Improvement of embryonic dopaminergic neurone survival in culture and after grafting into the striatum of hemiparkinsonian rats by CEP-1347.
Transplantation of embryonic nigral tissue ameliorates functional deficiencies in Parkinson's disease (PD). A main constraint of neural grafting is the poor survival of dopaminergic neurones grafted into patients. Studies in rats indicated that many grafted neurones die by apoptosis. CEP-1347 is a mixed-lineage-kinase (MLK) inhibitor with neuroprotective action in several in vitro and in vivo models of neuronal apoptosis. We studied the effect of CEP-1347 on the survival of embryonic rat dopaminergic neurones in culture, and after transplantation in hemiparkinsonian rats. CEP-1347 and the alternative MLK inhibitor CEP-11004 significantly increased the survival of dopaminergic neurones in primary cultures from rat ventral mesencephalon and in Mn2+-exposed PC12 cells, a surrogate model of dopaminergic lethal stress. Moreover, combined treatment of the grafting cell suspension and the host animal with CEP-1347 significantly improved the long-term survival of rat dopaminergic neurones transplanted into the striatum of hemiparkinsonian rats. Also, the protective effect of CEP-1347 resulted in an increase in total graft size and in enhanced fibre outgrowth. Thus, treatment with CEP-1347 improved dopaminergic cell survival under severe stress and might be useful to improve the positive outcome of transplantation therapy in PD and reduce the amount of human tissue required.
Boll
Jette Bisgaard
JB
Department of Molecular Disease Biology, H. Lundbeck A/S, Valby, Denmark. jbbo@lundbeck.com
Geist
Marie Aavang
MA
Kaminski Schierle
Gabriele S
GS
Petersen
Karina
K
Leist
Marcel
M
Vaudano
Elisabetta
E
D000818:Animals; D016380:Brain Tissue Transplantation / Q000379:methods*; D002227:Carbazoles / Q000494:pharmacology / Q000627:therapeutic use*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000187:drug effects* / Q000637:transplantation; D004298:Dopamine / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D016332:Fetal Tissue Transplantation / Q000379:methods*; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D009474:Neurons / Q000187:drug effects / Q000637:transplantation; D016716:PC12 Cells; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000601:surgery; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000637:transplantation
D002227:Carbazoles; D007211:Indoles; C106592:3,9-bis((ethylthio)methyl)-K-252a; D004298:Dopamine