Abstract for presentation at Australian and New Zealand Association of Neurologists Annual Scientific Meeting 2008

A Novel Moderate-Affinity Metal Binding Ligand Confers Neuroprotection Against 6-Hydroxydopamine Mediated Chronic Cell Death and Improves Rotational Behavior in a Mouse Model of Parkinson's Disease

  • Dr Simon Wilkins, The Mental Health Research Institute of Victoria, Australia
  • Ms Karoline Deleva, The Mental Health Research Institute of Victoria, Australia
  • Ms Mikhalina Cortes, The Mental Health Research Institute of Victoria, Australia
  • Ms Mila Nurjono, The Mental Health Research Institute of Victoria, Australia
  • Ms Irene Volitakis, The Mental Health Research Institute of Victoria, Australia
  • Ms Jessica George, The Mental Health Research Institute of Victoria, Australia
  • A/Prof David Finkelstein, The Mental Health Research Institute of Victoria, Australia
  • Dr Robert Cherny, The Mental Health Research Institute of Victoria, Australia

    • There is evidence that aberrant interactions between metals and and bioavailable reductants are involved in the destruction of substantia nigra (SN) cells in Parkinson's Disease (PD). Previously we showed that long term pre-treatment with clioquinol (CQ) a monodentate antioxidant with moderate affinity for copper, zinc and iron, reduced the susceptibility of SN neurons to the neurotoxin MPTP (Neuron, 2003, 37: 889-909). Because 6-hydroxydopamine (6-OHDA) is an oxidative metabolite of dopamine implicated in pathogenic pathways in PD we examined the effects of CQ using this nigral toxin. Initial studies showed administration of CQ commencing on the same day as 6-OHDA injection significantly diminished lesion size. We concluded that redox-active metals mediate both MPTP and 6-OHDA-induced neurotoxicity and because no pretreatment with CQ was required, neuroprotection was likely due more to its redox-neutralising effects than bulk metal chelation. To determine whether this class of drug might be effective when nigral degeneration was already advanced, we developed an experimental paradigm whereby drug is only administered in the days following initiation of the acute phase of nigral death by 6-OHDA. Drug efficacy is assessed by rotational behaviour in response to amphetamine challenge and by stereoscopic counting of residual nigral cells. A novel bioavailable analogue of CQ tested in this model (provided by Prana Biotechnology Ltd) significantly reduced post- amphetamine rotational behavior and preserved more SN neurons than in either CQ-treated or untreated lesioned animals. We conclude that these compounds merit further investigation for their potential as a novel therapy for PD.

    Conference Organiser - ICMS Pty Ltd