Endothelial proliferation and increased blood-brain barrier permeability in the basal ganglia in a rat model of 3,4-dihydroxyphenyl-L-alanine-induced dyskinesia.
3,4-Dihydroxyphenyl-L-alanine (L-DOPA)-induced dyskinesia is associated with molecular and synaptic plasticity in the basal ganglia, but the occurrence of structural remodeling through cell genesis has not been explored. In this study, rats with 6-hydroxydopamine lesions received injections of the thymidine analog 5-bromo-2'-deoxyuridine (BrdU) concomitantly with L-DOPA for 2 weeks. A large number of BrdU-positive cells were found in the striatum and its output structures (globus pallidus, entopeduncular nucleus, and substantia nigra pars reticulata) in L-DOPA-treated rats that had developed dyskinesia. The vast majority (60-80%) of the newborn cells stained positively for endothelial markers. This endothelial proliferation was associated with an upregulation of immature endothelial markers (nestin) and a downregulation of endothelial barrier antigen on blood vessel walls. In addition, dyskinetic rats exhibited a significant increase in total blood vessel length and a visible extravasation of serum albumin in the two structures in which endothelial proliferation was most pronounced (substantia nigra pars reticulata and entopeduncular nucleus). The present study provides the first evidence of angiogenesis and blood-brain barrier dysfunction in an experimental model of L-DOPA-induced dyskinesia. These microvascular changes are likely to affect the kinetics of L-DOPA entry into the brain, favoring the occurrence of motor complications.
Westin
Jenny E
JE
Basal Ganglia Unit, Department of Experimental Medical Science, Lund University, S-221 84 Lund, Sweden.
Lindgren
Hanna S
HS
Gardi
Jonathan
J
Nyengaard
Jens Randel
JR
Brundin
Patrik
P
Mohapel
Paul
P
Cenci
M Angela
MA
D000818:Animals; D000911:Antibodies, Monoclonal; D000941:Antigens / Q000378:metabolism; D001479:Basal Ganglia / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D015415:Biomarkers / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000503:physiopathology; D001973:Bromodeoxyuridine; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000633:toxicity; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism / Q000503:physiopathology*; D042783:Endothelial Cells / Q000187:drug effects* / Q000473:pathology; D005260:Female; D007381:Intermediate Filament Proteins / Q000378:metabolism; D007980:Levodopa / Q000633:toxicity*; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009389:Neovascularization, Pathologic / Q000139:chemically induced* / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000188:drug therapy; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011509:Proteoglycans / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000099216:Chondroitin Sulfate Proteoglycan 4
D000911:Antibodies, Monoclonal; D000941:Antigens; D015415:Biomarkers; D001973:Bromodeoxyuridine; D015259:Dopamine Agents; D007381:Intermediate Filament Proteins; D007980:Levodopa; D009419:Nerve Tissue Proteins; D064231:Nestin; D016627:Oxidopamine; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011509:Proteoglycans; D000099216:Chondroitin Sulfate Proteoglycan 4; C577486:Nes protein, rat