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.

Hypoxia Induces an Increase in Intracellular Magnesium via Transient Receptor Potential Melastatin 7 (TRPM7) Channels in Rat Hippocampal Neurons in Vitro

“…Magnesium, the second most common intracellular cation and the most abundant intracellular divalent cation (32)(33)(34), has been shown to be neuroprotective in several experimental models of ischemic and excitotoxic brain injury (20,21). However, other studies have failed to detect a neuroprotective effect of magnesium (22,23).…”

Preclinical Drug Evaluation for Combination Therapy in Acute Stroke Using Systematic Review, Meta-Analysis, and Subsequent Experimental Testing

“…Almost one-quarter of magnesium studies (6 of 26) showed a worsening of infarct size. Furthermore, magnesium was not effective when combined with mexiletine (Lee et al, 1999). The use All, all treatment groups in the experiment; C, control group; Com, combination treatment group (magnesium, melatonin, and minocycline); M, mean; Mel, melatonin group; N, number of animals.…”

Delayed treatment with magnesium: reduction of brain infarction and improvement of electrophysiological recovery following transient focal cerebral ischemia in rats

“…It has also been proposed that the systemic adverse effects caused by NMDA antagonists may be greatly reduced and neuroprotective efficacy greatly enhanced, when Mg ϩϩ is adminis-tered directly via a proximal intraarterial infusion into the target organ. 13,20 Magnesium ion can readily cross the blood-brain barrier to bind specific receptors in the brain. 8,9 It prevents excitotoxicity in blocking various subtypes of Ca ϩϩ and NMDA channels and has proved to be neuroprotective in vitro and in vivo.…”

“…18 Alternatively, we have shown that pretreatment with Mg ϩϩ protects the brain against permanent focal cerebral ischemia. 13 In a delayed treatment paradigm, intravenous administration of Mg ϩϩ was shown in rats to offer a window of opportunity that extends up to 6 hours following embolic stroke, a model closer to permanent focal cerebral ischemia. 43 Taken together, it is evident that Mg ϩϩ has the ability to modulate cerebral bioenergetics during ischemia-reperfusion and, therefore, offers neuroprotection against both permanent and transient focal cerebral ischemia.…”