 |
 |
ABSTRACT: Improvement of embryonic dopaminergic neurone survival in culture and after grafting into the striatum of hemiparkinsonian rats by CEP-1347 Jette Bisgaard Boll*, Marie Aavang Geist*, Gabriele S. Kaminski Schierle, Karina Petersen, Marcel Leist* and Elisabetta Vaudano * Departments of Molecular Disease Biology Molecular Genetics Neurodegenerative Disorders, H. Lundbeck A/S, Valby, Denmark Cambridge Center for Brain Repair, University of Cambridge, Cambridge, UK Address correspondence and reprint requests to Jette Bisgaard Boll, H. Lundbeck A/S, Department of Molecular Disease Biology, Ottiliavej 9, 2500 Valby, Denmark. E-mail: [log in to unmask] 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. Key Words: CEP-1347 – dopaminergic – mixed-lineage-kinase – neuroprotection – substantia nigra – transplantation Abbreviations used: DAB, 3,3'-diaminobenzidine; DIV, days in vitro; DMEM, Dulbecco's modified Eagle's medium; HBSS, Hank's balanced salt solution; HRP, horseradish peroxidase; JNK, Jun-N-terminal kinase; MLK, mixed-lineage-kinase; 6- OHDA, 6-hydroxydopamine; PD, Parkinson's disease; TH, tyrosine hydroxylase; VM, ventral mesencephalon SOURCE: Journal of Neurochemistry, Vol. 88, No. 3, 2004 698-707 http://www.jneurochem.org/cgi/content/abstract/88/3/698 * * * ---------------------------------------------------------------------- To sign-off Parkinsn send a message to: mailto:[log in to unmask] In the body of the message put: signoff parkinsn