Inhibitors of Type IV Phosphodiesterases Reduce the Toxicity of MPTP in Substantia Nigra Neurons In Vivo
- 1 December 1995
- journal article
- Published by Wiley in European Journal of Neuroscience
- Vol. 7 (12), 2431-2440
- https://doi.org/10.1111/j.1460-9568.1995.tb01041.x
Abstract
The neuropathology of Parkinson's disease is characterized by the degeneration of dopaminergic neurons in the substantia nigra. We have recently shown that the activation of protein kinase A improves the survival of dopaminergic neurons in culture and, furthermore, protects them from the dopaminergic neurotoxin, 1‐methyl‐4‐phenylpyridinium ion (MPP+) in vitro. We have now analysed the potential of phosphodiesterase inhibitors to increase cAMP levels in dopaminergic neurons, to improve their survival in culture and to protect them from the toxicity of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) in vivo. Increasing intracellular cAMP with phosphodiesterase type IV‐specific inhibitors enhanced the survival of dopaminergic neurons in culture. Inhibitors of other phosphodiesterase types were not active. In vivo, phosphodiesterase type IV inhibitors reduced the MPTP‐induced dopamine depletion in the striatum of C57BL/6 mice. Furthermore, the loss of tyrosine hydroxylase‐immunopositive neurons in the substantia nigra of these animals was diminished. After Nissl staining, a similar reduction of the MPTP‐induced loss of neurons was observed in the substantia nigra. The protective effect of protein kinase A activation did not appear to be due to the blocking of MPP+ uptake into dopaminergic neurons. This was not decreased after treatment with forskolin or 8‐(4‐chlorophenylthio)‐cAMP. Thus, protein kinase A regulates the survival and differentiation of dopaminergic substantia nigra neurons in vivo, implicating a therapeutic potential for substances which regulate cAMP turnover in these neurons.Keywords
This publication has 49 references indexed in Scilit:
- Molecular cloning and functional expression in yeast of a human cAMP‐specific phosphodiesterase subtype (PDE IV‐C)FEBS Letters, 1995
- Enhanced recovery of the nigrostriatal dopaminergic system in MPTP-treated mice following intrastriatal injection of basic fibroblast growth factor in relation to agingBrain Research, 1993
- GDNF: a Glial Cell Line-Derived Neurotrophic Factor for Midbrain Dopaminergic NeuronsScience, 1993
- FGF‐2‐mediated protection of cultured mesencephalic dopaminergic neurons against MPTP and MPP+: Specificity and impact of culture conditions, non‐dopaminergic neurons, and astroglial cellsJournal of Neuroscience Research, 1993
- Cyclic AMP, but not basic FGF, increases the in vitro survival of mesencephalic dopaminergic neurons and protects them from MPP+‐induced degenerationJournal of Neuroscience Research, 1992
- MK‐801 Fails to Protect Against the Dopaminergic Neuropathology Produced by Systemic 1‐Methyl‐4‐Phenyl‐1,2,3,6‐Tetrahydropyridine in Mice or Intranigral 1‐Methyl‐4‐Phenylpyridinium in RatsJournal of Neurochemistry, 1992
- Apoptosis and DNA degradation induced by 1-methyl-4-phenylpyridinium in neuronsBiochemical and Biophysical Research Communications, 1991
- Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexesCell, 1991
- Primary sequence of cyclic nucleotide phosphodiesterase isozymes and the design of selective inhibitorsTrends in Pharmacological Sciences, 1990
- Mitochondrial Complex I Deficiency in Parkinson's DiseaseJournal of Neurochemistry, 1990