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.

Acute administration of Ginkgo biloba extract (EGb 761) affords neuroprotection against permanent and transient focal cerebral ischemia in Sprague‐Dawley rats

“…The consequence of the energy imbalance is the depletion of ATP, which not only increases the susceptibility of brain tissues to oxidative stress but also triggers the onset of numerous ischemic cascades, leading to neuronal death (Siesjö, 1992; Small and Buchan, 1996; Ames, 2000). One strategy, therefore, to protect the brain against ischemic damage is to improve the energy supply to the tissues “at risk,” and/or to reduce the energy demands of the neuronal tissue (Ames et al, 1995; Maynard et al, 1998, 1999; Ayoub et al, 1999; Lee et al, 1999). It is also presumed that the multifactorial pathogenicity of cerebral ischemia may demand a multimode therapeutic approach.…”

Attenuation of microtubule associated protein-2 degradation after mild head injury by mexiletine and calpain-2 inhibitor

“…This was another reason why we have used mexiletine as a pretreatment. 33 Confocal microscopic examination of these groups showed remarkable spatial impairment as detected in three-dimensional neuronal level. Compared with calpain-2 inhibitor group, the mexiletine group showed better cytoskeletal preservation (e.g.…”

Magnesium protects in episodes of critical perfusion after aneurysmal SAH

“…Several groups investigated the protective efficacy in experimental studies of permanent focal ischemia and consistently found reduced infarct volumes [1, 2, 20]. Likewise, a reduction of infarct volumes and improved neurological outcome was reported in animal models of temporary ischemia after intravenous administration of magnesium [3, 21].…”

“…Experimental results in cerebral ischemia [1, 2, 3, 4] and early clinical data in stroke patients [5, 6] supported the idea that magnesium may act as a neuroprotective agent in cerebral ischemia and SAH. In the last two decades, several clinical studies have shown beneficial effects of magnesium in SAH [7, 8, 9, 10, 11, 12, 13, 14].…”