6-Hydroxydopamine-induced alterations in blood-brain barrier permeability.
Vascular inflammation is well known for its ability to compromise the function of the blood--brain barrier (BBB). Whether inflammation on the parenchymal side of the barrier, such as that associated with Parkinson's-like dopamine (DA) neuron lesions, similarly disrupts BBB function, is unknown. We assessed BBB integrity by examining the leakage of FITC-labeled albumin or horseradish peroxidase from the vasculature into parenchyma in animals exposed to the DA neurotoxin 6-hydroxydopamine (6OHDA). Unilateral injections of 6OHDA into the striatum or the medial forebrain bundle produced increased leakage in the ipsilateral substantia nigra and striatum 10 and 34 days following 6OHDA. Microglia were markedly activated and DA neurons were reduced by the lesions. The areas of BBB leakage were associated with increased expression of P-glycoprotein and beta 3-integrin expression suggesting, respectively, a compensatory response to inflammation and possible angiogenesis. Behavioural studies revealed that domperidone, a DA antagonist that normally does not cross the BBB, attenuated apomorphine-induced stereotypic behaviour in animals with 6OHDA lesions. This suggests that drugs which normally have no effect in brain can enter following Parkinson-like lesions. These data suggest that the events associated with DA neuron loss compromise BBB function.
Carvey
P M
PM
Rush University Medical Center, Department of Pharmacology, Cohn 406, Chicago, IL 60612, USA. pcarvey@rush.edu
Zhao
C H
CH
Hendey
B
B
Lum
H
H
Trachtenberg
J
J
Desai
B S
BS
Snyder
J
J
Zhu
Y G
YG
Ling
Z D
ZD
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000418:Albumins / Q000378:metabolism; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000502:physiology; D002452:Cell Count / Q000379:methods; D004298:Dopamine / Q000378:metabolism; D007839:Functional Laterality; D006735:Horseradish Peroxidase / Q000378:metabolism; D006892:Hydroxydopamines / Q000494:pharmacology*; D007150:Immunohistochemistry / Q000379:methods; D039661:Integrin beta3 / Q000378:metabolism; D008297:Male; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000418:Albumins; D006892:Hydroxydopamines; D039661:Integrin beta3; D006735:Horseradish Peroxidase; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine