Brain Mg2 Research Articles

Intracellular magnesium optimizes transmission efficiency and plasticity of hippocampal synapses by reconfiguring their connectivity

AbstractSynapses at dendritic branches exhibit specific properties for information processing. However, how the synapses are orchestrated to dynamically modify their properties, thus optimizing information processing, remains elusive. Here, we observed at hippocampal dendritic branches diverse configurations of synaptic connectivity, two extremes of which are characterized by low transmission efficiency, high plasticity and coding capacity, or inversely. The former favors information encoding, pertinent to learning, while the latter prefers information storage, relevant to memory. Presynaptic intracellular Mg2+ crucially mediates the dynamic transition continuously between the two extreme configurations. Consequently, varying intracellular Mg2+ levels endow individual branches with diverse synaptic computations, thus modulating their ability to process information. Notably, elevating brain Mg2+ levels in aging animals restores synaptic configuration resembling that of young animals, coincident with improved learning and memory. These findings establish intracellular Mg2+ as a crucial factor reconfiguring synaptic connectivity at dendrites, thus optimizing their branch-specific properties in information processing.

Hippocampal synaptic dysfunction and spatial memory impairment in omeprazole-treated rats.

Although the association of prolonged use of proton pump inhibitors, such as omeprazole, with memory impairment has been reported more than two decades ago, its underlying molecular mechanism is yet to be determined. Thus, in this study, we aimed to determine the mechanisms underlying the effect of prolonged omeprazole treatment on hippocampal synaptic function and spatial memory in male rats. Adult rats were subcutaneously administered with omeprazole for 12 or 24 weeks. Spatial memory was assessed using the Morris water maze (MWM) test. We examined the hippocampal protein expression of synaptic plasticity proteins, including the AMPA receptor subunit GluA1, postsynaptic density-95 (PSD-95), and activity-regulated cytoskeleton-associated protein (Arc), and the hippocampal expression and localization of androgen receptor (AR). In the MWM test, the escape latency was found to be significantly higher, and the number of platform crossings and the time spent in the target quadrant were significantly lower in the rats treated with omeprazole compared to the control rats. Hypomagnesemia and lower bone and brain Mg2+ content were also detected in the omeprazole-treated groups compared with the control group. The expression of GluA1, PSD-95, and Arc in the hippocampus and the expression of AR in the dentate gyrus and CA1 of the hippocampus were significantly lower in the omeprazole-treated groups than in the control group. These results suggest that prolonged omeprazole treatment might lead to memory deficit by impairing glutamate receptor trafficking or synaptic anchoring. Hypomagnesemia and brain Mg2+ deficiency may be, at least in part, involved in omeprazole-induced memory impairment.

Elevation of brain magnesium with Swiss chard and buckwheat extracts in an animal model of reduced magnesium dietary intake

ABSTRACT Objectives Inadequate dietary magnesium (Mg) intake is a growing public health concern. Mg is critical for diverse metabolic processes including energy production, macromolecule biosynthesis, and electrolyte homeostasis. Inadequate free Mg2+ ion concentration ([Mg2+]) in the brain is associated with several neurological and behavioral disorders. Elevating [Mg2+]in the brain using oral Mg supplementation has proven to be challenging due to the tight regulation of Mg2+ transport to the brain. This study explored the effect of short-term moderate reduction in dietary Mg intake (87% of normal Mg diet for 30 days) on [Mg2+] in the cerebrospinal fluid (CSF) ([Mg2+]CSF) and red blood cells (RBCs) ([Mg2+]RBC) in adult male rats. In addition, we investigated the effectiveness of magnesium-rich blend of Swiss chard and buckwheat extracts (SC/BW extract) in increasing brain [Mg2+] compared to various Mg salts commonly used as dietary supplements. Methods Animals were assigned to either normal or low Mg diet for 30 - 45 days. Following this, animals maintained on low Mg diet were supplemented with various Mg compounds. [Mg2+]CSF and [Mg2+]RBC were measured at baseline and following Mg administration. Anxiety-like behavior and cognitive function were also evaluated. Results The present study showed that a short-term and moderate reduction in Mg dietary intake results in a significant decline in [Mg2+]CSF and [Mg2+]RBC and the emergence of anxiety-like behavior in comparison to animals maintained on normal Mg diet. Supplementation with SC/BW extract significantly elevated [Mg2+]CSF and improved animal performance in the novel object recognition test in comparison with animals maintained on reduced Mg intake and supplemented with various Mg compounds. Discussion These observations indicate that brain [Mg2+] is more sensitive to a short-term and moderate reduction in Mg dietary intake than previously thought and emphasizes the importance of dietary Mg in replenishing brain Mg2+ reserves.

