Inhibitors of p38 MAP kinase increase the survival of transplanted dopamine neurons

W. Michael Zawada, Mary K. Meintzer, Pravin Rao, Jonathan Marotti, Xiaomin Wang, James E. Esplen, Edward D. Clarkson, Curt R. Freed, Kim A. Heidenreich

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

Fetal cell transplantation therapies are being developed for the treatment of a number of neurodegenerative disorders including Parkinson's disease [10-12,21,22,24,36,43]. Massive apoptotic cell death is a major limiting factor for the success of neurotransplantation. We have explored a novel protein kinase pathway for its role in apoptosis of dopamine neurons. We have discovered that inhibitors of p38 MAP kinase (the pyridinyl imidazole compounds: PD169316, SB203580, and SB202190) improve survival of rat dopamine neurons in vitro and after transplantation into hemiparkinsonian rats. In embryonic rat ventral mesencephalic cultures, serum withdrawal led to 80% loss of dopamine neurons due to increased apoptosis. Incubation of the cultures with p38 MAP kinase inhibitors at the time of serum withdrawal prevented dopaminergic cell death by inhibiting apoptosis. In the hemiparkinsonian rat, preincubation of ventral mesencephalic tissue with PD169316 prior to transplantation accelerated behavioral recovery and doubled the survival of transplanted dopamine neurons. We conclude that inhibitors of stress-activated protein kinases improve the outcome of cell transplantation by preventing apoptosis of neurons after grafting.

Original languageEnglish (US)
Pages (from-to)185-196
Number of pages12
JournalBrain research
Volume891
Issue number1-2
DOIs
StatePublished - Feb 9 2001
Externally publishedYes

Keywords

  • Apoptosis
  • Dopamine neuron
  • Neurodegeneration
  • Neurotransplantation
  • Parkinson's disease
  • Pyridinyl imidazole
  • p38 MAP kinase

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

Fingerprint

Dive into the research topics of 'Inhibitors of p38 MAP kinase increase the survival of transplanted dopamine neurons'. Together they form a unique fingerprint.

Cite this