Publications by authors named "Bo Young Choi"

68 Publications

The Role of NADPH Oxidase in Neuronal Death and Neurogenesis after Acute Neurological Disorders.

Antioxidants (Basel) 2021 May 7;10(5). Epub 2021 May 7.

Department of Physiology, College of Medicine, Hallym University, Chuncheon 24252, Korea.

Oxidative stress is a well-known common pathological process involved in mediating acute neurological injuries, such as stroke, traumatic brain injury, epilepsy, and hypoglycemia-related neuronal injury. However, effective therapeutic measures aimed at scavenging free reactive oxygen species have shown little success in clinical trials. Recent studies have revealed that NADPH oxidase, a membrane-bound enzyme complex that catalyzes the production of a superoxide free radical, is one of the major sources of cellular reactive oxygen species in acute neurological disorders. Furthermore, several studies, including our previous ones, have shown that the inhibition of NADPH oxidase can reduce subsequent neuronal injury in neurological disease. Moreover, maintaining appropriate levels of NADPH oxidase has also been shown to be associated with proper neurogenesis after neuronal injury. This review aims to present a comprehensive overview of the role of NADPH oxidase in neuronal death and neurogenesis in multiple acute neurological disorders and to explore potential pharmacological strategies targeting the NADPH-related oxidative stress pathways.
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http://dx.doi.org/10.3390/antiox10050739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151966PMC
May 2021

Zinc in the Brain: Friend or Foe?

Int J Mol Sci 2020 Nov 25;21(23). Epub 2020 Nov 25.

Department of Physiology, College of Medicine, Hallym University, Chuncheon 24252, Korea.

Zinc is a trace metal ion in the central nervous system that plays important biological roles, such as in catalysis, structure, and regulation. It contributes to antioxidant function and the proper functioning of the immune system. In view of these characteristics of zinc, it plays an important role in neurophysiology, which leads to cell growth and cell proliferation. However, after brain disease, excessively released and accumulated zinc ions cause neurotoxic damage to postsynaptic neurons. On the other hand, zinc deficiency induces degeneration and cognitive decline disorders, such as increased neuronal death and decreased learning and memory. Given the importance of balance in this context, zinc is a biological component that plays an important physiological role in the central nervous system, but a pathophysiological role in major neurological disorders. In this review, we focus on the multiple roles of zinc in the brain.
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http://dx.doi.org/10.3390/ijms21238941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728061PMC
November 2020

Phenotypic Discovery of Neuroprotective Agents by Regulation of Tau Proteostasis via Stress-Responsive Activation of PERK Signaling.

Angew Chem Int Ed Engl 2021 01 23;60(4):1831-1838. Epub 2020 Dec 23.

CRI Center for Chemical Proteomics, Department of Chemistry, Seoul National University, Seoul, 08826, Korea.

Tau protein aggregates are a recognized neuropathological feature in Alzheimer's disease as well as many other neurodegenerative disorders, known as tauopathies. The development of tau-targeting therapies is therefore extremely important but efficient strategies or protein targets are still unclear. Here, we performed a cell-based phenotypic screening under endoplasmic reticulum (ER) stress conditions and identified a small molecule, SB1617, capable of suppressing abnormal tau protein aggregation. By applying label-free target identification technology, we revealed that the transient enhancement of protein kinase-like endoplasmic reticulum kinase (PERK) signaling pathway through the inhibition of stress-responsive SB1617 targets, PDIA3 and DNAJC3, is an effective strategy for regulating proteostasis in tauopathies. The molecular mechanism and the promising efficacy of SB1617 were demonstrated in neuronal cells and a mouse model with traumatic brain injury, a tauopathy known to involve ER stress.
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http://dx.doi.org/10.1002/anie.202013915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898623PMC
January 2021

Effects of Cerebrolysin on Hippocampal Neuronal Death After Pilocarpine-Induced Seizure.

Front Neurosci 2020 16;14:568813. Epub 2020 Oct 16.

Department of Physiology, College of Medicine, Hallym University, Chuncheon, South Korea.

Epilepsy is one of the most common and severe brain diseases. The exact cause of epilepsy is unclear. Epilepsy often occurs following brain damage, such as traumatic brain injury (TBI) and ischemia. Cerebrolysin is a porcine brain peptide that is a unique neurotropic and neuroprotective agent. Cerebrolysin has been reported to increase neuroprotective effects after TBI, ischemia, and other CNS diseases. However, the effects of cerebrolysin on seizures are not known. Therefore, this study aimed to investigate the effects of neuropeptide cerebrolysin on neuronal death in the hippocampus after a seizure. To confirm the effects of cerebrolysin, we used a pilocarpine-induced seizure animal model. Cerebrolysin (2.5 ml/kg, i.p., once per day for 7 days) was immediately injected after a seizure induction. After 1 week, we obtained brain tissues and performed staining to histologically evaluate the potentially protective effects of cerebrolysin on seizure-induced neuronal death in the hippocampus. We found that cerebrolysin decreased hippocampal neuronal death after a seizure. In addition, an increase in brain-derived neurotrophic factor (BDNF) was confirmed through Western blot analysis to further support our hypothesis. Therefore, the present study suggests that the administration of cerebrolysin can be a useful therapeutic tool for preventing neuronal death after a seizure.
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http://dx.doi.org/10.3389/fnins.2020.568813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596733PMC
October 2020

Effects of Transient Receptor Potential Cation 5 (TRPC5) Inhibitor, NU6027, on Hippocampal Neuronal Death after Traumatic Brain Injury.

Int J Mol Sci 2020 Nov 4;21(21). Epub 2020 Nov 4.

Department of Physiology, College of Medicine, Hallym University, Chuncheon 24252, Korea.

Traumatic brain injury (TBI) can cause physical, cognitive, social, and behavioral changes that can lead to permanent disability or death. After primary brain injury, translocated free zinc can accumulate in neurons and lead to secondary events such as oxidative stress, inflammation, edema, swelling, and cognitive impairment. Under pathological conditions, such as ischemia and TBI, excessive zinc release, and accumulation occurs in neurons. Based on previous research, it hypothesized that calcium as well as zinc would be influx into the TRPC5 channel. Therefore, we hypothesized that the suppression of TRPC5 would prevent neuronal cell death by reducing the influx of zinc and calcium. To test our hypothesis, we used a TBI animal model. After the TBI, we immediately injected NU6027 (1 mg/kg, intraperitoneal), TRPC5 inhibitor, and then sacrificed animals 24 h later. We conducted Fluoro-Jade B (FJB) staining to confirm the presence of degenerating neurons in the hippocampal cornus ammonis 3 (CA3). After the TBI, the degenerating neuronal cell count was decreased in the NU6027-treated group compared with the vehicle-treated group. Our findings suggest that the suppression of TRPC5 can open a new therapeutic window for a reduction of the neuronal death that may occur after TBI.
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http://dx.doi.org/10.3390/ijms21218256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662546PMC
November 2020

Gestational weight gain in twin pregnancies in Korea: application of the 2009 Institute of Medicine recommendations.

Obstet Gynecol Sci 2020 Nov 3;63(6):690-699. Epub 2020 Nov 3.

Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.

Objective: To investigate the effect of gestational weight gain (GWG) on maternal and neonatal outcomes based on the Institute of Medicine (IOM) guidelines for twin pregnancies.

Methods: This study included women with twin pregnancies who delivered at Seoul National University Bundang Hospital. Based on the weight gain per gestational week according to the 2009 IOM guidelines, the subjects were divided into the following 3 groups: inadequate, adequate, and excessive GWG. We compared the maternal and neonatal outcomes of each group.

Results: A total of 1,738 twin pregnancies were included in our study. Of these cases, 881, 694, and 163 (50.7%, 39.9%, and 9.4%, respectively) twin pregnancies were categorized into the inadequate, adequate, and excessive GWG groups, respectively. In the inadequate GWG group, the risks of preterm birth <34 weeks (aOR, 2.33, 95% confidence interval [CI], 1.63-3.34) and delivering neonates who were small for gestational age (aOR, 1.92, 95% CI, 1.42-2.60) were increased, and the risk of preeclampsia (aOR, 0.49, 95% CI, 0.32-0.76) was decreased. The excessive GWG group had an increased risk of the neonates being large for gestational age (aOR, 1.79, 95% CI, 1.15-2.81).

Conclusion: The 2009 IOM recommendations for GWG can be applied to Korean women with twin pregnancies to help achieve optimal maternal and neonatal outcomes. However, more than half of the women were categorized as having inadequate weight gain according to the guidelines. Further studies should be performed to obtain Korean national references for GWG in twin pregnancies.
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http://dx.doi.org/10.5468/ogs.20133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677065PMC
November 2020

Enantioselective Catalysis of an Anionic Oxy-Cope Rearrangement Enabled by Synergistic Ion Binding.

Isr J Chem 2020 Mar 6;60(3-4):461-474. Epub 2020 Mar 6.

Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138.

Charge-accelerated rearrangements present interesting challenges to enantioselective catalysis, due in large part to the competing requirements for maximizing reactivity (ion-pair separation) and stereochemical communication. Herein, we describe application of a synergistic ion-binding strategy to catalyze the anionic oxy-Cope rearrangement of a symmetric -styrenyl allyl alcohol in up to 75:25 e.r. Structure-reactivity-selectivity relationship studies, including linear free-energy-relationship analyses, with bifunctional urea catalysts indicate that H-bonding and cation-binding interactions act cooperatively to promote the chemo- and enantioselective [3,3]-rearrangement. Implications for catalyst designs applicable to other transformations involving oxyanionic intermediates are discussed.
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http://dx.doi.org/10.1002/ijch.201900168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592710PMC
March 2020

The Transient Receptor Potential Melastatin 7 (TRPM7) Inhibitors Suppress Seizure-Induced Neuron Death by Inhibiting Zinc Neurotoxicity.

Int J Mol Sci 2020 Oct 24;21(21). Epub 2020 Oct 24.

Department of Physiology, Hallym University, College of Medicine, Chuncheon 24252, Korea.

Transient receptor potential melastatin 7 (TRPM7) is an ion channel that mediates monovalent cations out of cells, as well as the entry of divalent cations, such as zinc, magnesium, and calcium, into the cell. It has been reported that inhibitors of TRPM7 are neuroprotective in various neurological diseases. Previous studies in our lab suggested that seizure-induced neuronal death may be caused by the excessive release of vesicular zinc and the subsequent accumulation of zinc in the neurons. However, no studies have evaluated the effects of carvacrol and 2-aminoethoxydiphenyl borate (2-APB), both inhibitors of TRPM7, on the accumulation of intracellular zinc in dying neurons following seizure. Here, we investigated the therapeutic efficacy of carvacrol and 2-APB against pilocarpine-induced seizure. Carvacrol (50 mg/kg) was injected once per day for 3 or 7 days after seizure. 2-APB (2 mg/kg) was also injected once per day for 3 days after seizure. We found that inhibitors of TRPM7 reduced seizure-induced TRPM7 overexpression, intracellular zinc accumulation, and reactive oxygen species production. Moreover, there was a suppression of oxidative stress, glial activation, and the blood-brain barrier breakdown. In addition, inhibitors of TRPM7 remarkably decreased apoptotic neuron death following seizure. Taken together, the present study demonstrates that TRPM7-mediated zinc translocation is involved in neuron death after seizure. The present study suggests that inhibitors of TRPM7 may have high therapeutic potential to reduce seizure-induced neuron death.
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http://dx.doi.org/10.3390/ijms21217897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7663745PMC
October 2020

Reinforced-hydrogel encapsulated hMSCs towards brain injury treatment by trans-septal approach.

