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An intermittent, controlled-rate, slow progressive degeneration model of Parkinson's disease: antiparkinson effects of Sinemet and protective effects of methylphenidate.
Behav Brain Res. 2005 Jan 30; 156(2):201-13.BB

Abstract

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.

Authors+Show Affiliations

Department of Psychology, Institute for Neuroscience, University of Texas, Austin, TX 78712, USA. sfleming@ucla.eduNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15582106

Citation

Fleming, Sheila M., et al. "An Intermittent, Controlled-rate, Slow Progressive Degeneration Model of Parkinson's Disease: Antiparkinson Effects of Sinemet and Protective Effects of Methylphenidate." Behavioural Brain Research, vol. 156, no. 2, 2005, pp. 201-13.
Fleming SM, Delville Y, Schallert T. An intermittent, controlled-rate, slow progressive degeneration model of Parkinson's disease: antiparkinson effects of Sinemet and protective effects of methylphenidate. Behav Brain Res. 2005;156(2):201-13.
Fleming, S. M., Delville, Y., & Schallert, T. (2005). An intermittent, controlled-rate, slow progressive degeneration model of Parkinson's disease: antiparkinson effects of Sinemet and protective effects of methylphenidate. Behavioural Brain Research, 156(2), 201-13.
Fleming SM, Delville Y, Schallert T. An Intermittent, Controlled-rate, Slow Progressive Degeneration Model of Parkinson's Disease: Antiparkinson Effects of Sinemet and Protective Effects of Methylphenidate. Behav Brain Res. 2005 Jan 30;156(2):201-13. PubMed PMID: 15582106.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - An intermittent, controlled-rate, slow progressive degeneration model of Parkinson's disease: antiparkinson effects of Sinemet and protective effects of methylphenidate. AU - Fleming,Sheila M, AU - Delville,Yvon, AU - Schallert,Timothy, PY - 2003/08/22/received PY - 2004/05/18/revised PY - 2004/05/20/accepted PY - 2004/12/8/pubmed PY - 2005/3/8/medline PY - 2004/12/8/entrez SP - 201 EP - 13 JF - Behavioural brain research JO - Behav Brain Res VL - 156 IS - 2 N2 - 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. SN - 0166-4328 UR - https://www.unboundmedicine.com/medline/citation/15582106/An_intermittent_controlled_rate_slow_progressive_degeneration_model_of_Parkinson's_disease:_antiparkinson_effects_of_Sinemet_and_protective_effects_of_methylphenidate_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0166-4328(04)00190-1 DB - PRIME DP - Unbound Medicine ER -