Mexiletine and magnesium independently, but not combined, protect against permanent focal cerebral ischemia in Wistar rats.
ABSTRACT The neuroprotective effect of mexiletine (Mex), a potent Na(+) channel blocker which decreases neuronal energy demands and prevents energy depletion during ischemia, was evaluated in Wistar rats subjected to permanent middle cerebral artery (MCA) occlusion. Postmortem infarct volumes were determined by quantitative image analysis of triphenyltetrazolium (TTC)-stained brain sections. Pretreatment with Mex resulted in a significant infarct volume reduction when administered intraperitoneally, either at the dosage of 50 or 60 mg/kg, 1 hr before MCA occlusion (P < 0.05). Delayed treatment with Mex (50 mg/kg) also had neuroprotective effects when given at 0.5 hr (< 0.05), but not 2-4 hr, after MCA occlusion. Intraarterial administration of MgSO(4) (90 mg/kg), in combination with Mex at 60 mg/kg, showed no additive neuroprotective effect, although each agent independently reduced the MCA occlusion-induced infarction volume (P < 0.05). Our results indicate that a single, acute administration of Mex is neuroprotective against permanent focal cerebral ischemia, but perhaps chronic administration is needed to establish a more effective therapeutic window beyond 0.5 hr. Moreover, the present in vivo data do not favor a combined use of Mg(2+) with Mex for limiting ischemic injury in the brain, since these agents caused cardiopulmonary suppression, which may have led to the loss of the neuroprotective effect of each agent independently.
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ABSTRACT: Objective To determine the grade of neuroprotection of combined treatment with moderate hypothermia, tirilazad and magnesium sulfate. Cerebral ischemia is one of the problems of great interest at present, with limited therapeutic measures. Hypothermia, one of the more efficient measures, together with neuroprotector pharmaceuticals, could be a valid alternative. Design Experimental study with a control group and two levels of application of therapeutic measures. Context Experimental laboratory of the Medicine Faculty. Participants and method Twenty-eight Wistar rats underwent global cerebral ischemia of 10 minutes duration by the combination of bilateral carotid clamping and controlled hypotension (mean arterial pressure: 45 mmHg). Three groups were used: group I, normothermia maintenance; group II, moderate hypothermia (32-33 °C) for 2 hours; group III, hypothermia and administration of tirilazad mesylate and magnesium sulfate during the reperfusion and two hours after ischemia. The animals were sacrificed at 7 days and, after processing the tissue, the neurons preserved in layer CA1 of the hippocampus were counted. Results There is a significantly greater neuronal preservation in group III with regard to group I (55.4 ± 5.1 versus 38.7 ± 8.8, p < 0.0001). If we compare groups II and III, significant differences are only obtained on the right side and in the hippocampus considered globally, favoring the group with hypothermia and drugs. When groups I and II are compared there are no significant differences. Conclusions Association of moderate hypothermia, magnesium sulfate and tirilazad mesylate in the experimental model of transitory global ischemia used is confirmed as an effective neuroprotector measure, surpassing the degree of neuronal preservation of hypothermia alone.Medicina Intensiva 04/2007; 31(3):113-119. · 1.24 Impact Factor
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ABSTRACT: TRPM7, a divalent cation channel, plays an important role in neurons damaged from cerebral ischemia due to permitting intracellular calcium overload. This study aimed to explore whether magnesium was transported via a TRPM7 channel into the intracellular space of rat hippocampal neurons after 1 h of oxygen-glucose deprivation (OGD) and acute chemical ischemia (CI) by using methods of the Mg(2+) fluorescent probe Mag-Fura-2 to detect intracellular magnesium concentration ([Mg(2+)](i)) and flame atomic absorption spectrometry to measure extracellular magnesium concentration ([Mg(2+)](o)). The results showed that the neuronal [Mg(2+)](i) was 1.51-fold higher after 1 h of OGD at a basal level, and the increase of neuronal [Mg(2+)](i) reached a peak after 1 h of OGD and was kept for 60 min with re-oxygenation. Meanwhile, the [Mg(2+)](o) decreased after 1 h of OGD and recovered to the pre-ischemic level within 15 min after re-oxygenation. In the case of CI, the [Mg(2+)](i) peak immediately appeared in hippocampal neurons. This increase of [Mg(2+)](i) declined by removing extracellular magnesium in OGD or CI. Furthermore, by using Gd(3+) or 2-aminoethoxydiphenyl borate to inhibit TRPM7 channels, the [Mg(2+)](i) increase, which was induced by OGD or CI, was attenuated without altering the basal level of [Mg(2+)](i). By silencing TRPM7 with shRNA in hippocampal neurons, it was found that not only was the increase of [Mg(2+)](i) induced by OGD or CI but also the basal levels of [Mg(2+)](i) were attenuated. In contrast, overexpression of TRPM7 in HEK293 cells exaggerated both the basal levels and increased [Mg(2+)](i) after 1 h of OGD/CI. These results suggest that anoxia induced the increase of [Mg(2+)](i) via TRPM7 channels in rat hippocampal neurons.Journal of Biological Chemistry 06/2011; 286(23):20194-207. · 4.60 Impact Factor
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ABSTRACT: Studies on the neuroprotective effect of magnesium treatment in animal models of focal and global cerebral ischemia have produced inconsistent results. Nevertheless, two magnesium acute stroke phase III trials (IMAGES and FAST-MAG) have either been completed or are planned. Therefore, we decided to re-evaluate the efficacy of magnesium following focal cerebral ischaemia in rats. Two experiments were carried out in two independent laboratories based in Australia. Both used the intraluminal thread method to induce focal cerebral ischemia in the rat. In the Perth study the middle cerebral artery (MCA) was occluded for 45 min and body temperature was controlled during and after ischemia. In the Canberra laboratory the MCA was occluded for 2 h and body temperature was only controlled during surgery. Three different doses (180, 360, or 720 μmol/kg) of MgSO4 in the Perth study and two different MgSO4 doses (370 or 740 μmol/kg) in the Canberra study were intravenously or intra-arterially administered immediately before ischemia. Control animals were given an equal volume of normal saline just before ischemia in both studies. Twenty-four or 72 h post-ischemia, infarct volume was determined following 2′,3′,5′-triphenyl-2H-tetrazolium chloride (TTC) staining. No significant differences (P>0.05) in total, cortical and striatal infarct volumes between saline and MgSO4 treated animals were observed in either study. We conclude MgSO4 does not reduce infarct volume when administered before focal cerebral ischemia in rats.Neuroscience Research 05/2004; · 2.15 Impact Factor