Blood-brain barrier disruption induces in vivo degeneration of nigral dopaminergic neurons.
We have evaluated the possibility that changes in the vascular system may constitute a contributing factor for the death of nigral dopaminergic neurons in Parkinson's disease. Thus, we have employed intranigral injections of vascular endothelial growth factor (VEGF), the most potent inducer of blood-brain barrier (BBB) permeability. A single dose of 1 mug of VEGF, chosen from a dose-response study, highly disrupted the BBB in the ventral mesencephalon in a time-dependent manner. A strong regional correlation between BBB disruption and loss of tyrosine hydroxylase-positive neurons was evident. Moreover, Fluoro-Jade B labelling showed the presence of dying neurons in the substantia nigra in response to VEGF injection. High number of TUNEL-positive nuclei was observed in this area along with activation of caspase 3 within nigral dopaminergic neurons. Analysis of the glial population demonstrated a strong inflammatory response and activation of astroglia in response to BBB disruption. We conclude that disruption of the BBB may be a causative factor for degeneration of nigral dopaminergic neurons.
Rite
Inmaculada
I
Departamento de Bioquímica, Bromatología, Toxicología y Medicina Legal. Facultad de Farmacia, Universidad de Sevilla, C/Prof. García González, Sevilla, Spain.
Machado
Alberto
A
Cano
Josefina
J
Venero
José L
JL
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001253:Astrocytes / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects*; D004298:Dopamine / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects; D008297:Male; D017628:Microglia / Q000187:drug effects; D009410:Nerve Degeneration / Q000209:etiology*; D051381:Rats; D017208:Rats, Wistar; D013378:Substantia Nigra / Q000166:cytology* / Q000187:drug effects; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D042461:Vascular Endothelial Growth Factor A; D005680:gamma-Aminobutyric Acid; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine