Conjugated deferoxamine reduces blood-brain barrier disruption in experimental optic neuritis.
The purpose of this paper was to investigate the role of deferoxamine (DFO) scavenging of hydroxyl radical (.OH) on disruption of the blood-brain barrier (BBB) and demyelination in experimental optic neuritis. Eighteen strain-13 guinea pigs were sensitized for experimental allergic encephalomyelitis. Nine animals received 100 mg/kg of hydroxyethyl starch-conjugated (HES) DFO by daily intraperitoneal injection commencing the day of antigenic sensitization. Nine paired litter mates received daily IP injections of HES. Serial fat-suppressed magnetic resonance imaging of the optic nerves was obtained with a T2 weighting (T2w) to evaluate demyelination and after intravascular administration of Gd-DTPA to evaluate BBB disruption. The intensity of Gd-DTPA enhancement and T2w signal of the optic nerves was quantitated 3, 7, 10 and 14 days after antigenic sensitization. Animals were then sacrificed and the optic nerves processed for light and transmission electron microscopy with ultracytochemical localization of endogenous hydrogen peroxide (H2O2) and immunogold colocalization of extravasated serum albumin. The area of the optic nerve head, intensity of toluidine blue staining, and the cellular infiltrate were digitized and quantitated. Administration of HES-DFO significantly reduced the intensity of Gd-DTPA enhancement in the optic nerves of HES-DFO-treated animals compared to paired control HES animals (p = 0.0236), with the mean difference between control and treated animals of 19.39. The difference in T2w signal was not significant (p = 0.39), with a mean difference between control and treated animals of -5.51. The intensity of toluidine blue staining of optic nerve specimens was slightly less with HES-DFO compared to untreated animals (mean pair difference 2.48), and the inflammatory infiltrate was reduced with HES-DFO compared to untreated animals (mean pair difference = 61.57); these differences were not statistically significant. In the optic nerve specimens of both groups cerium perhydroxide-derived H2O2 reaction product was evident in a predominantly perivascular and perineural distribution. Immunogold-labeled serum albumin showed extravasation at foci of perivascular inflammation in both the presence and absence of H2O2-derived reaction product. Conjugated DFO reduces disruption of the BBB, as measured by Gd-DTPA enhancement, suggesting the .OH radical generated from perivascular H2O2 may play a role in alterations of vascular permeability in experimental optic neuritis.
Guy
J
J
Department of Ophthalmology, University of Florida, Gainesville.
McGorray
S
S
Qi
X
X
Fitzsimmons
J
J
Mancuso
A
A
Rao
N
N
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D002199:Capillary Permeability; D003676:Deferoxamine / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D019786:Gadolinium DTPA; D006168:Guinea Pigs; D006861:Hydrogen Peroxide / Q000378:metabolism; D006895:Hydroxyethyl Starch Derivatives / Q000008:administration & dosage / Q000494:pharmacology*; D017665:Hydroxyl Radical / Q000378:metabolism; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D008279:Magnetic Resonance Imaging; D009186:Myelin Sheath / Q000378:metabolism; D009898:Optic Disk / Q000378:metabolism / Q000648:ultrastructure; D009900:Optic Nerve / Q000378:metabolism / Q000473:pathology; D009902:Optic Neuritis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D009942:Organometallic Compounds; D004369:Pentetic Acid / Q000031:analogs & derivatives
D006895:Hydroxyethyl Starch Derivatives; D009942:Organometallic Compounds; C068460:hydroxyethyl starch-deferoxamine conjugate; D017665:Hydroxyl Radical; D004369:Pentetic Acid; D006861:Hydrogen Peroxide; D003676:Deferoxamine; D019786:Gadolinium DTPA