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Neuroprotective Effect of PACAP on Translational Control Alteration and Cognitive Decline in MPTP Parkinsonian Mice

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Abstract

Parkinson’s disease (PD) is characterized by a triade of motor symptoms due to the degeneration of nigrostriatal pathway. In addition to these motor impairments, cognitive disturbances have been reported to occur in PD patients in the early stage of the disease. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin widely used to produce experimental models of PD. In a previous work, we showed that MPTP altered the expression of proteins involved in mTOR antiapoptotic and PKR apoptotic pathways of translational control (TC) in neuroblastoma cells. In the present study, the results indicated that a subchronic MPTP intoxication in mice decreased the dopaminergic neuron number, produced an activation of PKR way and an inhibition of mTOR way of TC especially in striatum and frontal cortex associated with a great activation of PKR in hippocampus. Moreover, in parallel to biochemical analysis, the mnesic disturbances induced by MPTP were characterized in C57Bl/6 mice, by testing their performance in three versions of the Morris Water Maze task. Behavioral results showed that the MPTP lesion altered mice learning of a spatial working memory, of a cued version and of a spatial reference memory task in the water maze. Furthermore, we previously demonstrated that the neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP) could counteract the MPTP toxicity on TC factors in neuroblastoma cells. Thus, the second objective of our study was to assess the PACAP effect on MPTP-induced TC impairment and cognitive deficit in mice. The pretreatment with PACAP27 by intravenous injections partially protected TH-positive neuron loss induced by MPTP, prevented the MPTP-induced protein synthesis control dysregulation and mnesic impairment of mice. Therefore, our results could indicate that PACAP may be a promising therapeutic agent in Parkinson’s disease.

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Abbreviations

4E-BP1:

4E-Binding protein 1

eIF2α:

Eukaryotic initiation factor 2α

eIF4E:

Eukaryotic initiation factor 4E

FBS:

Fetal bovine serum

mTOR:

Mammalian target of rapamycin

PACAP:

Pituitary adenylate cyclase activating polypeptide

PFC:

Prefrontal cortex

PKR:

Double-stranded RNA-protein dependent kinase

p70S6K:

Ribosomal p70S6 kinase

MPP+ :

1-Methyl-4-phenylpyridinium ion

MPTP:

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

PD:

Parkinson’s disease

SN:

Substantia nigra

TH:

Tyrosine hydroxylase

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Acknowledgments

This study was mainly supported by the French Ministry of Education and Research, with a grant to the Research Unit GREVIC, EA 3808 and by the Poitiers University Hospital. The authors wish to thank Tanguy Maurice for helpful discussions and Raymond Pontcharraud for technical assistance.

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Deguil, J., Chavant, F., Lafay-Chebassier, C. et al. Neuroprotective Effect of PACAP on Translational Control Alteration and Cognitive Decline in MPTP Parkinsonian Mice. Neurotox Res 17, 142–155 (2010). https://doi.org/10.1007/s12640-009-9091-4

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