Enhanced cerebral expression of MCT1 and MCT2 in a rat ischemia model occurs in activated microglial cells.

Monocarboxylate transporters (MCTs) are essential for the use of lactate, an energy substrate known to be overproduced in brain during an ischemic episode. The expression of MCT1 and MCT2 was investigated at 48 h of reperfusion from focal ischemia induced by unilateral extradural compression in Wistar rats. Increased MCT1 mRNA expression was detected in the injured cortex and hippocampus of compressed animals compared to sham controls. In the contralateral, uncompressed hemisphere, increases in MCT1 mRNA level in the cortex and MCT2 mRNA level in the hippocampus were noted. Interestingly, strong MCT1 and MCT2 protein expression was found in peri-lesional macrophages/microglia and in an isolectin B4+/S100beta+ cell population in the corpus callosum. In vitro, MCT1 and MCT2 protein expression was observed in the N11 microglial cell line, whereas an enhancement of MCT1 expression by tumor necrosis factor-alpha (TNF-alpha) was shown in these cells. Modulation of MCT expression in microglia suggests that these transporters may help sustain microglial functions during recovery from focal brain ischemia. Overall, our study indicates that changes in MCT expression around and also away from the ischemic area, both at the mRNA and protein levels, are a part of the metabolic adaptations taking place in the brain after ischemia.

Reduced HO-1 protein expression is associated with more severe neurodegeneration after transient ischemia induced by cortical compression in diabetic Goto-Kakizaki rats.

Pronounced hyperglycemia provoked by extradural compression (EC) of the sensorimotor cortex was recently described in the non-insulin dependent Goto-Kakizaki (GK) diabetic rat. Compared with control Wistar rats, GK rats exhibited more extensive brain damage after cortical ischemia at 48 h of reperfusion (Moreira et al, 2007). We hypothesized that the enhanced brain injury in GK rats could be caused by differential regulation of the heme degrading enzyme heme oxygenase (HO)-1, known to interact with the expression of other target genes implicated in antioxidant defense, inflammation and neurodegeneration, such as superoxide dismutase (SOD)-1, -2, inducible nitric oxide synthase (iNOS), and tumor necrosis factor-alpha (TNFalpha). At 48 h after ischemia, relative mRNA expression of such target genes was compared between ipsilateral (compressed) and contralateral (uncompressed) hemispheres of GK rats, along with baseline comparison of sham, uncompressed GK and Wistar rats. Immunohistochemistry was performed to detect cellular and regional localization of HO-1 at this time point. Baseline expression of HO-1, iNOS, and TNFalpha mRNA was increased in the cortex of sham GK rats. GK rats showed pronounced hyperglycemia during EC and transient attenuation of regional cerebral blood flow recovery. At 48 h after reperfusion, HO-1 mRNA expression was 7- to 8-fold higher in the ischemic cortex of both strains, being the most upregulated gene under study. Heme oxygenase-1 protein expression was significantly reduced in diabetic rats and was found in perilesional astrocytes and rare microglial cells, in both strains. The reduced HO-1 protein expression in GK rats at 48 h after reperfusion combined with more extensive neurodegeneration induced by EC, provides further in vivo evidence for a neuroprotective role of HO after brain ischemia.