Magnesium chloride alone or in combination with diazepam fails to prevent hippocampal damage following transient forebrain ischemia

Abstract

In the central nervous system, magnesium ion (Mg 2+ ) acts as an endogenous modulator of N-methyl-D-aspartate (NMDA)-coupled calcium channels, and may play a major role in the pathomechanisms of ischemic brain damage. In the present study, we investigated the effects of magnesium chloride (MgCl 2 , 2.5, 5.0 or 7.5 mmol/kg), either alone or in combination with diazepam (DZ), on ischemiainduced hippocampal cell death. Male Wistar rats (250-300 g) were subjected to transient forebrain ischemia for 15 min using the 4-vessel occlusion model. MgCl 2 was applied systemically (sc) in single (1x, 2 h post-ischemia) or multiple doses (4x, 1, 2, 24 and 48 h postischemia). DZ was always given twice, at 1 and 2 h post-ischemia. Thus, ischemia-subjected rats were assigned to one of the following treatments: vehicle (0.1 ml/kg, N = 34), DZ (10 mg/kg, N = 24), MgCl 2 (2.5 mmol/kg, N = 10), MgCl 2 (5.0 mmol/kg, N = 17), MgCl 2 (7.5 mmol/kg, N = 9) or MgCl 2 (5 mmol/kg) + DZ (10 mg/kg, N = 14). Seven days after ischemia the brains were analyzed histologically. Fifteen minutes of ischemia caused massive pyramidal cell loss in the subiculum (90.3%) and CA1 (88.4%) sectors of the hippocampus (P<0.0001, vehicle vs sham). Compared to the vehicle-treated group, all pharmacological treatments failed to attenuate the ischemia-induced death of both subiculum (lesion: 86.7-93.4%) and CA1 (lesion: 85.5-91.2%) pyramidal cells (P>0.05). Both DZ alone and DZ + MgCl 2 reduced rectal temperature significantly (P<0.05). No animal death was observed after drug treatment. These data indicate that exogenous magnesium, when administered systemically post-ischemia even in different multiple dose schedules, alone or with diazepam, is not useful against the histopathological effects of transient global cerebral ischemia in rats.

Magnesium Is Not Consistently Neuroprotective for Perinatal Hypoxia-Ischemia in Term-Equivalent Models in Preclinical Studies: A Systematic Review

“…These shorter survival times provide important information about acute histological outcomes, however, brain injury can evolve for many weeks [61], and neurodevelopmental outcome can be discordant from histological outcomes [60]. In adult rodents treated with MgSO 4 for cerebral injury, studies of survival times ≥7 days have rarely reported significant neuroprotection [44,45,48,62], and 9% of the adult studies surveyed in this review showed neuroprotective effects of magnesium per se after 7 days. Similarly, 43% of perinatal studies identified in the present review demonstrated no improvement in neurodevelopmental outcome after survival times of 7-11 days.…”

“…Eight studies reported improved histological outcome for MgSO 4 alone [35,36,37,38,39,40,41,42], of which only 2/8 documented temperature at limited times after ischemia [35,41]. Seven studies reported no improvement in histological outcome with MgSO 4 or MgCl 2 [43,44,45,46,47,48]. In all of these studies, postischemic temperature was monitored continuously and normothermia was maintained.…”

Brain lesions in newborns exposed to high-dose magnesium sulfate during preterm labor

“…[52][53][54][55][56] In the laboratory, the research findings seem to differ according to the animal species used for experimentation, and the kind of artificial insult used to initiate the biological injury. In immature rat pups, a dose-dependent reduction of intrastriatal N-methyl-D-aspartate-induced excitotoxic brain damage was reported after intraperitoneal application of MgSO 4 occurring 15 min or longer after the initiation of the artificial insult.…”

Tacrolimus (FK506) reduces ischemia-induced hippocampal damage in rats: a 7- and 30-day study

“…Transient global forebrain ischemia was induced by the 4-VO method (15) with modifications (16). Briefly, the animals were anesthetized with ether plus local application of 2% xylocaine, and were fixed in a stereotaxic-like frame; the vertebral arteries were then bilaterally electrocoagulated.…”