Threshold to N-methyl-D-aspartate-induced seizures in mice undergoing chronic nutritional magnesium deprivation is lowered in a way partly responsive to acute magnesium and antioxidant administrations

Abstract

Magnesium deficiency may be induced by a diet impoverished in magnesium. This nutritional deficit promotes chronic inflammatory and oxidative stresses, hyperexcitability and, in mice, susceptibility to audiogenic seizures. Potentiation by low-magnesium concentrations of the opening of N-methyl-D-aspartate (NMDA) receptor/calcium channel in in vitro and ex vivo studies, and responsiveness to magnesium of in vivo brain injury states are now well established. By contrast, little or no specific attention has been, however, paid to the in vivo NMDA receptor function/excitability in magnesium deficiency. The present work reports for the first time that, in mice undergoing chronic nutritional deprivation in magnesium (35 v. 930 parts per million for 27 d in OF1 mice), NMDA-induced seizure threshold is significantly decreased (38 % of normal values). The attenuation in the drop of NMDA seizure threshold (percentage of reversal) was 58 and 20 % upon acute intraperitoneal administrations of magnesium chloride hexahydrate (28 mg magnesium/kg) and the antioxidant ebselen (20 mg/kg), respectively. In nutritionally magnesium-deprived animals, audiogenic seizures are completely prevented by these compound doses. Taken as a whole, our data emphasise that chronic magnesium deprivation in mice is a nutritional in vivo model for a lowered NMDA receptor activation threshold. This nutritional model responds remarkably to acute magnesium supply and moderately to acute antioxidant administration. Magnesium and its deficiency present with many facets. The magnesium blockade of the N-methyl-D-aspartate (NMDA) receptor -calcium channel was reported more than 20 years ago (1) . Magnesium deficiency, which may be induced by chronic nutritional deprivation, has been shown to be a particular state affecting a great many tissue and cell physiological events. Among others, magnesium deficiency induces inflammatory and oxidative stresses, being associated with central hyperexcitability (2) and susceptibility towards audiogenic seizures. These seizures, which develop into four successive phases (latency, wild running, seizure and recovery), have been shown to respond to both anticonvulsant and neuroprotective compounds in a relatively discriminative way (3 -5) . Protection given by compounds in this peculiar nutritional model may result from either intrinsic anti-seizure or intrinsic antioxidant/anti-inflammatory neuroprotective properties, or both.Magnesium occupancy of the calcium channel lumen of the NMDA receptor results in a physiological block, which needs to be removed to allow the entry of calcium into the cell via this channel. In this respect, Nowak et al. (1) in their initial work demonstrated that NMDA receptor -calcium channel opening was greatly potentiated by exposure to low-magnesium concentrations. Despite this finding being corroborated by many in vitro and ex vivo (tissue slices) experiments, little or no direct information is currently available about this relationship in the † These authors contributed equally to the presen...

1,2-Ethane bis-1-amino-4-benzamidine is active against several brain insult and seizure challenges through anti-NMDA mechanisms targeting the 3H-TCP binding site and antioxidant action

“…Elucidation of underlying anticonvulsant or neuroprotective mechanisms requires additional compound testing which may include modulation of the audiogenic seizure phases mentioned above, specific anticonvulsant evaluation in classic animal seizure tests, and specific neuroprotective evaluation in well standardized brain injury models. This overall strategy previously emphasized original neuroprotective potentials of WEB2170 (an anti-PAF receptor antagonist) [4], FMOC-L-leucine (a PPARg agonist) [5] and 1-methyl-2-[3-trifluoromethylphenyl]-4-mercapto-imidazole (a synthetic ovothiol analogue) [6], and confirmed neuroprotective potentialities of melatonin [4], ebselen and magnesium [7]. Importantly, compounds described as neuroprotective but inactive in the MDDAS model, rosiglitazone [5] and fenofibrate (the authors, unpublished data), represent compounds which do not cross the intact BBB at a substantial rate [8,9].…”

“…Magnesiumdeficiency has been recently shown to be associated with a lowered threshold to NMDA-induced seizures [7], being consistent with a sensitivity of audiogenic seizures to EBAB. Ibotenate is a cyclic analogue of glutamate acting on glutamate receptors including metabotropic and NMDA receptors but neither alpha-3-aminohydroxy-5-methyl-4-isoxazole (AMPA) nor kainate receptors [28].…”

“…Both the magnesium deficiency [7] and the focal intracerebral ibotenate-poisoning challenge [14,15] are characterized, among other features, by an activation of the NMDA receptor. Polyamines towards which EBAB shares in common some structural analogies (see above) influences also the activity of the NMDA receptor [16].…”

Rapeseed oil and magnesium manipulations affect the seizure threshold to kainate in mice

“…These diets impoverished in magnesium were designed by restricting severely the magnesium content to 35AE5 ppm as described previously (Maurois et al, 1989;Maurois et al, 2009) and differed in fat content: ALA-poor (a mix of corn and sunflower oils (3:1)) or ALA-rich (pure rapeseed oil).…”

“…In mice, this particular nutritional animal model may be exploited for its susceptibility to audiogenic seizures to evaluate in vivo brain activity of anticonvulsant, neuroprotective, and antiinflammatory/antioxidant compounds (Bac et al, 1998;Vamecq et al, 2003;Maurois et al, 2008;Maurois et al, 2009;Pages et al, 2010;Vamecq et al, 2010;Pages et al, 2011). Chronic magnesium deprivation based on a vegetable oil diet devoided of v-3 polyunsaturated fatty acids (v3PUFA) (diet containing 5% corn/sunflower oil) in mice was also recently shown to represent an interesting nutritional model for in vivo exacerbated NMDA receptor function (reduction of NMDA seizures threshold) which responds remarkably to acute magnesium supply, adding experimental evidence that magnesium administration is a promising approach of glutamate-mediated brain disorders (Maurois et al, 2009).…”