Biomaterials 2021 01 30;266:120413. Epub 2020 Sep 30.

Nano-Bio Regenerative Medical Institute, College of Medicine, Hallym University, 1 Hallymdaehak-gil, Chuncheon, Gangwon-do, 24252, Republic of Korea; Department of Otorhinolaryngology-Head and Neck Surgery, Chuncheon Sacred Heart Hospital, School of Medicine, Hallym University, Chuncheon, 24253, Republic of Korea. Electronic address:

Encapsulated stem cells in various biomaterials have become a potentially promising cell transplantation strategy in the treatment of various neurologic disorders. However, there is no ideal cell delivery material and method for clinical application in brain diseases. Here we show silk fibroin (SF)-based hydrogel encapsulated engineered human mesenchymal stem cells (hMSCs) to overproduce brain-derived neurotrophic factor (BDNF) (BDNF-hMSC) is an effective approach to treat brain injury through trans-septal cell transplantation in the rat model. In this study, we observed SF induced sustained BDNF production by BDNF-hMSC both in 2D (9.367 ± 1.969 ng/ml) and 3D (7.319 ± 0.1025 ng/ml) culture conditions for 3 days. Through immunohistochemistry using α-tubulin, BDNF-hMSCs showed a significant increased average neurite length of co-cultured neuro 2a (N2a) cells, suggested that BDNF-hMSCs induced neurogenesis in vitro. Encapsulated BDNF-hMSC, pre-labeled with the red fluorescent dye PKH-26, exhibited intense fluorescence up to 14 days trans-septal transplantation, indicated excellent viability of the transplanted cells. Compared to the vehicle-treated, encapsulated BDNF- hMSC demonstrated significantly increased BDNF level both in the sham-operated and injured hippocampus (Hip) through immunoblot analysis after 7 days implantation. Transplantation of the encapsulated BDNF-hMSC promoted neurological functional recovery via significantly reduced neuronal death in the Hip 7 days post-injury. Using magnetic resonance imaging (MRI) analysis, we demonstrated that encapsulated BDNF-hMSC reduced lesion area significantly at 14 and 21 days in the damaged brain following trans-septal implantation. This stem cell transplantation approach represents a critical set up towards brain injury treatment for clinical application.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120413DOI Listing
January 2021

Transient Receptor Potential Melastatin 2 (TRPM2) Inhibition by Antioxidant, -Acetyl-l-Cysteine, Reduces Global Cerebral Ischemia-Induced Neuronal Death.

Int J Mol Sci 2020 Aug 21;21(17). Epub 2020 Aug 21.

Department of Physiology, College of Medicine, Hallym University, Chuncheon 24252, Korea.

A variety of pathogenic mechanisms, such as cytoplasmic calcium/zinc influx, reactive oxygen species production, and ionic imbalance, have been suggested to play a role in cerebral ischemia induced neurodegeneration. During the ischemic state that occurs after stroke or heart attack, it is observed that vesicular zinc can be released into the synaptic cleft, and then translocated into the cytoplasm via various cation channels. Transient receptor potential melastatin 2 (TRPM2) is highly distributed in the central nervous system and has high sensitivity to oxidative damage. Several previous studies have shown that TRPM2 channel activation contributes to neuroinflammation and neurodegeneration cascades. Therefore, we examined whether anti-oxidant treatment, such as with -acetyl-l-cysteine (NAC), provides neuroprotection via regulation of TRPM2, following global cerebral ischemia (GCI). Experimental animals were then immediately injected with NAC (150 mg/kg/day) for 3 and 7 days, before sacrifice. We demonstrated that NAC administration reduced activation of GCI-induced neuronal death cascades, such as lipid peroxidation, microglia and astroglia activation, free zinc accumulation, and TRPM2 over-activation. Therefore, modulation of the TRPM2 channel can be a potential therapeutic target to prevent ischemia-induced neuronal death.
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http://dx.doi.org/10.3390/ijms21176026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504640PMC
August 2020

Role of Excitatory Amino Acid Carrier 1 () in Neuronal Death and Neurogenesis After Ischemic Stroke.

Int J Mol Sci 2020 Aug 7;21(16). Epub 2020 Aug 7.

Department of Physiology, Hallym University, College of Medicine, Chuncheon 24252, Korea.

Although there have been substantial advances in knowledge regarding the mechanisms of neuron death after stroke, effective therapeutic measures for stroke are still insufficient. Excitatory amino acid carrier 1 () is a type of neuronal glutamate transporter and considered to have an additional action involving the neuronal uptake of cysteine, which acts as a crucial substrate for glutathione synthesis. Previously, our lab demonstrated that genetic deletion of leads to decreased neuronal glutathione synthesis, increased oxidative stress, and subsequent cognitive impairment. Therefore, we hypothesized that reduced neuronal transport of cysteine due to deletion of the gene might exacerbate neuronal injury and impair adult neurogenesis in the hippocampus after transient cerebral ischemia. gene deletion profoundly increased ischemia-induced neuronal death by decreasing the antioxidant capacity. In addition, genetic deletion of also decreased the overall neurogenesis processes, such as cell proliferation, differentiation, and survival, after cerebral ischemia. These studies strongly support our hypothesis that is crucial for the survival of newly generated neurons, as well as mature neurons, in both physiological and pathological conditions. Here, we present a comprehensive review of the role of in neuronal death and neurogenesis induced by ischemic stroke, focusing on its potential cellular and molecular mechanisms.
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http://dx.doi.org/10.3390/ijms21165676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460875PMC
August 2020

An Inhibitor of the Sodium-Hydrogen Exchanger-1 (NHE-1), Amiloride, Reduced Zinc Accumulation and Hippocampal Neuronal Death after Ischemia.

