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Vink R, Nechifor M, editors. Magnesium in the Central Nervous System [Internet]. Adelaide (AU): University of Adelaide Press; 2011.
Abstract
The blood-brain barrier (BBB) is constituted primarily of brain capillary endothelial cells and is a pre- requisite for the maintenance of brain homeostasis that is essential for optimal brain function. However, a variety of pathological conditions, such as sepsis, multiple sclerosis and epilepsia disrupt the BBB integrity and lead to the development of brain edema. Ionized magnesium (Mg2+) is a crucial cofactor that plays an essential role within the cell and regulates a variety of biochemical reactions. Changes in intra- and extracellular Mg2+ concentrations influence the functions of cells and tissues. A growing body of evidence suggests that Mg2+ plays a pivotal role in ameliorating BBB disruption via a number of mechanisms during certain neurological diseases. Systemic delivery of Mg2+ may constitute an alternative approach in the future, both to improve BBB integrity and to decrease brain edema in the course of a variety of diseases involving brain tissue.
Introduction
Blood-Brain Barrier
The blood-brain barrier (BBB) is composed mainly of brain capillary endothelial cells and represents a dynamic structure that regulates the trafficking of molecules between blood and brain tissue. The passage of many circulating substances from the capillary bed into the brain parenchyma is tightly controlled by physical and enzymatic barriers provided by the endothelial cells of capillaries in the brain parenchyma (Abbott et al., 2010; Cardoso et al., 2010). In this way, the BBB is equipped with regulating means that enable the maintenance of neuronal homeostasis. In addition, the BBB harbours transport mechanisms that provide bidirectional control of exchange of nutrients, electrolytes and neurotoxins, and thus establishes an optimum milieu that is strictly essential to neuronal survival. Although the BBB appears to possess a static structure, it has the ability to adapt readily to sudden changes.
About 95% of the microvessels in the brain display BBB properties, and almost every neuron is estimated to be nourished by a distinct capillary vessel (Pardridge, 2005). When regulating its own activities, the mature BBB receives support from at least three different cell types: 1) pericytes which share the same basement membrane with endothelial cells; 2) astrocytes which envelope 99% of the abluminal face of endothelial cells; and 3) neurons (Guo and Lo, 2009; Correale and Villa, 2009). Nevertheless, under normal conditions, BBB function is regulated primarily by capillary endothelial cells (Fisher, 2009; Abbott et al., 2010).
In brain tissue, the barrier-type endothelial cells have a continuous basal membrane and do not exhibit fenestrations. These cells contain many mitochondria, but harbour very few caveola (pinocytotic vesicles) in their luminal surfaces. Tight junctions (TJs) between adjacent brain capillary endothelial cells possess occludin and claudin proteins that serve to preserve junctional integrity. Meanwhile, zonula occludens (ZO)-1 and ZO-2, cingulin, cadherin, cathenin, vinculin and actin constitute accessory proteins that aid in the assembly of TJs.
Passive diffusion across the BBB mainly depends on the lipid solubility and molecular weight of molecules. Lipophilic substances with molecular weights less than 400-600 Da can pass readily into the brain tissue by passive diffusion. In the normally functioning BBB, oxygen, carbon dioxide, nicotine, ethanol, lipid-soluble substances such as heroin, and amphiphilic drugs (containing both hydrophobic and hydrophilic moieties) are carried by this route. In addition, a number of molecules are transported across the BBB by other mechanisms including carrier- and receptor-mediated transport, adsorptive-mediated endocytosis and fluid phase-mediated endo- cytosis (Loscher and Potschka, 2005; Pardridge, 2007). However, many pathological conditions alter the functional and structural characteristics of the BBB impairing the maintenance of neural homeostasis.
Magnesium Physiology
Magnesium ion (Mg2+), the most abundant divalent cation in living cells, exists not only in the intracellular compartment but also in circulation and cerebrospinal fluid (CSF). Serum Mg2+ concentration normally ranges between 1.7-2.3 mEq/L in humans and may decrease during several pathological conditions (Romani and Scarpa, 2000; Musso, 2009). Cell membranes have a particularly low permeability to Mg2+ and hence the ion moves slowly between intracellular and interstitial compartments. Under physiol- ogical conditions, the Mg2+ concentration within the cell is maintained in a relatively narrow range between 0.5 and 1 mM (Dai and Quamme, 1991; Romani and Scarpa, 2000). Mg2+ acts as a regulatory cation at the systemic and cellular levels, and participates in almost all anabolic and catabolic processes in the body. It plays a fundamental role in a wide range of cellular events, biochemical reactions and physiological functions, by activating over 325 enzyme systems, including those involved in ATP synthesis, carbohydrate metabolism, K+ and Ca2+ transport, cell proliferation and membrane stability and function (Grubbs and Maguire, 1987; Saris et al., 2000; Wolf and Trapani, 2008; Barbagallo and Dominguez, 2010).
During normal physiological processes, Mg2+ works as a voltage dependent antagonist and a noncompetitive inhibitor of the N-methyl-D- aspartic acid (NMDA) receptors and ion channels in the brain. Although pharmacokinetic and pharmacodynamic studies in rats have shown Mg2+ entry into the brain upon systemic treatment (Hallak et al., 1992; Hoane, 2007), no concomitant rise of Mg2+ in CSF was noted following parenteral administration in humans with brain insults (McKee et al., 2005).
A reduction of Mg2+ level within the cell in pathological states can be considered as an injury factor in the brain and may lead to serious biological and metabolic dysfunction. Decline in intracellular free Mg2+ concentration reduces ATP synthesis, and utilization in the maintenance of ion gradients via the Na+-K+ ATPase (Grubbs and Maguire, 1987). Also, the reduction in Mg2+ concentration within the cell results in an impairment of membrane stability by promoting free radical production (Ebel and Gunther, 1980; Bara and Guiet-Bara, 1984). Among the other events associated with Mg2+ deficiency in brain are opening of Ca2+ channels, cellular entry of Ca2+, release of certain neurotransmitters, activ- ation of NMDA receptors, membrane oxidation and activation of nuclear factor kappa B (NFKB) (Weglicki et al., 1994; Altura et al., 2003; Billard, 2006; Rayssiguier et al., 2010). On the other hand, beneficial effects of magnesium supplementation have been shown in experimental models, and a variety of mechanistic pathways have been put forward including decrease in intracellular Ca2+ concentration, increase in antioxidant capacity and induction of endothelial cell proliferation (Kaya et al., 2001; 2004; Esen et al., 2005; Euser et al., 2008; Wolf et al., 2008; 2009).
Brain edema and magnesium
Two major types of brain edema, termed cytotoxic and vasogenic edema, were described by Klatzo in the late 1960s, and later two more types were added to the classification (Klatzo, 1967; Marmarou, 2004; Nag et al., 2009). Cytotoxic brain edema is characterized by sustained intracellular water accumulation, causing cellular injury in the absence of BBB damage and involving mainly astrocytes. On the other hand, vasogenic edema results in extracellular water accumulation in brain parenchyma through BBB disruption. The other types of edema are interstitial edema, which is observed in patients with hydrocephalus, and osmotic edema caused by imbalances of osmotically active substances, promoting water influx into cells.
Energy depletion followed by a failure of the Na+- K+ ATPase plays a major role in the pathogenesis of cytotoxic brain edema, and increased uptake of Na+ into the cell cannot be equilibrated by the defective pump. Under certain pathological conditions, such as traumatic brain injury (TBI), cerebral ischemia and acute hypertension, thebrain edema, which is initially cytotoxic, acquires a vasogenic character in the following stages. Brain edema caused by trauma has also been proposed to be mainly vasogenic in nature due to the opening of TJs in the BBB (Unterberg et al., 2004). Magnesium supplementation has been reported to decrease regional brain tissue water content and attenuate brain edema formation after experimental TBI (Okiyama et al., 1995; Feldman et al., 1996). In addition, magnesium treatment protects the blood-spinal cord barrier, improves clinical recovery, and preserves normal spinal cord ultrastructure in experimental spinal cord injury in rats (Kaptanoglu et al., 2003).
Aquaporin (AQP)-4, a bidirectional transmembrane water channel expressed mainly in astrocytes and to a lesser extent in barrier type of endothelial cells and pial membranes, may play a crucial role in the pathogenesis of cytotoxic and vasogenic brain edema and aggravation/resolution of ischemic and traumatic brain edema (Amiry- Moghaddam et al., 2003; Zador et al., 2009). Experimental studies focusing on the treatment of brain edema showed beneficial effects of magnesium administered in combination with various pharmacological drugs in animal models (Royo et al., 2003; Sen and Gulati, 2010). Upreg- ulation of AQP-4 in brain injury leads to an increase in brain water content, resulting in brain edema (Taniguchi et al., 2000; Papadopoulos and Verkman, 2005) and treatment with magnesium causes the down-regulation of AQP-4 (Ghabriel et al., 2006) and thereby attenuates brain edema (Okiyama et al., 1995).
It has been reported that Mg2+ exerts neuroprotective effects in an anoxic insult by improving the recovery of synaptic transmission and blocking the loss of protein kinase C (PKC) (Libien et al., 2005). These data are mechanistically consistent with the observation that the treatment of the astrocytes with a PKC activator caused a rapid decrease in AQP-4 mRNA and that this effect was inhibited by a specific PKC inhibitor (Nakahama et al., 1999). Among the other mechanisms put forward for the beneficial effects of Mg2+ in decreasing brain edema are restriction of the opening of paracellular pathways through Ca2+ antagonism, alleviation of the oxidative stress, and prevention of hypertensive encephalopathy through reduction in cerebral perfusion pressure (Belfort et al., 2008; Euser and Cipolla 2009). Mg2+ has also been shown to reduce brain edema and protect brain morphology in experimental cold-injury by inhibition of lipid peroxidation (Turkoglu et al., 2008).
Blood-brain barrier and magnesium
Mg2+ is slowly transported across the BBB into the brain by transporters and exchangers located in endothelial cell membranes, including the Na+/Mg2+ exchanger, the Mg2+/Ca2+ exchanger and cation channels. Following systemic administration, regional increases in Mg2+ has been detected in the cerebral cortex and hippocampus in rats with an intact BBB (Hallak et al., 1992; Touyz, 2008). In both physiological and pathological conditions, Mg2+ can directly influence BBB properties. Low Mg2+ concentration in the circulation is associated with increase in endothelial permeability, decrease in vasodilator capacity and an increase in the production of vasoconstrictor substances, cytokines and oxidative products (Touyz, 2003; Maier et al., 2004). In pathological conditions with BBB impairment, Mg2+ passes into the extracellular compartment of the brain in significantly higher concentrations and plays an important role in the pathophysiological processes that follow BBB disruption. An elevation in free Mg2+ concentration in capillary endothelial cells increases the proliferation of endothelial cells, restores the cell's ability to generate and utilize ATP for cellular repair mechanisms, and improves disrupted BBB integrity in a variety of insults. In addition to the stimulatory effect of Mg2+ on endothelial cell migration and proliferation, the observation that high Mg2+ concentration facilitates the re-endothelialization of vascular injuries may also provide new insights into the role of Mg2+ in angiogenesis (Maier et al., 2004).
A decrease in Mg2+ level in the microcirculation of the cortical structures causes a rapid and progressive damage to microvessels, leading to focal haemorrhages and brain edema (Altura et al., 1991). Increasing brain bioavailability of parenterally administered magnesium by artificial BBB disruption has been considered as a necessary step in assessing the therapeutic benefits of magnesium supplementation after TBI (Sen and Gulati, 2010). Magnesium therapy has been shown to be effective in a variety of animal models of experimental BBB disruption. Accumulated data indicate that magnesium administration improves functional outcome following BBB disruption and decreases brain edema (Okiyama et al., 1995; Feldman et al., 1996; Kaya et al., 2004; Esen et al., 2005; Euser et al., 2008). Treatment with magnesium and MK- 801 (dizocilpine), a noncompetitive NMDA receptor antagonist, either alone or in combination, can reduce brain edema development and help to restore BBB permeability after experimental diffuse brain injury (Feng et al., 2004; Imer et al., 2009).
One of the major mechanisms responsible for the pharmacological action of Mg2+ is blockage of NMDA or alpha-amino-3-hydroxy-5-methyl isoxazole-4-proprionic acid (AMPA) channels/ receptors in cerebral vascular system as well as brain parenchyma (Huang et al., 1994). The observation that blockade of NMDA or AMPA receptors could attenuate BBB disruption in focal cerebral ischemia suggest that ionotropic glutamate receptors are involved, at least partly, in BBB disruption (Liu et al., 2010). Magnesium can modulate hypoxic-ischemic events in the cerebral cortex by blocking the action of local putative excitatory amino acid neurotransmitters and consequently, high extracellular Mg2+ has been shown to be effective in blocking the pathophysiological mechanisms of rupture and spasm in the brain microvasculature (Huang et al., 1994; Chaon et al., 2006). Other possible mechanisms of action of Mg2+ in regulating vascular function involve its antioxidant, anti- inflammatory, and growth regulatory properties via which burden of oxidative stress and inflammation in the endothelial cells of microvessels are attenuated (Weglicki et al., 1996; Mazur et al., 2007). In addition, treatment of human endothelial cells with magnesium has induced reduction of cellular pro-oxidant levels and diminished the release of pro-inflammatory cytokines (Wolf et al., 2008).
Although the effects of magnesium on BBB characteristics and the formation of brain edema in various pathophysiological conditions has not been thoroughly elucidated, the studies mentioned above suggest that magnesium provides protective effects on BBB integrity and reduces brain edema by more than one mechanism (Figure 1). Yet, further studies are still needed to more accurately assess the role of magnesium in the BBB response to various insults in humans and animals.

Figure 1.
Effects of magnesium on BBB integrity.
Blood-brain barrier, magnesium and traumatic brain injury
BBB disruption commonly occurs shortly after experimental and clinical TBI. Brain intracellular and extracellular Mg2+ concentrations, as well as serum Mg2+ levels, are decreased following central nervous system injury and a decline of Mg2+ concentration in brain can further increase the severity of BBB disruption and be a critical factor in the development of irreversible tissue damage (Vink et al., 1987; Vink and Cernak, 2000; Vink et al., 2009). Reduction in brain intracellular free Mg2+ is also associated with brain intracellular acidosis and a concomitant reduction of brain energy stores (Vink et al., 1988; Altura et al., 1995).
Magnesium salts, such as magnesium sulphate (MgSO4) or magnesium chloride were shown to penetrate the BBB and cause enhancement of brain intracellular free Mg2+ concentration following TBI (Heath and Vink, 1999). Accumulated data from animal models indicates that administration of magnesium salts into the circulation or extracellular brain compartments can provide an effective therapy for TBI (Vink and Cernak, 2000; Saatman et al., 2001; Hoane, 2007) by improving BBB integrity and decreasing brain edema (Esen et al., 2003). In contrast to the animal studies mentioned above, McKee and colleagues (McKee et al., 2005) described the functional characteristics of the BBB in patients with TBI by using MgSO4 infusions initiated at an average of 5 days after injury. The authors showed that the increased serum Mg2+ concentrations yielded only a marginal increase of total and ionized Mg2+ in CSF and they concluded that the regulation of magnesium by the constituents of the BBB remains largely intact following brain injuries. Meanwhile, in a double- blinded trial conducted to check the validity of animal data in humans, and to explore whether magnesium infusion initiated within 8 hours of major head injury and continued for 5 days would decrease mortality and improve the functional outcome in head-injured patients, it was reported that there was no clinical suggestion of a beneficial effect of the magnesium regimen in these patients (Temkin et al., 2007).
Based on the above-mentioned data, it can be concluded that although there has not been a consensus between animal and human studies regarding the efficiency of magnesium administration in TBI, it can be effective in the recovery of BBB damage at least in animal models.
Blood-brain barrier, magnesium and seizures
Eclampsia is a serious hypertensive disorder of pregnancy with seizures and associated BBB disruption and vasogenic edema in a similar manner to that observed in hypertensive encephalopathy (Schwartz et al., 2000; Euser and Cipolla, 2009). In animal models, magnesium treatment has been shown to contribute to the protection of the BBB during eclampsia, to decrease the increased BBB permeability, and to prevent the development of brain edema in certain experimental settings, including acute hypertension and hypoglycemia- induced seizures (Kaya et al., 2001 and 2004; Euser et al., 2008). The above-mentioned beneficial effects of magnesium on BBB integrity may be related to its ability to scavenge free radicals. The antioxidant action of magnesium has been reported in two recent studies (Ariza et al., 2005; Turkoglu et al., 2008), suggesting that it could protect against free radical surge associated with epileptic seizures. However, the exact mechanism/s of action of magnesium treatment in the improvement of BBB integrity in eclampsia still remains to be elucidated.
Blood-brain barrier, magnesium and sepsis
Magnesium supplementation is one of the experimental methods and pharmacological approaches developed for the treatment of BBB disruption and brain edema caused by septic encephalopathy. The impairment of BBB integrity during sepsis has been shown in several studies, and magnesium administration in the early stages of sepsis reduced BBB permeability and brain edema (Papadopoulos et al., 2005; Esen et al., 2005). Magnesium deficiency leads to an elevation in plasma inflammatory cytokines and excessive production of free radicals, and aggravates endotoxic shock (Weglicki et al., 1994; Matsui et al., 2007). Treatment with magnesium decreases the concentration of inflammatory cytokines and free radicals and increases antioxidant capacity and survival rate in rats (Salem et al., 1995). Finally, alterations in endothelial cells, which are protagonists in the vascular changes during inflammation, are reversible upon magnesium supplementation (Mazur et al., 2007). Although the above- mentioned studies suggest that magnesium is involved in the protection of the BBB and brain edema in sepsis, the literature data is quite limited at present and additional studies are needed to explain the pathophysiologic mechanisms involved in this protection.
Blood-brain barrier, magnesium and brain hypoxia/ischemia
Cerebral hypoxia/ischemia is known to cause disruption of BBB integrity, thereby increasing the permeability of the BBB and leading to the development of brain edema. Extracellular Mg2+ concentration has been shown to significantly decrease to approximately 60% of basal values in the ipsilateral cortex in hypoxia-ischemia (Lee et al., 2002). Meanwhile, magnesium deficient rats are more susceptible to cerebral hypoxia/ ischemia than rats fed with a normal or high magnesium diet (Demougeot et al., 2004). Magnesium administration significantly attenuates the hypoxia-induced increase in reactive oxygen species and contributes to the repair of the disrupted BBB in hypoxia/ischemia (Ravishankar et al., 2001; Goñi-de-Cerio et al., 2009). The protection of the BBB by magnesium in hypoxic conditions could be multifactorial and, in addition to the above mentioned effects, may involve other factors such as decrease in the production of cytokines, increase in antioxidative products and blockade of NMDA or AMPA channels/ receptors. There is at present only limited knowledge about the role of magnesium on BBB integrity and brain edema in hypoxia/ischemia and future research is needed to determine the possible mechanisms of magnesium supplement- ation in improving the functions of BBB.
Blood-brain barrier, magnesium and ethanol
Acute and chronic ethanol treatment gives rise to significant increases in BBB permeability to a variety of molecules that do not normally cross the BBB. Increase in free radical concentration in ethanol-treated endothelial cells leads to phosphorylation of TJ proteins, activation of paracellular pathway and thus disruption of the BBB (Haorah et al., 2005). A number of studies have provided evidence for the alterations in serum Mg2+ levels in acute and chronic ethanol treatments. A single dose of ethanol (2 g/kg) injected to mice significantly decreased total Mg2+ concentration in serum (Papierkowski et al., 1998). Furthermore, acute or chronic alcohol consumption impairs Mg2+ transport and homeostasis at the capillary level in the brain (Romani, 2008). However, little is known about whether any improvement in BBB integrity can be achieved by magnesium treatment in acute or chronic ethanol intake. Therefore, this lack of basic knowledge compounds the difficulty we face when interpreting the importance of efforts of increasing serum Mg2+ levels under these conditions.
Blood-brain barrier, magnesium and hydrocephalus
Human and animal studies have indicated that hydrocephalus leads to disruption of the BBB. In a study involving a total of 21 patients with normal- pressure hydrocephalus, a slight plasma-like protein pattern has been demonstrated in CSF in 38% of the patients prior to surgical intervention, indicating BBB dysfunction (Wikkelsø and Blomstrand, 1982). There is only one study in the current literature that evaluates the effects of magnesium in hydrocephalus, and a mild protection against brain damage was shown using MgSO4 therapy in a rat model of childhood-onset hydrocephalus (Khan et al., 2003). Further studies are necessary to increase our understanding of the effects of deficiency or supplementation of magnesium on the functional and structural characteristics of the BBB during hydrocephalus in both animal and human studies.
