Tissue plasminogen activator and urokinase plasminogen activator in human epileptogenic pathologies.
A growing body of evidence demonstrates the involvement of plasminogen activators (PAs) in a number of physiologic and pathologic events in the CNS. Induction of both tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA) has been observed in different experimental models of epilepsy and tPA has been implicated in the mechanisms underlying seizure activity. We investigated the expression and the cellular distribution of tPA and uPA in several epileptogenic pathologies, including hippocampal sclerosis (HS; n=6), and developmental glioneuronal lesions, such as focal cortical dysplasia (FCD, n=6), cortical tubers in patients with the tuberous sclerosis complex (TSC; n=6) and in gangliogliomas (GG; n=6), using immuno-cytochemical, western blot and real-time quantitative PCR analysis. TPA and uPA immunostaining showed increased expression within the epileptogenic lesions compared to control specimens in both glial and neuronal cells (hippocampal neurons in HS and dysplastic neurons in FCD, TSC and GG specimens). Confocal laser scanning microscopy confirmed expression of both proteins in astrocytes and microglia, as well as in microvascular endothelium. Immunoblot demonstrated also up-regulation of the uPA receptor (uPAR; P<0.05). Increased expression of tPA, uPA, uPAR and tissue PA inhibitor type mRNA levels was also detected by PCR analysis in different epileptogenic pathologies (P<0.05). Our data support the role of PA system components in different human focal epileptogenic pathologies, which may critically influence neuronal activity, inflammatory response, as well as contributing to the complex remodeling of the neuronal networks occurring in epileptogenic lesions.
Iyer
A M
AM
Department of (Neuro) Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Zurolo
E
E
Boer
K
K
Baayen
J C
JC
Giangaspero
F
F
Arcella
A
A
Di Gennaro
G C
GC
Esposito
V
V
Spliet
W G M
WG
van Rijen
P C
PC
Troost
D
D
Gorter
J A
JA
Aronica
E
E
D000293:Adolescent; D000328:Adult; D001253:Astrocytes / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D001921:Brain / Q000002:abnormalities / Q000378:metabolism* / Q000473:pathology; D001932:Brain Neoplasms / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D002648:Child; D004827:Epilepsy / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D018303:Ganglioglioma / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D054220:Malformations of Cortical Development / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D017628:Microglia / Q000378:metabolism; D008875:Middle Aged; D009421:Nervous System Malformations / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D010959:Tissue Plasminogen Activator / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D014402:Tuberous Sclerosis / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D014568:Urokinase-Type Plasminogen Activator / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
D015415:Biomarkers; D012333:RNA, Messenger; D055293:Receptors, Urokinase Plasminogen Activator; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator