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REGULATION IN GENETICALLY MODIFIED ANIMALS

Characterization of a new double-filament model of focal cerebral ischemia in heme oxygenase-2-deficient mice

Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University, Baltimore, Maryland 21287-4961

Submitted 4 February 2003 ; accepted in final form 24 March 2003

Variations in vascular anatomy in knockout mouse strains can influence infarct volume after middle cerebral artery (MCA) occlusion (MCAO). In wild-type (WT) and heme oxygenase-2 gene-deleted (HO2^-/-) mice, infarcts were not reproducibly achieved with the standard intraluminal filament technique. The present study characterizes a double-filament model of MCAO, which was developed to produce consistent infarcts in both WT and HO2^-/- mice. Diameters of most cerebral arteries were similar in WT and HO2^-/- mice, although the posterior communicating artery size was variable. In halothane-anesthetized mice, two 6-0 monofilaments with blunted tips were inserted into the left internal carotid artery 6.0 and 4.5 mm past the pterygopalatine artery junction to reside distal and proximal to the origin of the MCA. The tissue "volume at risk" determined by brief dye perfusion in WT (59 ± 2% of hemisphere; ±SE) was similar to HO2^-/- (62 ± 4%). The volume of tissue with cerebral blood flow <50 ml·min^-1·100 g^-1 was similar in WT (35 ± 9%) and HO2^-/- (36 ± 11%) during MCAO and at 3 h of reperfusion (<2%). After 1 h MCAO, infarct volume was greater in HO2^-/- (44 ± 6%) than WT (25 ± 3%). After increasing MCAO duration to 2 h, the difference between HO2^-/- (47 ± 4%) and WT (36 ± 3%) diminished, but infarct volume remained substantially less than the volume at risk. Infusion of tin protoporphyrin IX, an HO inhibitor, during reperfusion after 1 h MCAO increased infarct volume in WT but not significantly in HO2^-/- mice, although infarct volume remained less than the volume at risk. Thus greater infarct volume in HO2^-/- mice is not attributable to a greater volume at risk, lower intraischemic blood flow, or poor reflow, but rather to a neuroprotective effect of HO2 activity. The double-filament model may be of use as an alternative in other murine knockout strains in which the standard filament model does not yield consistent infarcts.

cerebral blood flow; cerebral circulation; focal cerebral ischemia; heme oxygenase; mouse

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