Conclusion
It is clear from the discussion above that magnesium plays a variety of essential roles within the cell by modulating the activity of more than 325 enzymes as a cofactor. These enzymes are important for the survival of various cell types including endothelial cells of the BBB. Meanwhile, magnesium deficiency leads to or worsens a variety of central nervous system pathologies by increasing inflammatory cytokines and reactive oxygen species and disturbing the activity of transporters in neurons, astrocytes, pericytes and capillary endothelial cells, which together constitute the neurovascular unit of the brain.
Besides, the alterations in the Mg2+ concentration in intra- and extracellular fluids are associated with development or aggravation of BBB disruption and brain edema in various clinical disorders and experimental settings. On the other hand, magnesium supplementation can play multiple roles in protecting BBB integrity and improving brain edema. However, owing to the availability of limited knowledge, it is hard to come to a full understanding of the highly specific actions of magnesium on BBB integrity and brain edema in the course of a variety of pathophysiologies involving the BBB. For this reason, research in this field should continue in order to provide a thorough explanation of the impact of magnesium on the BBB, brain edema and related pathologies.
References
- Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ. Structure and function of the blood- brain barrier. Neurobiol Dis. 2010;37:13–25. [PubMed: 19664713]
- Altura BM, Gebrewold A, Huang QF, Altura BT. Deficits in brain-CSF magnesium result in cerebrovasospasm and rupture of cerebral microvessels: Possible relation to stroke. Clin Res. 1991;39:394A.
- Altura BM, Gebrewold A, Altura BT, Gupta RK. Role of brain [Mg2+]i in alcohol-induced hemorrhagic stroke in a rat model: a 31P-NMR in vivo study. Alcohol. 1995;12(2):131–6. [PubMed: 7772264]
- Altura BM, Gebrewold A, Zhang A, Altura BT. Low extracellular magnesium ions induce lipid peroxidation and activation of nuclear factor-kappa B in canine cerebral vascular smooth muscle: possible relation to traumatic brain injury and strokes. Neurosci Lett. 2003;341:189–92. [PubMed: 12697280]
- Amiry-Moghaddam M, Otsuka T, Hurn PD, Traystman RJ, Haug FM, Froehner SC, Adams ME, Neely JD, Agre P, Ottersen OP, Bhardwaj A. An alpha- syntrophin-dependent pool of AQP4 in astroglial end- feet confers bidirectional water flow between blood and brain. Proc Natl Acad Sci USA. 2003;100:2106–11. [PMC free article: PMC149966] [PubMed: 12578959]
- Ariza AC, Bobadilla N, Fernandez C, Munoz-Fuentes RM, Larrea F, Halhali A. Effects of magnesium sulfate on lipid peroxidation and blood pressure regulators in pre-eclampsia. Clin Biochem. 2005;38:128–33. [PubMed: 15642274]
- Bara M, Guiet-Bara A. Potassium, magnesium and membranes. Magnesium. 1984;3:212–25. [PubMed: 6399343]
- Barbagallo M, Dominguez LJ. Magnesium and aging. Curr Pharm Des. 2010;16:832–39. [PubMed: 20388094]
- Billard JM. Ageing, hippocampal synaptic activity and magnesium. Magnes Res. 2006;19:199–215. [PubMed: 17172010]
- Belfort M, Allred J, Dildy G. Magnesium sulfate decreases cerebral perfusion pressure in preeclampsia. Hypertens Pregnancy. 2008;27:315–27. [PubMed: 19003633]
- Cardoso FL, Brites D, Brito MA. Looking at the blood-brain barrier: molecular anatomy and possible investigation approaches. Brain Res Rev. 2010;64:328–63. [PubMed: 20685221]
- Chaon A, Lisott E, Eblen-Zajjur A. Magnesium sulphate reduces cell volume in physiological conditions but not in the cytotoxic oedema during global brain ischemia. Brain Injury. 2006;20:1087–91. [PubMed: 17060142]
- Correale J, Villa A. Cellular Elements of the Blood-Brain Barrier. Neurochem Res. 2009;34:2067–77. [PubMed: 19856206]
- Dai LJ, Quamme G A. Intracellular Mg2+ and magnesium depletion in isolated renal thick ascending limb cells. J Clin Invest. 1991;88:1255–64. [PMC free article: PMC295594] [PubMed: 1655827]
- Demougeot C, Bobillier-Chaumont S, Mossiat C, Marie C, Berthelot A. Effect of diets with different magnesium content in ischemic stroke rats. Neurosci Lett. 2004;362:17–20. [PubMed: 15147771]
- Ebel H, Gunther T. Magnesium metabolism: a review. J Clin Chem Clin Biochem. 1980;18:257–70. [PubMed: 7000968]
- Esen F, Erdem T, Aktan D, Kalaycı R, Cakar N, Kaya M, Telci L. Effects of magnesium administration on brain edema and blood brain barrier breakdown after experimental traumatic brain injury in rats. J Neurosurg Anesthesiol. 2003;15:119–25. [PubMed: 12657997]
- Esen F, Erdem T, Aktan D, Orhan M, Kaya M, Eraksoy H, Cakar N, Telci L. Effect of magnesium sulfate administration on blood-brain barrier in a rat model of intraperitoneal sepsis: A randomized controlled experimental study. Critical Care. 2005;9:R18–23. [PMC free article: PMC1065104] [PubMed: 15693962]
- Euser AG, Bullinger L, Cipolla MJ. Magnesium sulphate treatment decreases blood brain barrier permeability during acute hypertension in pregnant rats. Exp Physiol. 2008;93:254–61. [PubMed: 17933863]
- Euser AG, Cipolla MJ. Magnesium Sulfate for the Treatment of Eclampsia. Stroke. 2009;40:1169–75. [PMC free article: PMC2663594] [PubMed: 19211496]