Int J Mol Sci 2020 Jun 14;21(12). Epub 2020 Jun 14.

Department of Physiology, College of Medicine, Hallym University, Chuncheon 24252, Korea.

Acidosis in the brain plays an important role in neuronal injury and is a common feature of several neurological diseases. It has been reported that the sodium-hydrogen exchanger-1 (NHE-1) is a key mediator of acidosis-induced neuronal injury. It modulates the concentration of intra- and extra-cellular sodium and hydrogen ions. During the ischemic state, excessive sodium ions enter neurons and inappropriately activate the sodium-calcium exchanger (NCX). Zinc can also enter neurons through voltage-gated calcium channels and NCX. Here, we tested the hypothesis that zinc enters the intracellular space through NCX and the subsequent zinc accumulation induces neuronal cell death after global cerebral ischemia (GCI). Thus, we conducted the present study to confirm whether inhibition of NHE-1 by amiloride attenuates zinc accumulation and subsequent hippocampus neuronal death following GCI. Mice were subjected to GCI by bilateral common carotid artery (BCCA) occlusion for 30 min, followed by restoration of blood flow and resuscitation. Amiloride (10 mg/kg, intraperitoneally ()) was immediately injected, which reduced zinc accumulation and neuronal death after GCI. Therefore, the present study demonstrates that amiloride attenuates GCI-induced neuronal injury, likely via the prevention of intracellular zinc accumulation. Consequently, we suggest that amiloride may have a high therapeutic potential for the prevention of GCI-induced neuronal death.
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http://dx.doi.org/10.3390/ijms21124232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352629PMC
June 2020

A Novel Zinc Chelator, 1H10, Ameliorates Experimental Autoimmune Encephalomyelitis by Modulating Zinc Toxicity and AMPK Activation.

Int J Mol Sci 2020 May 10;21(9). Epub 2020 May 10.

Department of Physiology, Hallym University College of Medicine, Chuncheon 24252, Korea.

Previous studies in our lab revealed that chemical zinc chelation or zinc transporter 3 () gene deletion suppresses the clinical features and neuropathological changes associated with experimental autoimmune encephalomyelitis (EAE). In addition, although protective functions are well documented for AMP-activated protein kinase (AMPK), paradoxically, disease-promoting effects have also been demonstrated for this enzyme. Recent studies have demonstrated that AMPK contributes to zinc-induced neurotoxicity and that 1H10, an inhibitor of AMPK, reduces zinc-induced neuronal death and protects against oxidative stress, excitotoxicity, and apoptosis. Here, we sought to evaluate the therapeutic efficacy of 1H10 against myelin oligodendrocyte glycoprotein 35-55-induced EAE. 1H10 (5 μg/kg) was intraperitoneally injected once per day for the entire experimental course. Histological evaluation was performed three weeks after the initial immunization. We found that 1H10 profoundly reduced the severity of the induced EAE and that there was a remarkable suppression of demyelination, microglial activation, and immune cell infiltration. 1H10 also remarkably inhibited EAE-associated blood-brain barrier (BBB) disruption, MMP-9 activation, and aberrant synaptic zinc patch formation. Furthermore, the present study showed that long-term treatment with 1H10 also reduced the clinical course of EAE. Therefore, the present study suggests that zinc chelation and AMPK inhibition with 1H10 may have great therapeutic potential for the treatment of multiple sclerosis.
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http://dx.doi.org/10.3390/ijms21093375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247014PMC
May 2020

Zinc transporter 3 modulates cell proliferation and neuronal differentiation in the adult hippocampus.

Stem Cells 2020 08 7;38(8):994-1006. Epub 2020 May 7.

Department of Physiology, Hallym University College of Medicine, Chuncheon, South Korea.

The subgranular zone of the dentate gyrus is a subregion of the hippocampus that has two uniquely defining features; it is one of the most active sites of adult neurogenesis as well as the location where the highest concentrations of synaptic zinc are found, the mossy fiber terminals. Therefore, we sought to investigate the idea that vesicular zinc plays a role as a modulator of hippocampal adult neurogenesis. Here, we used ZnT3 mice, which are depleted of synaptic-vesicle zinc, to test the effect of targeted deletion of this transporter on adult neurogenesis. We found that this manipulation reduced progenitor cell turnover as well as led to a marked defect in the maturation of newborn cells that survive in the DG toward a neuronal phenotype. We also investigated the effects of zinc (ZnCl ), n-acetyl cysteine (NAC), and ZnCl plus 2NAC (ZN) supplement on adult hippocampal neurogenesis. Compared with ZnCl or NAC, administration of ZN resulted in an increase in proliferation of progenitor cells and neuroblast. ZN also rescued the ZnT3 loss-associated reduction of neurogenesis via elevation of insulin-like growth factor-1 and ERK/CREB activation. Together, these findings reveal that ZnT3 plays a highly important role in maintaining adult hippocampal neurogenesis and supplementation by ZN has a beneficial effect on hippocampal neurogenesis, as well as providing a therapeutic target for enhanced neuroprotection and repair after injury as demonstrated by its ability to prevent aging-dependent cognitive decline in ZnT3 mice. Therefore, the present study suggests that ZnT3 and vesicular zinc are essential for adult hippocampal neurogenesis.
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http://dx.doi.org/10.1002/stem.3194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496127PMC
August 2020

Changes in plasma lipoxin A4, resolvins and CD59 levels after ischemic and traumatic brain injuries in rats.

Korean J Physiol Pharmacol 2020 Mar 20;24(2):165-171. Epub 2020 Feb 20.

