Reversals of blood-brain barrier disruption by catalase: a serial magnetic resonance imaging study of experimental optic neuritis.
OBJECTIVE
To investigate serially the role of catalase detoxification of endogenous H2O2 in the disruption of the blood-brain barrier (BBB) and demyelination of experimental optic neuritis.


METHODS
Serial contrast-enhanced magnetic resonance imaging (MRI) of the optic nerves (T1 weighted) and T2 weighted MRI without contrast were performed on 18 guinea pigs 3 to 14 days after sensitization with central myelin for experimental allergic encephalomyelitis. Sex and age-matched littermates were paired and sensitized with the identical antigenic emulsion. To detoxify endogenous hydrogen peroxide (H2O2), animals received daily intraperitoneal injections of polyethylene glycol (PEG)-catalase at a dose of 12,000 U/kg per day for 3 days, then 1,200 U/kg daily for the next week, commencing 3 days after antigenic sensitization. Littermates received an equal volume of preservative-free saline. The intensity of gadolinium-DTPA (Gd-DTPA) enhancement was quantitated by obtaining the value for a region of interest (ROI) of the right optic nerve and the left optic nerve. The effect of H2O2 detoxification by catalase was evaluated by differences in the intensity of Gd-DTPA enhancement and T2 weighted signal in the ROI of the right and the left optic nerves at 7, 10, and 14 days after antigenic sensitization, from the pretreatment value obtained at day 3. The effectiveness of catalase detoxification of H2O2 was assessed with quantitative ultracytochemical localization of electron-dense, H2O2-derived cerium perhydroxide in the optic nerves.


RESULTS
With PEG-catalase treatment, mean differences for Gd-DTPA enhancement in the ROI at 7, 10, and 14 days after antigenic sensitization were significantly reduced from the pretreatment values obtained 3 days after antigenic sensitization compared with the comparable interval values for untreated littermates. For T2 weighted signal intensity, only the 7- and 14-day values were significantly less with PEG-catalase compared with values for littermates obtained at comparable intervals. Quantitative ultracytochemical localization of H2O2-derived cerium perhydroxide reaction product revealed significant reductions in the medium number of cerium particle counts of the optic nerve head, sheath, and myelinated retrobulbar nerve.


CONCLUSIONS
PEG-catalase reduced H2O2-derived cerium perhydroxide reaction product in the optic nerve but did not eliminate it, reversed disruption of the BBB as measured by Gd-DTPA enhancement, and reduced demyelination and edema as measured by T2 weighted signal intensity, suggesting detoxification of H2O2 as a new treatment strategy for disorders of primary demyelination of the central nervous system.
Guy
J
J
Department of Ophthalmology, University of Florida, Gainesville 32610.
McGorray
S
S
Fitzsimmons
J
J
Beck
B
B
Mancuso
A
A
Rao
N A
NA
Hamed
L
L
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D002374:Catalase / Q000494:pharmacology*; D003287:Contrast Media; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D005260:Female; D005682:Gadolinium; D019786:Gadolinium DTPA; D006168:Guinea Pigs; D006861:Hydrogen Peroxide / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008279:Magnetic Resonance Imaging; D008297:Male; D009186:Myelin Sheath / Q000648:ultrastructure; 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
D003287:Contrast Media; D009942:Organometallic Compounds; D004369:Pentetic Acid; D005682:Gadolinium; D006861:Hydrogen Peroxide; D002374:Catalase; D019786:Gadolinium DTPA