Dataset Information

Neuroprotective effects of magnesium L-threonate in a hypoxic zebrafish model.

ABSTRACT:

Background

Hypoxia inhibits the uptake of glutamate (a major neurotransmitter in the brain closely related to cognitive function) into brain cells, and the initial response of cells to cortical hypoxia depends on glutamate. Previous studies have suggested that magnesium may have protective effects against hypoxic injuries. In particular, magnesium L-threonate (MgT) may increase magnesium ion concentrations in the brain better than MgSO₄ and improve cognitive function.

Methods

We evaluated cell viability under hypoxic conditions in the MgT- and MgSO₄-treated human SH-SY5Y neurons, in vivo behavior using the T-maze test following hypoxia in MgT-treated zebrafish, activity of brain mitochondrial dehydrogenase by 2,3,5-triphenyltetrazolium chloride (TTC) staining, and protein expression of the excitatory amino acid transporter (EAAT) 4 glutamate transporter by western blotting.

Results

Among the groups treated with hypoxia, cell viability significantly increased when pre-treated with 1 or 10 mM MgT (p = 0.009 and 0.026, respectively). Despite hypoxic insult, MgT-treated zebrafish showed preferences for the red compartment (p = 0.025 for distance and p = 0.007 for frequency of entries), suggesting memory preservation. TTC staining showed reduced cerebral infarction and preserved absorbance in the MgT-treated zebrafish brain after hypoxia (p = 0.010 compared to the hypoxia group). In addition, western blot showed upregulation of EAAT4 protein in the MgT treated group.

Conclusions

Pre-treatment with MgT attenuated cell death and cerebral infarction due to hypoxia and protected cognitive function in zebrafish. In addition, MgT appeared to modulate expression of the glutamate transporter, EAAT4.

SUBMITTER: Kim YS

PROVIDER: S-EPMC7318545 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Publications

Neuroprotective effects of magnesium L-threonate in a hypoxic zebrafish model.

Kim Young-Sung YS Won Young Ju YJ Lim Byung Gun BG Min Too Jae TJ Kim Yeon-Hwa YH Lee Il Ok IO

BMC neuroscience 20200626 1

<h4>Background</h4>Hypoxia inhibits the uptake of glutamate (a major neurotransmitter in the brain closely related to cognitive function) into brain cells, and the initial response of cells to cortical hypoxia depends on glutamate. Previous studies have suggested that magnesium may have protective effects against hypoxic injuries. In particular, magnesium L-threonate (MgT) may increase magnesium ion concentrations in the brain better than MgSO<sub>4</sub> and improve cognitive function.<h4>Metho ...[more]

PMID: 32590943

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Project description:Hypoxic-ischaemic encephalopathy remains a global health burden. Despite medical advances and treatment with therapeutic hypothermia, over 50% of cooled infants are not protected and still develop lifelong neurodisabilities, including cerebral palsy. Furthermore, hypothermia is not used in preterm cases or low resource settings. Alternatives or adjunct therapies are urgently needed. Exendin-4 is a drug used to treat type 2 diabetes mellitus that has also demonstrated neuroprotective properties, and is currently being tested in clinical trials for Alzheimer's and Parkinson's diseases. Therefore, we hypothesized a neuroprotective effect for exendin-4 in neonatal neurodisorders, particularly in the treatment of neonatal hypoxic-ischaemic encephalopathy. Initially, we confirmed that the glucagon like peptide 1 receptor (GLP1R) was expressed in the human neonatal brain and in murine neurons at postnatal Day 7 (human equivalent late preterm) and postnatal Day 10 (term). Using a well characterized mouse model of neonatal hypoxic-ischaemic brain injury, we investigated the potential neuroprotective effect of exendin-4 in both postnatal Day 7 and 10 mice. An optimal exendin-4 treatment dosing regimen was identified, where four high doses (0.5 µg/g) starting at 0 h, then at 12 h, 24 h and 36 h after postnatal Day 7 hypoxic-ischaemic insult resulted in significant brain neuroprotection. Furthermore, neuroprotection was sustained even when treatment using exendin-4 was delayed by 2 h post hypoxic-ischaemic brain injury. This protective effect was observed in various histopathological markers: tissue infarction, cell death, astrogliosis, microglial and endothelial activation. Blood glucose levels were not altered by high dose exendin-4 administration when compared to controls. Exendin-4 administration did not result in adverse organ histopathology (haematoxylin and eosin) or inflammation (CD68). Despite initial reduced weight gain, animals restored weight gain following end of treatment. Overall high dose exendin-4 administration was well tolerated. To mimic the clinical scenario, postnatal Day 10 mice underwent exendin-4 and therapeutic hypothermia treatment, either alone or in combination, and brain tissue loss was assessed after 1 week. Exendin-4 treatment resulted in significant neuroprotection alone, and enhanced the cerebroprotective effect of therapeutic hypothermia. In summary, the safety and tolerance of high dose exendin-4 administrations, combined with its neuroprotective effect alone or in conjunction with clinically relevant hypothermia make the repurposing of exendin-4 for the treatment of neonatal hypoxic-ischaemic encephalopathy particularly promising.

Project description:The zebrafish (Danio rerio) is a valuable model organism for studying human biology due to its easy genetic manipulation and small size. It is optically transparent and shares genetic similarities with humans, making it ideal for studying developmental processes, diseases, and drug screening via imaging-based approaches. Solid malignant tumors often contain hypoxic areas that stimulate the release of extracellular vesicles (EVs), lipid-bound structures released by cells into the extracellular space, that facilitate short- and long-range intercellular communication and metastatization. Here we investigate the effects of EVs derived from neuroblastoma (NB), a pediatric solid tumor, on metastatic niche formation using the zebrafish as an in vivo model. Intravascular injection in zebrafish embryos allows a non-invasive visualization of EVs dispersion, uptake, and interactions with host cells. To improve repeatability of our results and ease the injection steps, we used an agarose device replica molded from a custom designed micromilled aluminum mold. We first demonstrated that EVs released under hypoxic conditions promote angiogenesis and are more easily internalized by endothelial cells than those purified from normoxic cells. We also showed that injection of with hypoxic EVs increased macrophages mobilization. We then focused on the caudal hematopoietic tissue (CHT) region of the embryo as a potential metastatic site. After hypoxic EVs injection, we highlighted changes in the expression of mmp-9 and cxcl8b genes. Furthermore, we investigated the ability of NB-derived EVs to prime a metastatic niche by a two-step injection of EVs first, followed by NB cells. Interestingly, we found that embryos injected with hypoxic EVs had more proliferating NB cells than those injected with normoxic EVs. Our findings suggest that EVs released by hypoxic NB cells alter the behavior of recipient cells in the zebrafish embryo and promote metastatic outgrowth. In addition, we demonstrated the ability of the zebrafish embryo to be a suitable model for studying the interactions between EVs and recipient cells in the metastatic process.

Dataset Information

Neuroprotective effects of magnesium L-threonate in a hypoxic zebrafish model.

Background

Methods

Results

Conclusions

Publications

Neuroprotective effects of magnesium L-threonate in a hypoxic zebrafish model.

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