Brain Advance Access originally published online on June 20, 2007
Brain 2007 130(8):2129-2145; doi:10.1093/brain/awm137
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Survival of midbrain dopaminergic cells after lesion or deep brain stimulation of the subthalamic nucleus in MPTP-treated monkeys
1Department of Clinical and INSERM U318 Preclinical Neurosciences, University Joseph Fourier, Grenoble, France, 2Department of Neurosurgery, University of Florida, Gainesville, USA, 3Unit of Functional Neurosurgery, Institute of Neurology, London, England, 4Department of Anatomy & Histology, University of Sydney, Sydney and 5Medical School, Australian National University, Canberra, Australia
Correspondence to: Benabid Alim Louis, MD, PhD, INSERM U318, Pavillon B, CHU A Michallon, Grenoble, 38043, France E-mail: alimlouis{at}aol.com
We have examined dopaminergic cell survival after alteration of the subthalamic nucleus (STN) in methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys. The STN was lesioned with kainic acid (B series) or underwent deep brain stimulation (DBS) at high frequency (C series). In another series, MPTP-treated and non-MPTP-treated monkeys had no STN alteration (intact animals; A series). Animals were treated with MPTP either after (B1, C1) or before (B2, C2) STN alteration. We also explored the long-term (
7 months) effect of DBS in non-MPTP-treated monkeys (D series). Brains were aldehyde-fixed and processed for routine Nissl staining and tyrosine hydroxylase immunocytochemistry. Our results showed that there were significantly more (20–24%) dopaminergic cells in the substantia nigra pars compacta (SNc) of the MPTP-treated monkeys that had STN alteration, either with kainic acid lesion or DBS, compared to the non-MPTP-treated monkeys (intact animals). We suggest that this saving or neuroprotection was due to a reduction in glutamate excitotoxicity, as a result of the loss or reduction of the STN input to the SNc. Our results also showed that SNc cell number in the B1 and C1 series were very similar to those in the B2 and C2 series. In the cases that had long-term DBS of the STN (D series), there was no adverse impact on SNc cell number. In summary, these results indicated that STN alteration offered neuroprotection to dopaminergic cells that would normally die as part of the disease process.
Key Words: Parkinson disease; kainic acid; neuroprotection; glutamate toxicity; substantia nigra; primate
Abbreviations: 6OHDA, 6 hydroxydopamine; AC–PC, anterior commissure-posterior commissure; b, B series; c, C series; d, D series; DBS, deep brain stimulation; MG, medial geniculate nucleus; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MRI, magnetic resonance imaging; PaG, periaqueductal grey matter; PBS, phosphate buffer saline; PD, Parkinson disease; PpT, pedunculopontine tegmental nucleus; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata; STN, subthalamic nucleus; TH, tyrosine hydroxylase; VTA, ventral tegmental area; ZI, zona incerta
Received January 2, 2007. Revised May 9, 2007. Accepted May 18, 2007.
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