Matrix metalloproteinases 2 and 9 fail to influence drug-induced neuroapoptosis in developing rat brain.

Matrix metalloproteinases (MMPs) play an essential role in tissue repair, cell death, and morphogenesis. The aim of the present study was to investigate potential involvement of selected MMPs in the pathogenesis of neuronal apoptosis induced by the NMDA antagonist MK-801 (dizocilpine) or the GABA(A) agonist phenobarbital in infant rats, transgenic rats overexpressing MMP-9 and MMP-9 knockout mice. Seven-day-old rats or knockout mice received intraperitoneal injections of MK-801, 1 mg/kg, or phenobarbital, 50 mg/kg. At different survival intervals following administration of the compounds (1-72 h), pups were sacrificed, tissue from different brain regions was isolated, and the expression and activity of MMP-2 and MMP-9 were analyzed by real-time PCR, western blot, and zymography. In addition, brains were fixed and processed for TUNEL staining. In all the brain regions analyzed, we found an increased number of TUNEL-positive cells 24 h after administration of MK-801. After treatment, we detected no significant increase in MMP-2 or MMP-9 mRNA expression in cortical areas. No changes in the MMP-9 protein expression or gelatinolytic activity of MMP-2 were observed in conjunction with MK-801 or phenobarbital-induced neuroapoptosis in any brain region analyzed. The extent of neurodegeneration induced by MK-801 or phenobarbital was not altered in MMP-9 transgenic rats and was increased in MMP-9 knockout mice compared to wild-type rats and mice. Treatment with the panmetalloproteinase inhibitor GM6001 did not confer protection against MK-801-induced apoptotic cell death in the developing rat brain. Our results suggest that activation of MMP-9 and MMP-2 does not contribute to pathogenesis of neuronal apoptosis caused by NMDA antagonists or GABA(A) agonists in the developing rat and mouse brain.

Clinical predictors of early second event in patients with clinically isolated syndrome.

This study aimed to determine the predictors of increased risk of a second demyelinating event within the first year of an initial demyelinating event (IDE) suggestive of early multiple sclerosis (MS). Patients with MS or clinically isolated syndrome (CIS) seen at the UCSF MS Center within one year of the IDE were studied. Univariate and multivariate Cox models were used to analyze predictors of having a second event within 1 year of the IDE. Of 330 patients with MS/CIS, 111 had a second event within 1 year. Non-white race/ethnicity (HR = 2.39, 95% CI [1.58, 3.60], p < 0.0001) and younger age (HR for each 10-year decrease in age = 1.51, 95% CI [1.28, 1.80], p < 0.0001) were strongly associated with an increased risk of having a second event within one year of onset. Having a lower number of functional systems affected by the IDE was also associated with an increased risk of early second event (HR for every one less FS involved = 1.31, 95% CI [1.06, 1.61], p = 0.011). These results were similar after adjusting for treatment of the IDE with steroids and disease-modifying therapy. Non-white race/ethnicity, younger age, and a lower number of FS affected by the IDE are associated with a substantially increased hazard ratio for a second demyelinating event within 1 year. Since early relapse is predictive of worse long-term outcome, identifying and treating such patients after the IDE may be of benefit to them.