Chronic Oral Administration of Magnesium-L-Threonate Prevents Oxaliplatin-Induced Memory and Emotional Deficits by Normalization of TNF-α/NF-κB Signaling in Rats.

Antineoplastic drugs such as oxaliplatin (OXA) often induce memory and emotional deficits. At present, the mechanisms underlying these side-effects are not fully understood, and no effective treatment is available. Here, we show that the short-term memory deficits and anxiety-like and depression-like behaviors induced by intraperitoneal injections of OXA (4mg/kg per day for 5 consecutive days) were accompanied by synaptic dysfunction and downregulation of the NR2B subunit of N-methyl-D-aspartate receptors in the hippocampus, which is critically involved in memory and emotion. The OXA-induced behavioral and synaptic changes were prevented by chronic oral administration of magnesium-L-threonate (L-TAMS, 604mg/kg per day, from 2days before until the end of experiments). We found that OXA injections significantly reduced the free Mg2+ in serum and cerebrospinal fluid (from ~ 0.8mmol/L to ~ 0.6mmol/L). The Mg2+ deficiency (0.6mmol/L) upregulated tumor necrosis factor (TNF-α) and phospho-p65 (p-p65), an active form of nuclear factor-kappaB (NF-κB), and downregulated the NR2B subunit in cultured hippocampal slices. Oral L-TAMS prevented the OXA-induced upregulation of TNF-α and p-p65, as well as microglial activation in the hippocampus and the medial prefrontal cortex. Finally, similar to oral L-TAMS, intracerebroventricular injection of PDTC, an NF-κB inhibitor, also prevented the OXA-induced memory/emotional deficits and the changes in TNF-α, p-p65, and microglia. Taken together, the activation of TNF-α/NF-κB signaling resulting from reduced brain Mg2+ is responsible for the memory/emotional deficits induced by OXA. Chronic oral L-TAMS may be a novel approach to treating chemotherapy-induced memory/emotional deficits.

Regulation of structural and functional synapse density by L-threonate through modulation of intraneuronal magnesium concentration

Oral administration of the combination of L-threonate (threonate) and magnesium (Mg2+) in the form of L-Threonic acid Magnesium salt (L-TAMS) can enhance learning and memory in young rats and prevent memory decline in aging rats and in Alzheimer’s disease model mice. Recent results from a human clinical trial demonstrate the efficacy of L-TAMS in restoring global cognitive abilities of older adults. Previously, we reported that neuronal intracellular Mg2+ serves as a critical signaling molecule for controlling synapse density, a key factor that determines cognitive ability. The elevation of brain Mg2+ by oral administration of L-TAMS in intact animals plays a significant role in mediating the therapeutic effects of L-TAMS. The current study sought to elucidate the unique role of threonate. We aimed to understand if threonate acts directly to elevate intraneuronal Mg2+, and why Mg2+ given without threonate is ineffective for enhancing learning and memory ability. We discovered that threonate is naturally present in cerebrospinal fluid (CSF) and oral treatment with L-TAMS elevated CSF threonate. In cultured hippocampal neurons, threonate treatment directly induced an increase in intracellular Mg2+ concentration. Functionally, elevating threonate upregulated expression of NR2B-containing NMDAR, boosted mitochondrial membrane potential (ΔΨm), and increased functional synapse density in neuronal cultures. These effects are unique to threonate, as other common Mg2+ anions failed to have the same results. Mechanistically, threonate’s effects were specifically mediated through glucose transporters (GLUTs). We also evaluated the effects of threonate in human neural stem cell-derived neurons, and found it was equally effective at upregulating synapse density. The current study provides an explanation for why threonate is an essential component of L-TAMS and supports the use of L-TAMS to promote cognitive abilities in human.

Enhancement of Learning and Memory by Elevating Brain Magnesium

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.

In vivo assessment of Mg2+ in human brain and skeletal muscle by 31P-MRS.

Phosphorus magnetic resonance spectroscopy offers a unique opportunity to measure in vivo the free cytosolic magnesium [Mg2+] of different tissues. In particular, this technique has been employed in human brain and in skeletal muscle providing new hints on Mg2+ homeostasis and on its involvement in cellular bioenergetics. In skeletal muscle it has been shown that the changes of free Mg2+ concentration occurring during contraction and in post-exercise recovery are mainly due to the cytosolic pH influence. The possibility of assessing the free cytosolic [Mg2+] in the human brain offered the chance of studying the involvement of Mg2+ in different neurological pathologies, and particularly in those where defective mitochondrial energy production represents the primary causative factor in the pathogenesis. The results obtained, studying patients affected by different types of mitochondrial cytopathies, helped to clarify the functional relationship between energy metabolism and free [Mg2+], providing evidence that cytosolic [Mg2+] is regulated in brain cells to equilibrate any changes in rapidly available free energy. Moreover, it has also been shown that the measurement of brain Mg2+ can help in the differential diagnosis of neurodegenerative diseases sharing common clinical features, such as Multiple System Atrophy and Parkinson's disease.

Reduced Mg2+-ATPase activity in the hypoglycemic adult rat brain.

The effects of different a-D-Glucose (Glu) concentrations (0-16 mM) on Na+, K+-ATPase and Mg2+-ATPase activities were investigated in homogenates of adult male rat whole brain at 37 degrees C. The enzyme activities were determined after 1 h preincubation with Glu. Brain Na+, K+-ATPase was not affected by Glu different concentrations. On the contrary, Mg2+-ATPase activity was considerably reduced with Glu concentrations lower than 4 mM. The enzyme was inhibited 40%, 50% or 80% with 3, 2 or 1 mM of Glu, respectively. The above results suggest: a) The various concentrations of Glu have no effect on brain Na+, K+-ATPase activity. b) The inhibited brain Mg2+-ATPase in hypoglycemia produces low intracellular Mg2+, which could modulate the activity of Mg2+-dependent enzymes and the rates of protein synthesis and growth of the cell.

Chronic changes in brain Mg2+ concentration after forebrain ischemia in the rat

Brain Mg2+ ion concentrations, [Mg2+], were evaluated in three groups of animals subjected to either 8 minutes (n = 10), or 12 minutes (n = 10) of near-complete forebrain ischemia, or sham operation (n = 10), from their 31P NMR spectra. No significant differences were observed in [Mg2+] among sham operated animals prior to or at any time point after surgery. In the 8-min ischemia group, mean [Mg2+] were significantly lower at 48 (0.28 +/- 0.06 mM, p = 0.014) and 72 (0.29 +/- 0.07 mM, p = 0.005) hours post-ischemia when compared to their mean pre-ischemia levels (0.39 +/- 0.08 mM). [Mg2+] was restored to pre-ischemia values at 96 hours after induction of ischemia. In the 12 min ischemia group, [Mg2+] were lower at all time points post-ischemia when compared to their pre-ischemia levels. Our data shows that forebrain ischemia causes a chronic decline of cerebral Mg2+ concentration, and the observed reduction of this cation can be partially attributed to concurrent brain tissue alkalosis.

Linear regression analysis for enzyme kinetic studies in toxicant interactions

A new method based on linear regression of per cent modulation in enzyme activity over substrate concentration is proposed to give an interpretative base to the influence of more than one modulator/inhibitor/toxicant, a situation commonly met with in toxicological studies-toxicant interactions. Advantages of this method over the classical kinetic methods are discussed in detail using brain Mg2+ ATPase activity of the fish Tilapia mossambica under in vitro regimes of hexachlorocyclohexane and malathion.

Kinetics of Mg2+-ATPase inhibition by benthiocarb and its recovery by oximes and L-cysteine in brain of albino rat (Wistar strain)

Effects in vitro of benthiocarb on rat brain Mg2+-ATPase were studied to elucidate the interaction of benthiocarb with Mg2+-ATPase. Based on IC50 values, it was evident that Mg2+-ATPase was sensitive to benthiocarb. Non-competitive inhibition with respect to activation by ATP was indicated by decreased maximal velocity (V) without change in Michaelis Menten constant (Km). It was also noted that pyridine-2-aldoxime (30 microM), pyridine-4-aldoxime (35 microM) and L-cysteine (90 microM) neutralized the inhibition of benthiocarb (8 microM).