, M. et al. Nicotine-Induced Neuroprotection in Rotenone In Vivo and In Vitro Models of Parkinson’s Disease: Evidences for the Involvement of the Labile Iron Pool Level as the Underlying Mechanism. Neurotox Res 35, 71–82 (2019). https://doi.org/10.1007/s12640-018-9931-1
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DOI: https://doi.org/10.1007/s12640-018-9931-1