- Feldman Z, Gurevitch B, Artru AA, Oppenheim A, Shohami E, Reichenthal E, Shapira Y. Effect of magnesium given 1 hour after head trauma on brain edema and neurological outcome. J Neurosurg. 1996;85:131–7. [PubMed: 8683262]
- Feng DF, Zhu ZA, Lu YC. Effect of magnesium on traumatic brain edema in rats. Chin J Traumatol. 2004;7:148–52. [PubMed: 15294111]
- Fisher M. Pericyte signaling in the neurovascular unit. Stroke. 2009;40:S13–S15. [PMC free article: PMC2724312] [PubMed: 19064799]
- Ghabriel MN, Thomas A, Vink R. Magnesium restores altered aquaporin-4 immunoreactivity following traumatic brain injury to a pre-injury state. Acta Neurochir Suppl. 2006;96:402–6. [PubMed: 16671494]
- Goñi-de-Cerio F, Alvarez A, Alvarez FJ, Rey-Santano MC, Alonso-Alconada D, Mielgo VE, Gastiasoro E, Hilario E. MgSO4 treatment preserves the ischemia-induced reduction in S-100 protein without modification of the expression of endothelial tight junction molecules. Histol Histopathol. 2009;24(9):1129–38. [PubMed: 19609860]
- Grubbs RD, Maguire ME. Magnesium as a regulatory cation: criteria and evaluation. Magnes. 1987;6:113–27. [PubMed: 3306178]
- Guo S, Lo EH. Dysfunctional cell-cell signaling in the neurovascular unit as a paradigm for central nervous system disease. Stroke. 2009;40(3):S4–7. [PMC free article: PMC3712844] [PubMed: 19064781]
- Hallak M, Berman RF, Irtenkauf SM, Evans MI, Cotton DB. Peripheral magnesium sulfate enters the brain and increases the threshold for hippocampal seizures in rats. Am J Obstet Gynecol. 1992;167:1605–10. [PubMed: 1471674]
- Haorah J, Knipe B, Leibhart J, Ghorpade A, Persidsky Y. Alcohol-induced oxidative stress in brain endothelial cells causes blood-brain barrier dysfunction. J Leukoc Biol. 2005;78(6):1223–32. [PubMed: 16204625]
- Heath DL, Vink R. Improved motor outcome in response to magnesium therapy received up to 24 hours after traumatic diffuse axonal brain injury. J Neurosurg. 1999;90:504–9. [PubMed: 10067920]
- Hoane MR. Assessment of cognitive function following magnesium therapy in the traumatically injured brain. Magnes Res. 2007;20:229–36. [PubMed: 18271492]
- Huang Q F, Gebrewold A, Zhang A, Altura BT, Altura BM. Role of excitatory amino acids in regulation of rat pial microvasculature. Am J Physiol Regul Integr Comp Physiol. 1994;266:R158–63. [PubMed: 8304537]
- Imer M, Omay B, Uzunkol A, Erdem T, Sabanci PA, Karasu A, Albayrak SB, Sencer A, Hepgul K, Kaya M. Effect of magnesium, MK-801 and combination of magnesium and MK-801 on blood-brain barrier permeability and brain edema after experimental traumatic diffuse brain injury. Neurol Res. 2009;31:977–81. [PubMed: 19215660]
- Kaptanoglu E, Beskonakli E, Okutan O, Selcuk Surucu H, Taskin Y. Effect of magnesium sulphate in experimental spinal cord injury: evaluation and ultrastructural findings and early clinical results. J Clin Neurosci. 2003;10:329–34. [PubMed: 12763339]
- Kaya M, Küçük M, Bulut Kalayci R, Cimen V, Gürses C, Elmas I, Arican N. Magnesium sulfate attenuates increased blood–brain barrier permeability during insulin-induced hypoglycemia in rats. Can J Physiol Pharmacol. 2001;79:793–8. [PubMed: 11599780]
- Kaya M, Gulturk S, Elmas I, Arican N, Kocyildiz ZC, Kucuk M, Yorulmaz H, Sivas A. The effects of magnesium sulfate on blood-brain barrier disruption caused by intracarotid injection of hyperosmolar mannitol in rats. Life Sci. 2004;76:201–12. [PubMed: 15519365]
- Khan OH, Enno T, Del Bigio MR. Magnesium sulfate therapy is of mild benefit to young rats with kaolin-induced hydrocephalus. Pediatr Res. 2003;53:970–6. [PubMed: 12621098]
- Klatzo I. Presidental address: neuropathological aspects of brain edema. J Neuropathol Exp Neurol. 1967;26:1–14. [PubMed: 5336776]
- Lee MS, Wu YS, Yang DY, Lee JB, Cheng FC. Significantly decreased extracellular magnesium in brains of gerbils subjected to cerebral ischemia. Clin Chim Acta. 2002;318:121–5. [PubMed: 11880121]
- Libien J, Sacktor TC, Kass IS. Magnesium blocks the loss of protein kinase C, leads to a transient translocation of PKC (alpha) and PKC (epsilon), and improves recovery after anoxia in rat hippocampal slices. Brain Res Mol Brain Res. 2005;136:104–11. [PubMed: 15893593]
- Liu X, Hunter C, Weiss HR, Chi OZ. Effects of blockade of ionotropic glutamate receptors on blood- brain barrier disruption in focal cerebral ischemia. Neurol Sci. 2010;31:699–703. [PubMed: 20217443]
- Löscher W, Potschka H. Blood-brain barrier active efflux transporters: ATP-binding cassette gene family. NeuroRx. 2005;2:86–98. [PMC free article: PMC539326] [PubMed: 15717060]
- Maier JA, Bernardini D, Rayssiguier Y, Mazur A. High concentrations of magnesiummodulate vascular endothelial cell behaviour in vitro. Biochim Biophys Acta. 2004;1689:6–12. [PubMed: 15158908]
- Marmarou A. The pathophysiology of brain edema and elevated intracranial pressure. Cleveland Clin J Med. 2004;71:S6–8. [PubMed: 14964471]
- Matsui T, Kobayashi H, Hirai S, Kawachi H, Yano H. Magnesium deficiency stimulated mRNA expression of tumor necrosis factor-a in skeletal muscle of rats. Nutrition Research. 2007;27:66–8.
