Magnesium Abstracts 5

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Effects of elevation of brain magnesium on fear conditioning, fear extinction, and synaptic plasticity in the infralimbic prefrontal cortex and lateral amygdala

         (Abumaria, Yin et al. 2011) Download

Anxiety disorders, such as phobias and posttraumatic stress disorder, are among the most common mental disorders. Cognitive therapy helps in treating these disorders; however, many cases relapse or resist the therapy, which justifies the search for cognitive enhancers that might augment the efficacy of cognitive therapy. Studies suggest that enhancement of plasticity in certain brain regions such as the prefrontal cortex (PFC) and/or hippocampus might enhance the efficacy of cognitive therapy. We found that elevation of brain magnesium, by a novel magnesium compound [magnesium-l-threonate (MgT)], enhances synaptic plasticity in the hippocampus and learning and memory in rats. Here, we show that MgT treatment enhances retention of the extinction of fear memory, without enhancing, impairing, or erasing the original fear memory. We then explored the molecular basis of the effects of MgT treatment on fear memory and extinction. In intact animals, elevation of brain magnesium increased NMDA receptors (NMDARs) signaling, BDNF expression, density of presynaptic puncta, and synaptic plasticity in the PFC but, interestingly, not in the basolateral amygdala. In vitro, elevation of extracellular magnesium concentration increased synaptic NMDAR current and plasticity in the infralimbic PFC, but not in the lateral amygdala, suggesting a difference in their sensitivity to elevation of brain magnesium. The current study suggests that elevation of brain magnesium might be a novel approach for enhancing synaptic plasticity in a regional-specific manner leading to enhancing the efficacy of extinction without enhancing or impairing fear memory formation.


Magnesium supplement enhances spatial-context pattern separation and prevents fear overgeneralization

         (Abumaria, Luo et al. 2013) Download

Enhancement of pattern separation could be helpful in improving the quality of normal daily learning and in treating individuals with cognitive impairment and certain psychiatric disorders. Previously, we have shown that elevating brain magnesium, by a novel magnesium compound (magnesium-L-threonate; MgT), enhances extinction of fear memory without enhancing amygdala-dependent fear memory. Here, we investigated the effects of MgT treatment on contextual-fear memory and subsequent pattern separation. Sprague-Dawley male rats were treated with MgT for 4 weeks and memory was evaluated using a spatial-context fear conditioning task. The pattern separation ability of MgT-treated rats was assessed using a spatial-context-discrimination task. MgT treatment did not enhance the retention of contextual-fear memory. Interestingly, the ability to discriminate between two, more or less distinct, contexts was enhanced in MgT-treated rats. Our results suggest that elevation of brain magnesium might be helpful in enhancing spatial-context discrimination and/or pattern separation besides preventing aversive-event-induced overgeneralization of fear.

Elevation of brain magnesium prevents and reverses cognitive deficits and synaptic loss in Alzheimer's disease mouse model

         (Li, Yu et al. 2013) Download

Profound synapse loss is one of the major pathological hallmarks associated with Alzheimer's disease (AD) and might underlie memory impairment. Our previous work demonstrated that the magnesium ion is a critical factor in controlling synapse density/plasticity. Here, we investigated whether elevation of brain magnesium by the use of a recently developed compound, magnesium-l-threonate (MgT), can ameliorate the AD-like pathologies and cognitive deficits in the APPswe/PS1dE9 mice, a transgenic (Tg) mouse model of AD. MgT treatment reduced Abeta plaque and prevented synapse loss and memory decline in the Tg mice. Strikingly, MgT treatment was effective even when given to the mice at the end stage of their AD-like pathological progression. To explore how elevation of brain magnesium ameliorates the AD-like pathologies in the brains of Tg mice, we studied molecules critical for APP metabolism and signaling pathways implicated in synaptic plasticity/density. In the Tg mice, the NMDAR/CREB/BDNF signaling was downregulated, whereas calpain/calcineurin/Cdk5 neurodegenerative signaling and beta-secretase (BACE1) expression were upregulated. MgT treatment prevented the impairment of these signaling pathways, stabilized BACE1 expression, and reduced soluble APPbeta and beta-C-terminal fragments in the Tg mice. At the molecular level, elevation of extracellular magnesium prevented the high-Abeta-induced reductions in synaptic NMDARs by preventing calcineurin overactivation in hippocampal slices. Correlation studies suggested that the protection of NMDAR signaling might underlie the stabilization of BACE1 expression. Our results suggest that elevation of brain magnesium exerts substantial synaptoprotective effects in a mouse model of AD and may have therapeutic potential for treating AD in humans.

Analysis of the brain bioavailability of peripherally administered magnesium sulfate: A study in humans with acute brain injury undergoing prolonged induced hypermagnesemia

         (McKee, Brewer et al. 2005) Download

OBJECTIVE: Based on preclinical investigations, magnesium sulfate (MgSO4) has gained interest as a neuroprotective agent. However, the ability of peripherally administered MgSO4 to penetrate the blood-brain barrier is limited in normal brain. The current study measured the passage of intravenously administered Mg into cerebrospinal fluid in patients with brain injury requiring ventricular drainage. DESIGN: A prospective evaluation of the cerebrospinal fluid total and ionized magnesium concentration, [Mg], during sustained hypermagnesemia was performed. SETTING: Neurosciences intensive care unit at a major teaching institution. PATIENTS: Thirty patients with acute brain injury secondary to subarachnoid hemorrhage, traumatic brain injury, primary intracerebral hemorrhage, subdural hematoma, brain tumor, central nervous system infection, or ischemic stroke were studied. INTERVENTIONS: Patients underwent 24 hrs of induced hypermagnesemia during which total and ionized cerebrospinal fluid [Mg] was measured. Serum [Mg] was adjusted to 2.1-2.5 mmol/L. Cerebrospinal fluid [Mg] was measured at baseline, at 12 and 24 hrs after onset of infusion, and at 12 hrs following infusion termination. MEASUREMENTS AND MAIN RESULTS: At baseline, total (1.25 +/- 0.14 mmol/L) and ionized (0.80 +/- 0.10 mmol/L) cerebrospinal fluid [Mg] was greater than serum total (0.92 +/- 0.18 mmol/L) and ionized (0.63 +/- 0.07 mmol/L) [Mg] (p < .05). Total (1.43 +/- 0.13 mmol/L) and ionized (0.89 +/- 0.12 mmol/L) cerebrospinal fluid [Mg] was maximally increased by 15% and 11% relative to baseline, respectively, during induced hypermagnesemia (p < .05). CONCLUSIONS: Hypermagnesemia produced only marginal increases in total and ionized cerebrospinal fluid [Mg]. Regulation of cerebrospinal fluid [Mg] is largely maintained following acute brain injury and limits the brain bioavailability of MgSO4.

Chronic dietary magnesium-L-threonate speeds extinction and reduces spontaneous recovery of a conditioned taste aversion

         (Mickley, Hoxha et al. 2013) Download

Elevation of brain magnesium enhances synaptic plasticity and extinction of conditioned fear memories. This experiment examined the generalizability of this phenomenon by studying the effects of a novel magnesium compound, magnesium-L-threonate (MgT), on conditioned taste aversion (CTA) extinction and spontaneous recovery (SR). Adult male Sprague-Dawley rats were maintained on a 23-hour water deprivation cycle and acquired a CTA following the taste of a CS [0.3% saccharin+16mg/ml MgT (SAC+MgT)] paired with a US [81mg/kg (i.p.) lithium chloride (LiCl)]. Following CTA acquisition, rats drank a water+MgT solution for up to 1hour/day over the next 31days. For 14 additional days, some animals continued water+MgT treatment, but others drank water only to allow MgT to be eliminated from the body. We then employed 2 different extinction paradigms: (1) CS-Only (CSO), in which SAC was presented, every-other day, or (2) Explicitly Unpaired (EU), in which both SAC and LiCl were presented, but on alternate days. EU extinction procedures have been shown to speed CTA extinction and reduce spontaneous recovery of the aversion. Throughout extinction, half of the rats in each group continued to drink MgT (now in SAC or supplemental water+MgT solution), whereas the other half drank SAC only/water only until SAC drinking reached >/=90% of baseline (asymptotic extinction). Rats receiving MgT just before/during extinction drank less SAC on the first day of extinction suggesting that they had retained a stronger CTA. MgT enhanced the rate of extinction. Furthermore, the MgT-treated rats showed a relatively modest SR of the CTA 30days later - indicating that the extinction procedure was more effective for these animals. Our data suggest that long-term dietary MgT may enhance the consolidation/retention of a CTA, speed extinction, and inhibit SR of this learned aversion.


Enhancement of learning and memory by elevating brain magnesium

         (Slutsky, Abumaria et al. 2010) Download

Learning and memory are fundamental brain functions affected by dietary and environmental factors. Here, we show that increasing brain magnesium using a newly developed magnesium compound (magnesium-L-threonate, MgT) leads to the enhancement of learning abilities, working memory, and short- and long-term memory in rats. The pattern completion ability was also improved in aged rats. MgT-treated rats had higher density of synaptophysin-/synaptobrevin-positive puncta in DG and CA1 subregions of hippocampus that were correlated with memory improvement. Functionally, magnesium increased the number of functional presynaptic release sites, while it reduced their release probability. The resultant synaptic reconfiguration enabled selective enhancement of synaptic transmission for burst inputs. Coupled with concurrent upregulation of NR2B-containing NMDA receptors and its downstream signaling, synaptic plasticity induced by correlated inputs was enhanced. Our findings suggest that an increase in brain magnesium enhances both short-term synaptic facilitation and long-term potentiation and improves learning and memory functions.


References

Abumaria, N., L. Luo, et al. (2013). "Magnesium supplement enhances spatial-context pattern separation and prevents fear overgeneralization." Behav Pharmacol. [PMID: 23764903]

Abumaria, N., B. Yin, et al. (2011). "Effects of elevation of brain magnesium on fear conditioning, fear extinction, and synaptic plasticity in the infralimbic prefrontal cortex and lateral amygdala." J Neurosci 31(42): 14871-81. [PMID: 22016520]

Kwack, M. H., M. K. Kim, et al. (2010). "L-ascorbic acid 2-phosphate represses the dihydrotestosterone-induced dickkopf-1 expression in human balding dermal papilla cells." Exp Dermatol 19(12): 1110-2. [PMID: 20701628]

Li, W., J. Yu, et al. (2013). "Elevation of brain magnesium prevents and reverses cognitive deficits and synaptic loss in Alzheimer's disease mouse model." J Neurosci 33(19): 8423-41. [PMID: 23658180]

McKee, J. A., R. P. Brewer, et al. (2005). "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 33(3): 661-6. [PMID: 15753761]

Mickley, G. A., N. Hoxha, et al. (2013). "Chronic dietary magnesium-L-threonate speeds extinction and reduces spontaneous recovery of a conditioned taste aversion." Pharmacol Biochem Behav 106: 16-26. [PMID: 23474371]

Slutsky, I., N. Abumaria, et al. (2010). "Enhancement of learning and memory by elevating brain magnesium." Neuron 65(2): 165-77. [PMID: 20152124]