Department of Pharmacology, College of Medicine, Hallym University, Chuncheon 24252, Korea.

Ischemic and traumatic brain injuries are the major acute central nervous system disorders that need to be adequately diagnosed and treated. To find biomarkers for these acute brain injuries, plasma levels of some specialized pro-resolving mediators (SPMs, i.e., lipoxin A4 [LXA4], resolvin [Rv] E1, RvE2, RvD1 and RvD2), CD59 and interleukin (IL)-6 were measured at 0, 6, 24, 72, and 168 h after global cerebral ischemic (GCI) and traumatic brain injuries (TBI) in rats. Plasma LXA4 levels tended to increase at 24 and 72 h after GCI. Plasma RvE1, RvE2, RvD1, and RvD2 levels showed a biphasic response to GCI; a significant decrease at 6 h with a return to the levels of the sham group at 24 h, and again a decrease at 72 h. Plasma CD59 levels increased at 6 and 24 h post-GCI, and returned to basal levels at 72 h post-GCI. For TBI, plasma LXA4 levels tended to decrease, while RvE1, RvE2, RvD1, and RvD2 showed barely significant changes. Plasma IL-6 levels were significantly increased after GCI and TBI, but with different time courses. These results show that plasma LXA4, RvE1, RvE2, RvD1, RvD2, and CD59 levels display differential responses to GCI and TBI, and need to be evaluated for their usefulness as biomarkers.
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http://dx.doi.org/10.4196/kjpp.2020.24.2.165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7043996PMC
March 2020

Distinct dual roles of p-Tyr42 RhoA GTPase in tau phosphorylation and ATP citrate lyase activation upon different Aβ concentrations.

Redox Biol 2020 05 31;32:101446. Epub 2020 Jan 31.

Department of Biochemistry, Hallym University College of Medicine, Chuncheon, Kangwon-do, 24252, Republic of Korea; Institute of Cell Differentiation and Aging, Hallym University College of Medicine, Chuncheon, Kangwon-do, 24252, Republic of Korea; Hallym Clinical and Translational Science Institute, Hallym University College of Medicine, Chuncheon, Kangwon-do, 24252, Republic of Korea; eLmed Co., Hallym University College of Medicine, Chuncheon, Kangwon-do, 24252, Republic of Korea. Electronic address:

Both the accumulation of Amyloid-β (Aβ) in plaques and phosphorylation of Tau protein (p-Tau) in neurofibrillary tangles have been identified as two major symptomatic features of Alzheimer's disease (AD). Despite of critical role of Aβ and p-Tau in AD progress, the interconnection of signalling pathways that Aβ induces p-Tau remains elusive. Herein, we observed that a popular AD model mouse (APP/PS1) and Aβ-injected mouse showed an increase in p-Tyr42 Rho in hippocampus of brain. Low concentrations of Aβ (1 μM) induced RhoA-mediated Ser422 phosphorylation of Tau protein (p-Ser422 Tau), but reduced the expression of ATP citrate lyase (ACL) in the HT22 hippocampal neuronal cell line. In contrast, high concentrations of Aβ (10 μM) along with high levels of superoxide production remarkably attenuated accumulation of p-Ser422 Tau, but augmented ACL expression and activated sterol regulatory element-binding protein 1 (SREBP1), leading to cellular senescence. Notably, a high concentration of Aβ (10 μM) induced nuclear localization of p-Tyr42 Rho, which positively regulated NAD kinase (NADK) expression by binding to the NADK promoter. Furthermore, severe AD patient brain showed high p-Tyr42 Rho levels. Collectively, our findings indicate that both high and low concentrations of Aβ are detrimental to neurons via distinct two p-Tyr42 RhoA-mediated signalling pathways in Ser422 phosphorylation of Tau and ACL expression.
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http://dx.doi.org/10.1016/j.redox.2020.101446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264465PMC
May 2020

Focused ultrasound-induced blood-brain barrier opening improves adult hippocampal neurogenesis and cognitive function in a cholinergic degeneration dementia rat model.

Alzheimers Res Ther 2019 12 27;11(1):110. Epub 2019 Dec 27.

Department of Neurosurgery, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.

Background: The persistence of adult hippocampal neurogenesis (AHN) is sharply decreased in Alzheimer's disease (AD). The neuropathologies of AD include the presence of amyloid-β deposition in plaques, tau hyperphosphorylation in neurofibrillary tangles, and cholinergic system degeneration. The focused ultrasound (FUS)-mediated blood-brain barrier opening modulates tau hyperphosphorylation, the accumulation of amyloid-β proteins, and increases in AHN. However, it remains unclear whether FUS can modulate AHN in cholinergic-deficient conditions. In this study, we investigated the effect of FUS on AHN in a cholinergic degeneration rat model of dementia.

Methods: Adult male Sprague-Dawley rats (n = 48; 200-250 g) were divided into control (phosphate-buffered saline injection), 192 IgG-saporin (SAP), and SAP+FUS groups; in the two latter groups, SAP was injected bilaterally into the lateral ventricle. We applied FUS to the bilateral hippocampus with microbubbles. Immunohistochemistry, enzyme-linked immunosorbent assay, immunoblotting, 5-bromo-2'-deoxyuridine labeling, an acetylcholinesterase assay, and the Morris water maze test were performed to assess choline acetyltransferase, acetylcholinesterase activity, brain-derived neurotrophic factor expression, neural proliferation, and spatial memory, respectively. Statistical significance of differences in between groups was calculated using one-way and two-way analyses of variance followed by Tukey's multiple comparison test to determine the individual and interactive effects of FUS on immunochemistry and behavioral analysis. P < 0.05 was considered significant.

