Neurotoxicity Research

, Volume 17, Issue 2, pp 142–155 | Cite as

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

  • Julie Deguil
  • François Chavant
  • Claire Lafay-Chebassier
  • Marie-Christine Pérault-Pochat
  • Bernard Fauconneau
  • Stéphanie Pain
Article

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.

Keywords

Parkinson MPTP PACAP27 Translational control Memory task Neuroprotection Mice 

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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Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Julie Deguil
    • 1
  • François Chavant
    • 1
    • 2
  • Claire Lafay-Chebassier
    • 1
    • 2
  • Marie-Christine Pérault-Pochat
    • 1
    • 2
  • Bernard Fauconneau
    • 1
    • 2
  • Stéphanie Pain
    • 1
    • 2
  1. 1.Research Group on Brain Aging, GReViC, EA 3808, Pôle de Biologie SantéUniversity of PoitiersPoitiers cedexFrance
  2. 2.Department of Clinic PharmacologyPoitiers University HospitalPoitiers cedexFrance

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