An intermittent, controlled-rate, slow progressive degeneration model of Parkinson's disease: antiparkinson effects of Sinemet and protective effects of methylphenidate.
The causes of nigrostriatal neuron degeneration in Parkinson's disease (PD) are not known, but it has been suggested that exogenous or endogenous factors or neurotoxins may play a role. The degree of vulnerability to neurotoxins or other potential mediators of nigral dopamine cell death is thought to be important in understanding Parkinson's disease. In most animal models, the rate of terminal degeneration and corresponding functional impairment is too rapid to investigate effectively either cell vulnerability or the potential benefits of some neuroprotective treatments. In the present study, a new model of Parkinson's disease is described that might help in addressing the issue of nigral cell vulnerability and to evaluate interventions with clinical potential. 6-Hydroxydopamine (6-OHDA) was infused in escalating, intrastriatal doses over several weeks. Control animals received multiple infusions of vehicle at the same volume. Behavioral testing was carried out between each infusion, including forelimb-use and somatosensory function. A symptomatic threshold was established for each animal, indicating the amount of neurotoxin required to induce a stable deficit. Oral administration of L-DOPA (Sinemet) ameliorated limb-use asymmetries acutely. An immunocytochemical assay for tyrosine hydroxylase, a dopamine cell marker, revealed a partial loss of immunoreactive cells in the substantia nigra. Animals that were co-administered methylphenidate (MPH), a dopamine transport inhibitor, along with the 6-OHDA were spared from the behavioral and neurochemical effects of 6-OHDA, despite receiving more than twice as much neurotoxin as controls. These data suggest that establishing a symptomatic threshold preclinically may help researchers evaluate potential treatments and model individual and group resistance to nigrostriatal insults.
Fleming
Sheila M
SM
Department of Psychology, Institute for Neuroscience, University of Texas, Austin, TX 78712, USA. sfleming@ucla.edu
Delville
Yvon
Y
Schallert
Timothy
T
D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D002230:Carbidopa / Q000008:administration & dosage / Q000627:therapeutic use*; D002452:Cell Count / Q000379:methods; D004056:Differential Threshold / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D007150:Immunohistochemistry / Q000379:methods; D007980:Levodopa / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D008774:Methylphenidate / Q000008:administration & dosage / Q000627:therapeutic use*; D009043:Motor Activity / Q000187:drug effects; D009068:Movement / Q000187:drug effects; D009410:Nerve Degeneration / Q000139:chemically induced / Q000209:etiology / Q000517:prevention & control*; D009474:Neurons / Q000378:metabolism; D016627:Oxidopamine; D010300:Parkinson Disease / Q000150:complications / Q000188:drug therapy* / Q000209:etiology; D010302:Parkinson Disease, Secondary / Q000517:prevention & control; D051381:Rats; D020318:Rats, Long-Evans; D045442:Rotarod Performance Test / Q000379:methods; D013378:Substantia Nigra / Q000166:cytology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D000978:Antiparkinson Agents; D004338:Drug Combinations; C009265:carbidopa, levodopa drug combination; D008774:Methylphenidate; D007980:Levodopa; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D002230:Carbidopa