Results: Cholinergic degeneration in rats significantly decreased the number of choline acetyltransferase neurons (P < 0.05) in the basal forebrain, as well as AHN and spatial memory function. Rats that underwent FUS-mediated brain-blood barrier opening exhibited significant increases in brain-derived neurotrophic factor (BDNF; P < 0.05), early growth response protein 1 (EGR1) (P < 0.01), AHN (P < 0.01), and acetylcholinesterase activity in the frontal cortex (P < 0.05) and hippocampus (P < 0.01) and crossing over (P < 0.01) the platform in the Morris water maze relative to the SAP group after sonication.

Conclusions: FUS treatment increased AHN and improved spatial memory. This improvement was mediated by increased hippocampal BDNF and EGR1. FUS treatment may also restore AHN and protect against neurodegeneration, providing a potentially powerful therapeutic strategy for AD.
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http://dx.doi.org/10.1186/s13195-019-0569-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6933667PMC
December 2019

The Influence of Astaxanthin on the Proliferation of Adipose-derived Mesenchymal Stem Cells in Gelatin-Methacryloyl (GelMA) Hydrogels.

Materials (Basel) 2019 Jul 29;12(15). Epub 2019 Jul 29.

Interdisciplinary Program of Biomedical Mechanical & Electrical Engineering, Pukyong National University, Busan 48513, Korea.

Recently, astaxanthin, a red lipophilic pigment belonging to the xanthophyllic family of carotenoids, has shown the feasibility of its uses in tissue engineering and regenerative medicine, due to its excellent antioxidant activities and its abilities to enhance the self-renewal potency of stem cells. In this study, we demonstrate the influence of astaxanthin on the proliferation of adipose-derived mesenchymal stem cells in tissue-engineered constructs. The tissue engineered scaffolds were fabricated using photopolymerizable gelatin methacryloyl (GelMA) with different concentrations of astaxanthin. The effects of astaxanthin on cellular proliferation in two-dimensional environments were assessed using alamar blue assay and reverse transcription polymerase chain reaction (RT-PCR). Then, rheological properties, chemical structures and the water absorption of the fabricated astaxanthin-incorporated GelMA hydrogels were characterized using NMR analysis, rheological analysis and a swelling ratio test. Finally, the influence in three-dimensional environments of astaxanthin-incorporated GelMA hydrogels on the proliferative potentials of adipose-derived stem cells was assessed using alamar blue assay and the confocal imaging with Live/dead staining. The experimental results of the study indicate that an addition of astaxanthin promises to induce stem cell potency via proliferation, and that it can be a useful tool for a three-dimensional culture system and various tissue engineering applications.
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http://dx.doi.org/10.3390/ma12152416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6696170PMC
July 2019

Transitions in Problematic Internet Use: A One-Year Longitudinal Study of Boys.

Psychiatry Investig 2019 Jun 25;16(6):433-442. Epub 2019 Jun 25.

Departments of Psychiatry, Neuroscience and Child Study, Yale University School of Medicine, New Haven, CT, USA.

Objective: Longitudinal studies may help elucidate the factors associated with Problematic Internet Use (PIU); however, little prospective research has been conducted on the subject. The aim of the current study was to prospectively examine PIU in children/adolescents and identify the possible risk factors associated with transitions in PIU severity.

Methods: 650 middle-school boys were surveyed at two points one year apart and assessed for PIU using the Internet Addiction Proneness Scale for Youth (KS-II) and on other psychological characteristics.

Results: We found that 15.3% at baseline and 12.4% at one year met the criteria for at-risk/high-risk PIU (ARHRPIU). Both the persistent-ARHRPIU and emerging-ARHRPIU groups revealed greater depressive, motor impulsive, and smart-phone-addiction tendencies than the remitting-ARHRPIU group or the persistent low-risk group. In addition, we found that individuals exhibiting higher hyperkinetic attention-deficit/hyperactivity disorder (ADHD) scores were less likely to remit from ARHRPIU, and that individuals exhibiting more ADHD-related cognitive dysfunction and reporting fewer Internet-game-free days were more likely to demonstrate an emergence of ARHRPIU.

Conclusion: The present findings support previous studies in that specific negative-health features are linked to transitions in ARHRPIU. Furthermore, these findings suggest that intervention is needed and may be best targeted at specific groups of youths.
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http://dx.doi.org/10.30773/pi.2019.04.02.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6603706PMC
June 2019

The Effects of Sodium Dichloroacetate on Mitochondrial Dysfunction and Neuronal Death Following Hypoglycemia-Induced Injury.

Cells 2019 05 1;8(5). Epub 2019 May 1.

Department of Physiology, College of Medicine, Hallym University, Chuncheon 24252, Kangwon-Do, Korea.

Our previous studies demonstrated that some degree of neuronal death is caused by hypoglycemia, but a subsequent and more severe wave of neuronal cell death occurs due to glucose reperfusion, which results from the rapid restoration of low blood glucose levels. Mitochondrial dysfunction caused by hypoglycemia leads to increased levels of pyruvate dehydrogenase kinase (PDK) and suppresses the formation of ATP by inhibiting pyruvate dehydrogenase (PDH) activation, which can convert pyruvate into acetyl-coenzyme A (acetyl-CoA). Sodium dichloroacetate (DCA) is a PDK inhibitor and activates PDH, the gatekeeper of glucose oxidation. However, no studies about the effect of DCA on hypoglycemia have been published. In the present study, we hypothesized that DCA treatment could reduce neuronal death through improvement of glycolysis and prevention of reactive oxygen species production after hypoglycemia. To test this, we used an animal model of insulin-induced hypoglycemia and injected DCA (100 mg/kg, i.v., two days) following hypoglycemic insult. Histological evaluation was performed one week after hypoglycemia. DCA treatment reduced hypoglycemia-induced oxidative stress, microglial activation, blood-brain barrier disruption, and neuronal death compared to the vehicle-treated hypoglycemia group. Therefore, our findings suggest that DCA may have the therapeutic potential to reduce hippocampal neuronal death after hypoglycemia.
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http://dx.doi.org/10.3390/cells8050405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562710PMC
May 2019

Alcohol dependence treating agent, acamprosate, prevents traumatic brain injury-induced neuron death through vesicular zinc depletion.