- Mazur A, Maier JA, Rock E, Gueux E, Nowacki W, Rayssiguier Y (2007) Magnesium and the inflammatory response: potential physiopathological implications. [PubMed: 16712775]
- Arch Biochem Biophys. 458:48–56. [PubMed: 16712775]
- McKee JA, Brewer RP, Macy GE, Phillips-Bute B, Campbell KA, Borel CO, Reynolds JD, Warner DS. Analysis of the brain bioavailability of peripherally administered magnesium sulfate: a study in humans with acute brain injury undergoing prolonged induced hypermagnesemia. Crit Care Med. 2005;33:661–6. [PubMed: 15753761]
- Musso CG. Magnesium metabolism in health and disease. Int Urol Nephrol. 2009;41:357–62. [PubMed: 19274487]
- Nag S, Manias JL, Stewart DJ. Pathology and new players in the pathogenesis of brain edema. Acta Neuropathol. 2009;118(2):197–217. [PubMed: 19404652]
- Nakahama K, Nagano M, Fujioka A, Shinoda K, Sasaki H. Effect of TPA on aquaporin 4 mRNA expression in cultured rat astrocytes. Glia. 1999;25:240–6. [PubMed: 9932870]
- Okiyama K, Smith DH, Gennarelli TA, Simon RP, Leach M, McIntosh TK. The sodium channel blocker and glutamate release inhibitor BW1003C87 and magnesium attenuate regional cerebral edema following experimental brain injury in the rat. J Neurochem. 1995;64:802–9. [PubMed: 7830074]
- Papadopoulos MC, Verkman AS. Aquaporin-4 gene disruption in mice reduces brain swelling and mortality in pneumococcal meningitis. J Biol Chem. 2005;280:13906–12. [PubMed: 15695511]
- Papierkowski A, Pasternak K. The effect of a single dose of morphine and ethanol on magnesium level in blood serum and tissues in mice. Magnes Res. 1998;11:85–9. [PubMed: 9675752]
- Pardridge WM. Molecular biology of the blood- brain-barrier. Mol Biotechnol. 2005;30:57–70. [PubMed: 15805577]
- Pardridge WM. Blood-brain-barrier delivery. Drug Discov Today. 2007;12:54–61. [PubMed: 17198973]
- Rayssiguier Y, Libako P, Nowacki W, Rock E. Magnesium deficiency and metabolic syndrome: stress and inflammation may reflect calcium activation. Magnes Res. 2010;23(2):73–80. [PubMed: 20513641]
- Ravishankar S, Ashraf QM, Fritz K, Mishra OP, Delivoria-Papadopoulos M. Expression of Bax and Bcl-2 proteins during hypoxia in cerebral cortical neuronal nuclei of newborn piglets: effect of administration of magnesium sulfate. Brain Res. 2001;901:23–9. [PubMed: 11368946]
- Romani AM. Magnesium homeostasis and alcohol consumption. Magnes Res. 2008;21:197–204. [PubMed: 19271417]
- Romani AM, Scarpa A. Regulation of cellular magnesium. Frontiers in Bioscience. 2000;5:720–34. [PubMed: 10922296]
- Royo NC, Shimizu S, Schouten JW, Stover JF, McIntosh TK. Pharmacology of traumatic brain injury. Curr Opin Pharmacol. 2003;3:27–32. [PubMed: 12550738]
- Saatman KE, Bareyre FM, Grady MS, McIntosh TK. Acute cytoskeletal alterations and cell death induced by experimental brain injury are attenuated by magnesium treatment and exacerbated by magnesium deficiency. J Neuropathol Exp Neurol. 2001;60:183–94. [PubMed: 11273006]
- Salem M, Kasinski N, Munoz R, Chernow B. Progressive magnesium deficiency increases mortality from endotoxin challenge: protective effects of acute magnesium replacement therapy. Crit Care Med. 1995;23:108–18. [PubMed: 8001362]
- Saris NL, Mervaala E, Karppanen H, Khawaja JA, Lewenstam A. Magnesium: an update on physiological, clinical and analytical aspects. Clin Chim Acta. 2000;294:1–26. [PubMed: 10727669]
- Schwartz RB, Feske SK, Polak JF, DeGirolami U, Iaia A, Beckner KM, Bravo SM, Klufas RA, Chai RY, Repke JT. Preeclampsia-eclampsia: Clinical and neuroradiographic correlates and insights into the pathogenesis of hypertensive encephalopathy. Radiology. 2000;217:371–6. [PubMed: 11058630]
- Sen AP, Gulati A. Use of magnesium in traumatic brain injury. Neurotherapeutics. 2010;7:91–9. [PMC free article: PMC5084116] [PubMed: 20129501]
