Magnesium protects against cocaine-indiced hemorrhagic stroke in a rat model A31P-NMR em in-vivo em study

Abstract

In-vivo 31P-nuclear magnetic resonance (NMR) studies were undertaken with anesthetized rats to determine: a. whether systemic administration of MgCl2 could protect animals against cocaine-induced hemorrhagic stroke, and b. whether a relationship exists between basal levels of brain intracellular free magnesium ions ([Mg2+]i), phosphometabolites, and stroke risk. Repeat 31P-NMR spectra were obtained at various intervals of time (3-120 min, or up until death) after administration of cocaine (5 + 30 mg/kg). Ion selective electrodes were used to measure plasma Mg2+, K+, Na+ and Ca2+. Forty percent of animals died in the absence of Mg2+ infusion following high dosage of cocaine. Only 13% died with cocaine following Mg2+ infusion (p <0.005). In the Mg2+-protected animals, neither brain [Mg2+]i,intracellular pH (pHi), [phosphocreatine-PCr]/[ATP], nor brain [inorganic phosphate-Pi]/[ATP] fell when toxic and lethal doses of cocaine were given. Low basal brain [Mg2+]i (275 +/- 24 vs. 466 +/- 35 microM, p <0.01) and low basal brain [PCr] (3.36 +/- 0.35 vs. 4.26 +/- 0.24 mM, p <0.01) were found to be associated with a 3-fold increased incidence of stroke. A positive correlation (r = 0.31, p <0.03) between brain [Mg2+]1 and [PCr]/[ATP] was found. It is possible that both brain [Mg2+]i and [PCr] may be useful as important predictors of susceptibility to cocaine-induced hemorrhagic stroke.

The Effect of Magnesium on Oxidative Neuronal Injury In Vitro

“…Dietary magnesium restriction in the weeks before brain fluid-percussion injury increased mortality and worsened neurologic outcome in surviving animals . Furthermore, exogenous magnesium administration improved outcome in models ofbrain and spinal cord ischemia and trauma, as assessed by behavioral and cognitive parameters (Vacanti and Ames, 1984;McIntosh et al, 1989;Smith et al, 1993), mortality (Altura et al, 1995a, and analysis of lesion volume (Izumi et al, 1991;Marinov et al, 1996), edema formation (Feldman et al, 1996), and cellular bioenergetic state Altura et al, 1995aAltura et al, , 1997.…”

Optical Spectroscopy and Prevention of Deleterious Brain- damaging Cerebral Vascular Effects of Cocaine by Magnesium Ions: Effects on Brain Mitochondrial Oxidase, Deoxyhemoglobin, Ceramide and Sphingomyelin Levels and Their Potential Application to Human Substance Abuse

“…Increasing doses of cocaine HCl induced hemorrhagic strokes in these rat models preceded by falls in phosphocreatine and ATP and rises in intracellular phosphate levels [12]. Several additional studies on the intact rat brain, using in situ 31 P-NMR spectroscopy and direct invivo observations of the cerebral microcirculation suggest that administration of Mg 2+ can prevent these hemorrhagic strokes [9,12]. Whether or not these effects of Mg 2+ result in diminution or a complete loss of mitochondrial ischemic events in the brain caused by cocaine is not known.…”

“…Moreover, examination of isolated canine, rat, monkey and baboon cerebral and basilar arteries contracted in a dose-dependent manner upon the addition of cocaine HCl in isolated organ baths maintained under physiologic conditions [10,11]. In addition, we have shown in intact, unopened rat brains, using 31P-nuclear magnetic resonance (NMR) spectroscopy, that administration of cocaine HCl can produce concentrationdependent brain ischemia, preceded by rapid falls in brain intracellular free Mg 2+ ([Mg 2+ ] i ) [12]. Increasing doses of cocaine HCl induced hemorrhagic strokes in these rat models preceded by falls in phosphocreatine and ATP and rises in intracellular phosphate levels [12].…”

“…In addition, we have shown in intact, unopened rat brains, using 31P-nuclear magnetic resonance (NMR) spectroscopy, that administration of cocaine HCl can produce concentrationdependent brain ischemia, preceded by rapid falls in brain intracellular free Mg 2+ ([Mg 2+ ] i ) [12]. Increasing doses of cocaine HCl induced hemorrhagic strokes in these rat models preceded by falls in phosphocreatine and ATP and rises in intracellular phosphate levels [12]. Several additional studies on the intact rat brain, using in situ 31 P-NMR spectroscopy and direct invivo observations of the cerebral microcirculation suggest that administration of Mg 2+ can prevent these hemorrhagic strokes [9,12].…”

Alterations in Ionized and Total Blood Magnesium After Experimental Traumatic Brain Injury

“…Others have demonstrated that pre‐ or posttraumatic administration of magnesium chloride (MgCl 2 ) or magnesium sulfate (MgSO 4 ) can restore brain free magnesium levels, attenuate brain edema, and improve both neurologic and cognitive outcome in various models of experimental TBI (McIntosh et al, 1989 a ; Vink and McIntosh, 1990; Smith et al, 1993; Okiyama et al, 1995; Feldman et al, 1996; Heath and Vink, 1998 a ; Hoane et al, 1998). It has also been shown (Altura et al, 1995 a , 1997 a ) that preinjury magnesium supplementation can restore brain free magnesium levels, attenuate brain injury, and improve the outcome following experimentally induced stroke.…”