Transl Res 2019 05 17;207:1-18. Epub 2019 Jan 17.

Department of Physiology, Hallym University, College of Medicine, Chuncheon, Korea. Electronic address:

Acamprosate, also known as N-acetyl homotaurine, is an N-methyl-d-aspartate receptor antagonist that is used for treating alcohol dependence. Although the exact mechanism of acamprosate has not been clearly established, it appears to work by promoting a balance between the excitatory and inhibitory neurotransmitters, glutamate, and gamma-aminobutyric acid, respectively. Several studies have demonstrated that acamprosate provides neuroprotection against ischemia-induced brain injury. However, no studies have been performed evaluating the effect of acamprosate on traumatic brain injury (TBI). In the present study, we sought to evaluate the therapeutic potential of acamprosate to protect against neuronal death following TBI. Rats were given oral acamprosate (200 mg/kg/d for 2weeks) and then subjected to a controlled cortical impact injury localized over the parietal cortex. Histologic analysis was performed at 3hours, 24hours, and 7days after TBI. We found that acamprosate treatment reduced the concentration of vesicular glutamate and zinc in the hippocampus. Consequently, this reduced vesicular glutamate and zinc level resulted in a reduction of reactive oxygen species production after TBI. When evaluated 24hours after TBI, acamprosate administration reduced the number of degenerating neurons, zinc accumulation, blood-brain barrier disruption, neutrophil infiltration, and dendritic loss. Acamprosate also reduced glial activation and neuronal loss at 7days after TBI. In addition, acamprosate rescued TBI-induced neurologic and cognitive dysfunction. The present study demonstrates that acamprosate attenuates TBI-induced brain damage by depletion of vesicular glutamate and zinc levels. Therefore, this study suggests that acamprosate may have high therapeutic potential for prevention of TBI-induced neuronal death.
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http://dx.doi.org/10.1016/j.trsl.2019.01.002DOI Listing
May 2019

Carvacrol Attenuates Hippocampal Neuronal Death after Global Cerebral Ischemia via Inhibition of Transient Receptor Potential Melastatin 7.

Cells 2018 Nov 26;7(12). Epub 2018 Nov 26.

Department of Physiology, College of Medicine, Hallym University, Chuncheon 24252, Korea.

Over the last two decades, evidence supporting the concept of zinc-induced neuronal death has been introduced, and several intervention strategies have been investigated. Vesicular zinc is released into the synaptic cleft, where it then translocates to the cytoplasm, which leads to the production of reactive oxygen species and neurodegeneration. Carvacrol inhibits transient receptor potential melastatin 7 (TRPM7), which regulates the homeostasis of extracellular metal ions, such as calcium and zinc. In the present study, we test whether carvacrol displays any neuroprotective effects after global cerebral ischemia (GCI), via a blockade of zinc influx. To test our hypothesis, we used eight-week-old male Sprague⁻Dawley rats, and a GCI model was induced by bilateral common carotid artery occlusion (CCAO), accompanied by blood withdrawal from the femoral artery. Ischemic duration was defined as a seven-minute electroencephalographic (EEG) isoelectric period. Carvacrol (50 mg/kg) was injected into the intraperitoneal space once per day for three days after the onset of GCI. The present study found that administration of carvacrol significantly decreased the number of degenerating neurons, microglial activation, oxidative damage, and zinc translocation after GCI, via downregulation of TRPM7 channels. These findings suggest that carvacrol, a TRPM7 inhibitor, may have therapeutic potential after GCI by reducing intracellular zinc translocation.
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http://dx.doi.org/10.3390/cells7120231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6315386PMC
November 2018

Carvacrol Attenuates Hippocampal Neuronal Death after Global Cerebral Ischemia via Inhibition of Transient Receptor Potential Melastatin 7.

Cells 2018 Nov 26;7(12). Epub 2018 Nov 26.

Department of Physiology, College of Medicine, Hallym University, Chuncheon 24252, Korea.

Over the last two decades, evidence supporting the concept of zinc-induced neuronal death has been introduced, and several intervention strategies have been investigated. Vesicular zinc is released into the synaptic cleft, where it then translocates to the cytoplasm, which leads to the production of reactive oxygen species and neurodegeneration. Carvacrol inhibits transient receptor potential melastatin 7 (TRPM7), which regulates the homeostasis of extracellular metal ions, such as calcium and zinc. In the present study, we test whether carvacrol displays any neuroprotective effects after global cerebral ischemia (GCI), via a blockade of zinc influx. To test our hypothesis, we used eight-week-old male Sprague⁻Dawley rats, and a GCI model was induced by bilateral common carotid artery occlusion (CCAO), accompanied by blood withdrawal from the femoral artery. Ischemic duration was defined as a seven-minute electroencephalographic (EEG) isoelectric period. Carvacrol (50 mg/kg) was injected into the intraperitoneal space once per day for three days after the onset of GCI. The present study found that administration of carvacrol significantly decreased the number of degenerating neurons, microglial activation, oxidative damage, and zinc translocation after GCI, via downregulation of TRPM7 channels. These findings suggest that carvacrol, a TRPM7 inhibitor, may have therapeutic potential after GCI by reducing intracellular zinc translocation.
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http://dx.doi.org/10.3390/cells7120231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6315386PMC
November 2018

Inhibition of NADPH Oxidase Activation by Apocynin Rescues Seizure-Induced Reduction of Adult Hippocampal Neurogenesis.

