Neuroprotective strategies for Parkinson's disease: conceptual limits of animal models and clinical trials

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Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder. Although therapies that treat the symptoms of the disease have proven efficacy, strategies that slow or stop the neurodegenerative process are currently not available. Recently, the National Institute of Neurological Disorders and Stroke (NINDS) conducted a systematic assessment of candidate pharmacological agents with putative neuroprotective properties. Twelve agents have been selected as potential candidates for upcoming clinical trials. However, the data resulting from the use of these agents in animal models of PD using a clinically driven design have not been published. Furthermore, the selection of interesting candidates should be based on the soundest clinically driven preclinical validation. This lack of published data, associated with the conceptual limits of the current way of testing drugs in clinical trials, prompts us to argue for further preclinical validation of the 12 candidates.

Section snippets

Conceptual limits of animal models of PD and their use

Surprisingly, data resulting from the use of the above-mentioned agents in animal models of PD using what we propose to call a ‘clinically driven design’ have not been published. Such a design should ideally satisfy the following three criteria. First, the chosen animal model should recapitulate most, if not all, features of sporadic PD, including its progressiveness (all acute models are excluded, although useful for initial screening) and its pathological landmark (i.e. the replication of

Conceptual limits of clinical trials

Even using the best experimental approach, clinical trials suffer from drawbacks that cause us to doubt our ability to demonstrate soundly the protective capacity of a drug, a fact that explains why the regulatory authorities view the field with suspicion. Several human studies have investigated putative neuroprotective effects of DA receptor agonists on nigrostriatal degeneration using imaging techniques [14]. These imaging techniques assess either DA terminal function or DA transporter

Concluding remarks

Current clinical trials and animal models of PD are insufficient to assess neuroprotective properties of any tested agent. Although this is in agreement with the concept of clinical equipoise (a state of genuine uncertainty on the part of the clinical investigator regarding the comparative therapeutic merits of each arm in a trial [18]), the selection of interesting agents for upcoming clinical trials should be based on the most sound, clinically driven preclinical validation. Thus, we herein

Acknowledgments

W.M. is a Marie Curie Fellow of the European Community (HPMF-2001–01300). M.H. is Chief Operating Officer and E.B. is Non-Executive Director of Motac Neuroscience, Manchester, UK.

References (44)

  • O. Hornykiewicz

    Dopamine and brain function

    Pharmacol. Rev.

    (1966)
  • F. Stocchi

    Neuroprotection in Parkinson's disease: clinical trials

    Ann. Neurol.

    (2003)
  • B.M. Ravina

    Neuroprotective agents for clinical trials in Parkinson's disease: a systematic assessment

    Neurology

    (2003)
  • J. Heemskerk

    From chemical to drug: neurodegeneration drug screening and the ethics of clinical trials

    Nat. Neurosci.

    (2002)
  • Johnson, R.T. ed. (2003) Neurodegeneration and prospects for neuroprotection and rescue in Parkinson's disease. Ann....
  • Diguet, E. et al. Deleterious effects of minocycline in animal models of Parkinson's disease and Huntington's disease....
  • E. Bezard

    Relationship between the appearance of symptoms and the level of nigrostriatal degeneration in a progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaque model of Parkinson's disease

    J. Neurosci.

    (2001)
  • K. Marek

    Dopamine agonists and Parkinson's disease progression: what can we learn from neuroimaging studies

    Ann. Neurol.

    (2003)
  • P. Martinez-Martin

    Unified Parkinson's disease rating scale characteristics and structure. The cooperative multicentric group

    Mov. Disord.

    (1994)
  • The Parkinson Study Group (2003) Does levodopa slow or hasten the rate of progression of Parkinson's disease? The...
  • I. Shoulson

    DATATOP: a decade of neuroprotective inquiry. Parkinson study group. Deprenyl and tocopherol antioxidative therapy of parkinsonism

    Ann. Neurol.

    (1998)
  • B. Freedman

    Equipoise and the ethics of clinical research

    New Engl. J. Med.

    (1987)
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