Corticotropin-releasing factor decreases vasogenic brain edema.
We report the first series of studies comparing the anti-edematous effects of human corticotropin-releasing factor (hCRF) and dexamethasone in an experimental model of vasogenic peritumoral brain edema. Both hCRF and dexamethasone effectively decreased blood-brain barrier (BBB) permeability of intracerebral RG2 gliomas in rats as observed by contrast-enhanced T(1)-weighted magnetic resonance imaging. A decrease in the water content of tumor and peritumoral brain tissue was observed with proton-density magnetic resonance imaging and confirmed by direct wet/dry tissue measurements. The calculated ED(50) for hCRF was 59 micrograms/kg s.c. twice a day, and that for dexamethasone was 0.61 mg/kg i.m. twice a day; the hCRF:dexamethasone dose-potency ratio was 120:1 on a molar basis. The anti-edematous action of hCRF is not mediated by the release of adrenal corticosteroids. A direct action of hCRF on the tumor microvasculature results in restoration of BBB integrity and up-regulation of BBB-specific protein expression. The average survival time with chronic treatment was prolonged significantly in the hCRF-treated group (35 days) compared with the dexamethasone-treated group (28 days; P < 0.05) and the saline-treated control group (22 days; P < 0.0001). hCRF, as an alternative to corticosteroid therapy, may provide substantial benefits with respect to reducing the major side effects encountered with long-term, high-dose corticosteroid treatment.
Tjuvajev
J
J
Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York 10021, USA.
Uehara
H
H
Desai
R
R
Beattie
B
B
Matei
C
C
Zhou
Y
Y
Kreek
M J
MJ
Koutcher
J
J
Blasberg
R
R
D000315:Adrenalectomy; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000941:Antigens / Q000032:analysis; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001834:Body Water / Q000187:drug effects; D001929:Brain Edema / Q000097:blood / Q000188:drug therapy* / Q000209:etiology / Q000401:mortality; D001932:Brain Neoplasms / Q000097:blood / Q000150:complications* / Q000188:drug therapy / Q000401:mortality; D002199:Capillary Permeability / Q000187:drug effects; D003345:Corticosterone / Q000097:blood; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology / Q000627:therapeutic use*; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000276:immunology; D005910:Glioma / Q000097:blood / Q000150:complications* / Q000188:drug therapy / Q000401:mortality; D008279:Magnetic Resonance Imaging; D051381:Rats; D011916:Rats, Inbred F344
D000893:Anti-Inflammatory Agents; D000941:Antigens; D003907:Dexamethasone; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone