Does increased excitatory drive from the subthalamic nucleus contribute to dopaminergic neuronal death in Parkinson's disease?
Excitotoxicity has been suggested to play a pivotal role in the pathogenesis of Parkinson disease (PD). As subthalamic nucleus (STN) neurons express glutamate and are overactivated in parkinsonism, it seems that in PD dopaminergic (DA) neurons are under the influence of abnormally high levels of glutamate and consequently might be more vulnerable to neurodegeneration. To determine the contribution of the overactivated STN-SN pathway to the progression of PD, we studied the effect of prior unilateral STN lesion on the toxicity induced by subsequent administration of 1-methyl-4-phenyl-1,2,3,6, tetrahydropyridine (MPTP) to non-human primates. In animals from group 1, kainic-induced lesion of the STN was performed prior to the administration of MPTP whereas in animals from group 2, STN lesion was caused after animals had been chronically treated with MPTP. The lesion of the STN elicited a contralateral hemiballism in animals from group 1, and they developed an asymmetrical parkinsonism after being exposed to MPTP. The STN lesion produced an improvement in the contralateral parkinsonism and mild choreic movements in animals from group 2. Cell counting of tyrosine hydroxylase immunoreactive (TH-ir) cells was performed by stereology and showed a similar loss of TH-ir cells (approximately 85%) in the ipsilateral and contralateral SN to the lesioned STN. These data indicate that the surgical removal of the excitatory drive from the STN to SN neurons does not protect dopaminergic neurons against a chronic and extended toxic effect of MPTP and do not support the assumption that STN blockade might delay the progression of PD.
Luquin
M Rosario
MR
Laboratory of Neurobiology of Parkinson Disease, Department of Neurology, University of Navarra, Foundation for Applied Medical Research, Pamplona, Spain. rluquin@unav.es
Saldise
Laura
L
Guillén
Javier
J
Belzunegui
Silvia
S
San Sebastián
Waldy
W
Izal
Amaya
A
Garrido
Pablo
P
Vázquez
Marianne
M
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D002452:Cell Count; D016923:Cell Death / Q000502:physiology; D004298:Dopamine / Q000378:metabolism*; D007150:Immunohistochemistry; D007608:Kainic Acid; D008252:Macaca fascicularis; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D020531:Subthalamic Nucleus / Q000473:pathology / Q000503:physiopathology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D007608:Kainic Acid; D004298:Dopamine