Genetic inactivation of pleiotrophin triggers amphetamine-induced cell loss in the substantia nigra and enhances amphetamine neurotoxicity in the striatum.
Pleiotrophin (PTN) is a neurotrophic factor with important effects in survival and differentiation of dopaminergic neurons that has been suggested to play important roles in drug of abuse-induced neurotoxicity. To test this hypothesis, we have studied the effects of amphetamine (10 mg/kg, four times, every 2 h) on the nigrostriatal pathway of PTN genetically deficient (PTN-/-) mice. We found that amphetamine causes a significantly enhanced loss of dopaminergic terminals in the striatum of PTN-/- mice compared to wild type (WT+/+) mice. In addition, we found a significant decrease ( approximately 20%) of tyrosine hydroxylase (TH)-positive neurons only in the substantia nigra of amphetamine-treated PTN-/- mice, whereas this area of WT+/+ animals remained unaffected after amphetamine treatment. This effect was accompanied by enhanced amphetamine-induced astrocytosis in the substantia nigra of PTN-/- mice. Interestingly, we found a significant decrease in the phosphorylation levels of p42 extracellular-signal regulated kinase (ERK2) in both saline- and amphetamine-treated PTN-/- mice, whereas phosphorylation of p44 ERK (ERK1) was almost abolished in the striatum of PTN-/- mice compared to WT+/+ mice, suggesting that basal deficiencies in the phosphorylation levels of ERK1/2 could underlie the higher vulnerability of PTN-/- mice to amphetamine-induced neurotoxic effects. The data suggest an important role of PTN in the protection of nigrostriatal pathways against amphetamine insult.
Gramage
E
E
Lab. Pharmacology and Toxicology, University San Pablo CEU, 28668 Boadilla del Monte, Madrid, Spain.
Rossi
L
L
Granado
N
N
Moratalla
R
R
Herradón
G
G
D000661:Amphetamine / Q000633:toxicity*; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D002452:Cell Count / Q000379:methods; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D016207:Cytokines / Q000172:deficiency* / Q000235:genetics*; D020868:Gene Silencing / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology / Q000502:physiology*
D002352:Carrier Proteins; D016207:Cytokines; C066845:pleiotrophin; D000661:Amphetamine