Treatment of Cold Injury–Induced Brain Edema with a Nonspecific Matrix Metalloproteinase Inhibitor MMI270 in Rats

Abstract

Blood-brain barrier (BBB) disruption is a critical event leading to vasogenic brain edema and secondary brain damage after cold injury-induced brain trauma. Matrix metalloproteinases (MMPs), a family of proteolytic enzymes which degrade the extracellular matrix, are implicated in BBB disruption in this model. The purpose of this study was to examine the effects of MMI270 (N-hydroxy-2(R)-[(4-methoxysulfony)(3-picolyl)-amino]-3-metylbutaneamide hydrochloride monohydrate), a synthetic nonspecific MMP inhibitor, on cold injury-induced brain edema in rats. Cold injury was induced by applying a copper probe cooled with liquid nitrogen on the parietal skull for 30 sec in 38 rats. Treatment with MMI270, a bolus injection at a dose of 30 mg/kg, was started immediately after the induction of cold injury and was continued for 24 h at a dose of 40 mg/kg/day using an intraperitoneal osmotic minipump (n = 7). In the untreated control group (n = 7), rats were administered a vehicle and implanted with a vehicle-containing osmotic pump. Two percent Evans Blue (EB) in saline (1 mL/kg) was administrated intravenously immediately after the cold injury in another group of rats, six of which were untreated and six of which were treated with MMI270 at the above dose. At 24 h after the cold injury, the brain water content and the BBB permeability to EB were determined. To assess the protective effect of MMI270 on secondary brain lesion after the cold injury, the MMI270-treated rats received a bolus injection at a dose of 30 mg/kg, followed by a continuous administration of MMI270 for 7 days at a dose of 40 mg/kg/day using an osmotic minipump (n = 6). In the untreated control group (n = 6), the rats were administered the vehicle and implanted with a vehicle-containing osmotic pump. At 7 days after cold injury, the secondary brain lesion was assessed using hematoxylin and eosin (H-E) staining. Compared with the untreated control group, treatment with MMI270 significantly reduced the brain water content in the ipsilateral core and intermediate areas (p < 0.05 and p < 0.01) and protected the BBB integrity to EB in the ipsilateral core area (p < 0.05) at 24 h after the cold injury. The secondary lesion was significantly smaller in the MMI270-treated animals compared with the untreated animals (p < 0.05) a 7 days after the cold injury. O kur results indicate that treatment with MMI270 in rats exhibits protection in acute brain edema formation and secondary brain damage by attenuating the BBB permeability after cold injury.