- Taniguchi M, Yamashita T, Kumura E, Tamatani M, Kobayashi A, Yokawa T, Maruno M, Kato A, Ohnishi T, Kohmura E, Tohyama M, Yoshimine T. Induction of aquaporin-4 water channel mRNA after focal cerebral ischemia in rat. Mol Brain Res. 2000;78:131–7. [PubMed: 10891592]
- Temkin NR, Anderson GD, Winn HR, Ellenbogen RG, Britz GW, Schuster J, Lucas T, Newell DW, Mansfield PN, Machamer JE, Barber J, Dikmen SS. Magnesium sulfate for neuroprotection after traumatic brain injury: a randomised controlled trial. Lancet Neurol. 2007;6:29–38. [PubMed: 17166799]
- Touyz RM. Role of magnesium in the pathogenesis of hypertension. Mol Aspects Med. 2003;24:107–36. [PubMed: 12537992]
- Touyz RM. Transient receptor potential melastatin 6 and 7 channels, magnesium transport, and vascular biology: implications in hypertension. Am J Physiol Heart Circ Physiol. 2008;294:H1103–8. [PubMed: 18192217]
- Turkoglu OF, Eroglu H, Okutan O, Tun MK, Bodur E, Sargon MF, Oner L, Beskonakli E. A comparative study of treatment for brain edema Magnesium sulphate versus dexamethasone sodium phosphate. J Clin Neurosci. 2008;15:60–5. [PubMed: 18061457]
- Unterberg AW, Stover J, Kress B, Kiening KL. Edema and brain trauma. Neuroscience. 2004;129:1021–9. [PubMed: 15561417]
- Vink R, McIntosh T K, Demediuk P, Faden AI. Decrease in total and free magnesium concentration following traumatic brain injury in rats. Biochem Biophys Res Commun. 1987;149:594–9. [PubMed: 3426591]
- Vink R, McIntosh TK, Demediuk P, Weiner MW, Faden AI. Decline in intracellular free Mg2+ is associated with irreversible tissue injury after brain trauma. J Biol Chem. 1988;263:757–61. [PubMed: 3335524]
- Vink R, Cernak I. Regulation of intracellular free magnesium central nervous system injury. Front Biosci. 2000;1:656–65. [PubMed: 10922299]
- Vink R, Cook NL, van den Heuvel C. Magnesium in acute and chronic brain injury: an update. Magnes Res. 2009;22:158S–162S. [PubMed: 19780402]
- Weglicki WB, Phillips TM, Mak IT, Cassidy MM, Dickens BF, Stafford R, Kramer JH. Cytokines, neuropeptides, and reperfusion injury during magnesium deficiency. Ann N Y Acad Sci. 1994;723:246–57. [PubMed: 7518201]
- Weglicki WB, Mak IT, Kramer JH, Dickens BF, Cassidy MM, Stafford RE, Phillips TM. Role of free radicals and substance P in magnesium deficiency. Cardiovasc Res. 1996;31:677–82. [PubMed: 9138860]
- Wikkelsø C, Blomstrand C. Cerebrospinal fluid proteins and cells in normal-pressure hydrocephalus. J Neurol. 1982;228:171–80. [PubMed: 6186790]
- Wolf FI, Trapani V, Simonacci M, Ferré S, Maier JAM. Magnesium deficiency and endothelial dysfunction: is oxidative stress involved? Magnes Res. 2008;21:58–64. [PubMed: 18557135]
- Wolf FI, Trapani V. Cell (patho) physiology of magnesium. Clin Sci. 2008;114:27–35. [PubMed: 18047467]
- Wolf FI, Trapani V, Simonacci M, Boninsegna A, Mazur A, Maier JA. Magnesium deficiency affects mammary epithelial cell proliferation: involvement of oxidative stress. Nutr Cancer. 2009;61:131–6. [PubMed: 19116883]
- Zador Z, Stiver S, Wang V, Manley GT (2009) Role of aquaporin-4 in cerebral edema and stroke. In: Aquaporins- Handbook of experimental pharmacology 190 (Beitz E, eds), Springer, Heidelberg, pp 159-70. [PMC free article: PMC3516842] [PubMed: 19096776]
- Abstract
- Introduction
- Brain edema and magnesium
- Blood-brain barrier, magnesium and traumatic brain injury
- Blood-brain barrier, magnesium and seizures
- Blood-brain barrier, magnesium and sepsis
- Blood-brain barrier, magnesium and brain hypoxia/ischemia
- Blood-brain barrier, magnesium and ethanol
- Blood-brain barrier, magnesium and hydrocephalus
- Conclusion
- References
- The role of magnesium in edema and blood brain barrier disruption - Magnesium in...The role of magnesium in edema and blood brain barrier disruption - Magnesium in the Central Nervous System
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