Inhibitors of Type IV Phosphodiesterases Reduce the Toxicity of MPTP in Substantia Nigra Neurons In Vivo

Authors

  • Philippa Hulley,

    1. Preclinical Research, Sandoz Pharma Ltd, 4002 Basel, Switzerland and Sandoz Research Institute, Monbijoustrasse 115, 3001 Bern, Switzerland
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  • Jukka Hartikka,

    1. Preclinical Research, Sandoz Pharma Ltd, 4002 Basel, Switzerland and Sandoz Research Institute, Monbijoustrasse 115, 3001 Bern, Switzerland
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  • Samir Abdel'Al,

    1. Preclinical Research, Sandoz Pharma Ltd, 4002 Basel, Switzerland and Sandoz Research Institute, Monbijoustrasse 115, 3001 Bern, Switzerland
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  • Peter Engels,

    1. Preclinical Research, Sandoz Pharma Ltd, 4002 Basel, Switzerland and Sandoz Research Institute, Monbijoustrasse 115, 3001 Bern, Switzerland
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  • Hans-Rudolf Buerki,

    1. Preclinical Research, Sandoz Pharma Ltd, 4002 Basel, Switzerland and Sandoz Research Institute, Monbijoustrasse 115, 3001 Bern, Switzerland
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  • Karl-Heinz Wiederhold,

    1. Preclinical Research, Sandoz Pharma Ltd, 4002 Basel, Switzerland and Sandoz Research Institute, Monbijoustrasse 115, 3001 Bern, Switzerland
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  • Thomas Müller,

    1. Preclinical Research, Sandoz Pharma Ltd, 4002 Basel, Switzerland and Sandoz Research Institute, Monbijoustrasse 115, 3001 Bern, Switzerland
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  • Peter Kelly,

    1. Preclinical Research, Sandoz Pharma Ltd, 4002 Basel, Switzerland and Sandoz Research Institute, Monbijoustrasse 115, 3001 Bern, Switzerland
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  • David Lowe,

    1. Preclinical Research, Sandoz Pharma Ltd, 4002 Basel, Switzerland and Sandoz Research Institute, Monbijoustrasse 115, 3001 Bern, Switzerland
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  • Hermann Lübbert

    Corresponding author
    1. Preclinical Research, Sandoz Pharma Ltd, 4002 Basel, Switzerland and Sandoz Research Institute, Monbijoustrasse 115, 3001 Bern, Switzerland
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Correspondence to: PD Dr Hermann Lübbert, Preclinical Research 386-226, Sandoz Pharma Ltd, 4002 Basel, Switzerland

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.

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