Simultaneous intrastriatal 6-hydroxydopamine and quinolinic acid injection: a model of early-stage striatonigral degeneration.
Animal models reproducing early stages of striatonigral degeneration (SND), the core pathology underlying parkinsonism in multiple system atrophy, are lacking. We have developed a new model of early-stage SND by using a simultaneous unilateral administration of quinolinic acid (QA) and 6-hydroxydopamine (6-OHDA) into the putaminal equivalent of the rat striatum. Spontaneous and drug-induced behavior, thigmotactic scanning, paw reaching deficits, and histopathology were studied in rat groups: group 1 (control), group 2 (QA), group 3 (6-OHDA), and group 4 (QA + 6-OHDA). The double toxin administration resulted in reduction of the spontaneous and the amphetamine-induced ipsiversive bias in the 6-OHDA group and in a reduction of the apomorphine-induced ipsiversive rotations in the QA group. Simultaneous QA and 6-OHDA also reduced the thigmotactic bias observed in the 6-OHDA rats. Combined toxin elicited a nonsignificant contralateral deficit in paw reaching but a significant deficit on the ipsilateral side. Histopathology revealed a significant reduction of the lesioned striatal surface (-27%) with neuronal loss and increased astrogliosis in group 4 compared to group 2, consistent with an exacerbation of QA toxicity by additional 6-OHDA. By contrast, the mean loss of the TH-positive neurons in the ipsilateral substantia nigra pars compacta (SNc) of group 4 was less marked (-15%) than in the 6-OHDA group (-36%), indicating a possible protective action of intrastriatal QA upon 6-OHDA retrograde SNc degeneration. This study shows that a combined unilateral intrastriatal administration of QA and 6-OHDA may serve as a model of early stage SND which is more suitable for early therapeutic interventions.
Ghorayeb
I
I
Laboratoire de Neurophysiologie, CNRS-UMR 5543, Université Victor Segalen Bordeaux 2, Bordeaux Cedex, 33076, France.
Puschban
Z
Z
Fernagut
P O
PO
Scherfler
C
C
Rouland
R
R
Wenning
G K
GK
Tison
F
F
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002452:Cell Count; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D004195:Disease Models, Animal; D005552:Forelimb; D008297:Male; D008845:Microinjections; D009043:Motor Activity / Q000187:drug effects; D009048:Motor Skills / Q000187:drug effects; D019578:Multiple System Atrophy / Q000473:pathology / Q000503:physiopathology; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology; D009474:Neurons / Q000201:enzymology / Q000473:pathology; D016627:Oxidopamine / Q000008:administration & dosage; D017378:Quinolinic Acid / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D014110:Touch / Q000187:drug effects; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D017378:Quinolinic Acid