Progressive and extensive dopaminergic degeneration induced by convection-enhanced delivery of 6-hydroxydopamine into the rat striatum: a novel rodent model of Parkinson disease.
OBJECTIVE
A striatal dopamine lesion induces progressive nigral degeneration in rodents; however, intrastriatal injection of 6-hydroxydopamine (6-OHDA) causes only limited lesions due to spontaneous regeneration of the neurons that survive. To make an extensive lesion, the authors used a convection-enhanced delivery (CED) method for intrastriatal infusion of 6-OHDA and evaluated the animals for a model of Parkinson disease (PD).


METHODS
Different doses of 6-OHDA were infused into the unilateral striatum in rats by using the CED method. The dopaminergic neuronal degeneration was evaluated based on morphological, biochemical, and behavioral measurements until 8 weeks postlesion. Due to the wide distribution of the drug, CED of 20 microg of 6-OHDA into the striatum was sufficient to obtain a progressive and extensive nigrostriatal lesion as defined by morphological (> 80% cell loss in the substantia nigra [SN]) and biochemical (> 95% decrease in striatal dopamine) criteria. The extent of the lesion manifested as a stable turning behavior with amphetamine (> 6 turns/minute) and apomorphine (> 4 turns/minute). It also appeared that at I week postlesion the apoptotic markers were maximal in neurons of the SN.


CONCLUSIONS
A rat model of PD with a progressive and extensive dopamine lesion was successfully made by intrastriatal CED of 6-OHDA. In this model, the therapeutic value can be assessed using behavioral, biochemical, and histochemical measurements. The delay of nigral neuronal death with respect to the time of 6-OHDA administration may provide a therapeutic window for testing neuroprotective strategies.
Oiwa
Yoshitsugu
Y
Molecular Therapeutics Section, Laboratory of Molecular Medicine and Neuroscience, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA. oiwa@wakayama-med.ac.jp
Sanchez-Pernaute
Rosario
R
Harvey-White
Judith
J
Bankiewicz
Krys S
KS
D018663:Adrenergic Agents / Q000008:administration & dosage* / Q000009:adverse effects*; D000818:Animals; D002316:Cardiotonic Agents / Q000032:analysis; D018481:Convection; D003342:Corpus Striatum / Q000187:drug effects* / Q000473:pathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000032:analysis; D016503:Drug Delivery Systems; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000473:pathology; D016627:Oxidopamine / Q000008:administration & dosage* / Q000009:adverse effects*; D010302:Parkinson Disease, Secondary / Q000139:chemically induced* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology; D013997:Time Factors
D018663:Adrenergic Agents; D002316:Cardiotonic Agents; D016627:Oxidopamine; D004298:Dopamine