Neuroprotective effect of PACAP on translational control alteration and cognitive decline in MPTP parkinsonian mice.
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.
Deguil
Julie
J
Research Group on Brain Aging, GReViC, EA 3808, Pôle de Biologie Santé, University of Poitiers, Poitiers cedex, France.
Chavant
François
F
Lafay-Chebassier
Claire
C
Pérault-Pochat
Marie-Christine
MC
Fauconneau
Bernard
B
Pain
Stéphanie
S
D000818:Animals; D002452:Cell Count / Q000379:methods; D003071:Cognition / Q000187:drug effects*; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology; D003463:Cues; D004195:Disease Models, Animal; D004347:Drug Interactions; D005786:Gene Expression Regulation / Q000187:drug effects*; D007275:Injections, Intravenous / Q000379:methods; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D020267:MPTP Poisoning / Q000150:complications* / Q000188:drug therapy / Q000473:pathology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000494:pharmacology* / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013028:Space Perception / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D014796:Visual Perception / Q000187:drug effects
D047908:Intracellular Signaling Peptides and Proteins; D018696:Neuroprotective Agents; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D043562:Receptors, G-Protein-Coupled; D014446:Tyrosine 3-Monooxygenase; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases