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We conducted an ex-vivo analysis and a study in healthy subjects to compare magnesium bioavailability after administration of Sucrosomial® magnesium or commercially available preparations of magnesium citrate, magnesium oxide and magnesium bisglycinate.In the ex-vivo study we simulated magnesium intestinal absorption after digestion through sections of intestinal mucosa isolated from rats. We compared the absorption of magnesium oxide and Sucrosomial® magnesium at two different concentrations: 32.9 mg/ml and 329 mg/ml. The human study was a single day double-blinded repeated crossover study in healthy subjects. Each subject was administered 350 mg magnesium in different formulations (Sucrosomial® magnesium, magnesium citrate, magnesium oxide or magnesium bisglycinate) after 1 week of washout. We collected blood and urine samples to measure magnesium concentration in blood, urine and red blood cells.The ex-vivo evaluation showed that magnesium absorption after administration of Sucrosomial® magnesium was faster and with higher rates compared to a standard formulation of magnesium oxide. This finding was further confirmed by the results of the study in healthy subjects, that showed a more evident increase in magnesium concentration after administration of Sucrosomial® magnesium compared to the other formulations. In particular, the increase in magnesium concentration from baseline to 24 h was statistically higher in blood and in urine for Sucrosomial® magnesium compared to magnesium oxide, while in red blood cells Sucrosomial® magnesium had a statistically significant advantage compared to magnesium bisglycinate.Our findings suggest that Sucrosomial® magnesium leads to an increased bioavailability of magnesium compared to other formulations. Further studies are needed to investigate if this advantage turns into more evident clinical efficacy.

In the present study, we demonstrate a direct role for d-aspartate in regulating hippocampal synaptic plasticity. These evidences were obtained using two different experimental strategies which enabled a non-physiological increase of endogenous d-aspartate levels in the mouse hippocampus: a genetic approach based on the targeted deletion of d-aspartate oxidase gene and another based on the oral administration of d-aspartate. Overall, our results indicate that increased d-aspartate content does not affect basal properties of synaptic transmission but enhances long-term potentiation in hippocampal slices from both genetic and pharmacological animal models. Besides electrophysiological data, behavioral analysis suggests that altered levels of d-aspartate in the hippocampus do not perturb basal spatial learning and memory abilities, but may selectively interfere with the dynamic NMDAR-dependent processes underlying cognitive flexibility. In the present study, we demonstrate a direct role for d-aspartate in regulating hippocampal synaptic plasticity. These evidences were obtained using two different experimental strategies which enabled a non-physiological increase of endogenous d-aspartate levels in the mouse hippocampus: a genetic approach based on the targeted deletion of d-aspartate oxidase gene and another based on the oral administration of d-aspartate. Overall, our results indicate that increased d-aspartate content does not affect basal properties of synaptic transmission but enhances long-term potentiation in hippocampal slices from both genetic and pharmacological animal models. Besides electrophysiological data, behavioral analysis suggests that altered levels of d-aspartate in the hippocampus do not perturb basal spatial learning and memory abilities, but may selectively interfere with the dynamic NMDAR-dependent processes underlying cognitive flexibility. © 2007 Elsevier Inc. All rights reserved.

Neural stem cells (NSCs) have become promising tools for basic research and regenerative medicine. Intracerebral transplantation studies have suggested that these cells may be able to adopt neuronal phenotypes typical of their engraftment site and to establish appropriate connections in the recipient circuitries. Here, we examined the in vivo neurogenic competence of well-characterized NSC lines subjected to in vitro priming and subsequent implantation into the adult intact mouse brain. Upon implantation into the hippocampus and, less frequently, in the striatum and in the cerebral cortex, numerous green fluorescent protein (GFP)-tagged cells acquired differentiated features indistinguishable from resident neurons. Upon closer examination, however, we found that this outcome resulted from fusion of donor cells with local neuronal elements generating long-term persistent GFP+ neuronal hybrids. This fusogenic behavior of NSCs was unexpected and also observed in coculture with E18 hippocampal immature neural cells, but not with microglia or astrocytes. Similar findings were consistently obtained with different NSC lines, mouse recipients, and donor cell-labeling methods. The frequent and cell type-specific fusion of donor NSCs with host neurons highlights a previously underestimated biological property of the nervous tissue that might prove profitable for basic and therapeutically oriented studies. © Copyright 2013, Mary Ann Liebert, Inc. 2013.

Brain cholesterol biosynthesis and cholesterol levels are reduced in mouse models of Huntington's disease (HD), suggesting that locally synthesized, newly formed cholesterol is less available to neurons. This may be detrimental for neuronal function, especially given that locally synthesized cholesterol is implicated in synapse integrity and remodeling. Here, we used biodegradable and biocompatible polymeric nanoparticles (NPs) modified with glycopeptides (g7) and loaded with cholesterol (g7-NPs-Chol), which per se is not blood-brain barrier (BBB) permeable, to obtain high-rate cholesterol delivery into the brain after intraperitoneal injection in HD mice. We report that g7-NPs, in contrast to unmodified NPs, efficiently crossed the BBB and localized in glial and neuronal cells in different brain regions. We also found that repeated systemic delivery of g7-NPs-Chol rescued synaptic and cognitive dysfunction and partially improved global activity in HD mice. These results demonstrate that cholesterol supplementation to the HD brain reverses functional alterations associated with HD and highlight the potential of this new drug-administration route to the diseased brain. Synopsis: Cholesterol in brain is largely derived by local synthesis. One affected pathway in Huntington's disease (HD) implicates that reduced production and/or availability of brain cholesterol may be detrimental for neuronal function. Polymeric nanoparticles (NPs) loaded with cholesterol, modified with glycopeptides g7 (g7-NPs-Chol) to cross the BBB after systemic injection, have been used to deliver cholesterol to the brain of HD mice. These NPs, applied for the first time to a brain disorder, are made of PLGA, which is approved by FDA in various drug delivery systems in humans. Systemic administration of g7-NPs-Chol (i) rescued synaptic communication in striatal medium-sized spiny neurons, (ii) prevented cognitive decline, and (iii) restored the levels of proteins that compose the synaptic machinery in HD mice. g7-NPs or cholesterol itself did not induce inflammatory response in the periphery, where almost all g7-NPs are localized. Cholesterol in brain is largely derived by local synthesis. One affected pathway in Huntington's disease (HD) implicates that reduced production and/or availability of brain cholesterol may be detrimental for neuronal function.

The peroxisome-proliferator-activated receptor gamma coactivator 1 alpha (PGC1 alpha) has been implicated in the pathogenesis of several neurodegenerative disorders, including Huntington's disease (HD). Recent data demonstrating white matter abnormalities in PGC1 alpha knock-out (KO) mice prompted us to examine the role of PGC1 alpha in CNS myelination and its relevance to HD pathogenesis. We found deficient postnatal myelination in the striatum of PGC1 alpha KO mice, accompanied by a decrease in myelin basic protein (MBP). In addition, brain cholesterol, its precursors, and the rate-limiting enzymes for cholesterol synthesis, HMG CoA synthase (HMGCS1) and HMG CoA reductase (HMGCR), were also reduced in PGC1 alpha KO mice. Moreover, knockdown of PGC1 alpha in oligodendrocytes by lentiviral shRNA led to a decrease in MBP, HMGCS1, and Hmgcr mRNAs. Chromatin immunoprecipitations revealed the recruitment of PGC1 alpha to MBP promoter in mouse brain, and PGC1 alpha over-expression increased MBP and SREBP-2 promoter activity, suggesting that PGC1 alpha regulates MBP and cholesterol synthesis at the transcriptional level. Importantly, expression of mutant huntingtin (Htt) in primary oligodendrocytes resulted in decreased expression of PGC1 alpha and its targets HmgcS1, Hmgcr, and MBP. Decreased expression of MBP and deficient myelination were found postnatally and in adult R6/2 mouse model of HD. Diffusion tensor imaging detected white matter abnormalities in the corpus callosum of R6/2 mice, and electron microscopy revealed thinner myelin sheaths and increased myelin periodicity in BACHD [bacterial artificial chromosome (BAC)-mediated transgenic model for Huntington's disease] mice expressing full-length mutant Htt. Together, these data suggest that PGC1 alpha plays a role in postnatal myelination and that deficient PGC1 alpha activity in oligodendrocytes may contribute to abnormal myelination in HD.