Int J Mol Sci 2018 Oct 9;19(10). Epub 2018 Oct 9.

Department of Physiology, College of Medicine, Hallym University, Chuncheon 24252, Korea.

Apocynin, also known as acetovanillone, is a natural organic compound structurally related to vanillin. Apocynin is known to be an inhibitor of NADPH (Nicotinamide adenine dinucleotide phosphate) oxidase activity and is highly effective in suppressing the production of superoxide. The neuroprotective effects of apocynin have been investigated in numerous brain injury settings, such as stroke, traumatic brain injury (TBI), and epilepsy. Our lab has demonstrated that TBI or seizure-induced oxidative injury and neuronal death were reduced by apocynin treatment. Several studies have also demonstrated that neuroblast production is transiently increased in the hippocampus after seizures. Here, we provide evidence confirming the hypothesis that long-term treatment with apocynin may enhance newly generated hippocampal neuronal survival by reduction of superoxide production after seizures. A seizure was induced by pilocarpine [(25 mg/kg intraperitoneal (i.p.)] injection. Apocynin was continuously injected for 4 weeks after seizures (once per day) into the intraperitoneal space. We evaluated neuronal nuclear antigen (NeuN), bromodeoxyuridine (BrdU), and doublecortin (DCX) immunostaining to determine whether treatment with apocynin increased neuronal survival and neurogenesis in the hippocampus after seizures. The present study indicates that long-term treatment of apocynin increased the number of NeuN⁺ and DCX⁺ cells in the hippocampus after seizures. Therefore, this study suggests that apocynin treatment increased neuronal survival and neuroblast production by reduction of hippocampal oxidative injury after seizures.
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http://dx.doi.org/10.3390/ijms19103087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6212849PMC
October 2018

Antimicrotubule Agent-Induced Zinc Neurotoxicity.

Biol Pharm Bull 2018 ;41(7):1001-1005

Department of Physiology, College of Medicine, Hallym University.

Colchicine or vincristine depolymerize microtubules, an action which blocks neuron axonal transport. Thus, these chemicals showed selective neurotoxicity in hippocampal neurons. However, the mechanism of neurotoxicity by these antimicrotubule agents has remained unclear. Our previous studies have suggested that colchicine-induced hippocampal neuron death is caused by incremental increases in intraneuronal free zinc. We have demonstrated that zinc transporter 3 gene deletion (ZnT3) reduces dentate granule cell death after colchicine injection. This ZnT3-mediated reduction of dentate granule cell death was accompanied by a decrease in the incidence of oxidative injury. Unexpectedly, we found that ZnT3 mice contain a higher glutathione (GSH) level in the hippocampal neurons than wild type mice. Thus, ZnT3 mice showed less neuronal GSH depletion by colchicine injection, and thus less neuronal death. These results suggest that the higher levels of neuronal GSH in ZnT3 mice result in less dentate granule cell death after colchicine injection. In addition to colchicine, our lab also demonstrated that a chemotherapeutic agent, pacritaxel (Taxol), which is a microtubule stabilizing agent, depleted vesicular zinc in the presynaptic terminals and induced a reduction of neurogenesis. Therefore, in the present review, we discussed how antimicrotubule agent-induced neurotoxicity and cognitive impairment is associated with zinc dyshomeostasis in the brain.
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http://dx.doi.org/10.1248/bpb.b17-00937DOI Listing
October 2018

Human Placenta-Derived Mesenchymal Stem Cells Reduce Mortality and Hematoma Size in a Rat Intracerebral Hemorrhage Model in an Acute Phase.

Stem Cells Int 2018 2;2018:1658195. Epub 2018 May 2.

Department of Emergency Medicine, CHA University School of Medicine, 59 Yatap-Ro, Bundang-Gu, Seongnam 13496, Republic of Korea.

Intracerebral hemorrhage (ICH) is a critical disease, highly associated with mortality and morbidity. Several studies have demonstrated the beneficial effect of mesenchymal stem cells (MSCs) on ICH, mostly focused on their mid-to-long-term effect. Acute hematoma expansion is one of the most important prognostic factors of ICH. We hypothesized that MSCs would decrease mortality and hematoma size in acute ICH, based on the findings of a few recent researches reporting their effect on blood-brain barrier and endothelial integrity. Rat ICH models were made using bacterial collagenase. One hour after ICH induction, the rats were randomly divided into MSC-treated and control groups. Mortality, hematoma volume, ventricular enlargement, brain edema, and degenerating neuron count were compared at 24 hours after ICH induction. Expression of tight junction proteins (ZO-1, occludin) and coagulation factor VII mRNA was also compared. Mortality rate (50% versus 8.3%), hematoma size, ventricular size, hemispheric enlargement, and degenerating neuron count were significantly lower in the MSC-treated group ( = 0.034, 0.038, 0.001, 0.022, and <0.001, resp.), while the expression of ZO-1 and occludin was higher ( = 0.007 and 0.012). Administration of MSCs may prevent hematoma expansion in the hyperacute stage of ICH and decrease acute mortality by enhancing the endothelial integrity of cerebral vasculature.
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http://dx.doi.org/10.1155/2018/1658195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5954892PMC
May 2018

Zinc Promotes Adipose-Derived Mesenchymal Stem Cell Proliferation and Differentiation towards a Neuronal Fate.

Stem Cells Int 2018 18;2018:5736535. Epub 2018 Apr 18.

Department of Physiology, College of Medicine, Hallym University, Chuncheon, Republic of Korea.

Zinc is an essential element required for cell division, migration, and proliferation. Under zinc-deficient conditions, proliferation and differentiation of neural progenitors are significantly impaired. Adipose-derived mesenchymal stem cells (AD-MSCs) are multipotent stem cells that can differentiate into neurons. The aim of this study was to evaluate the effect of zinc on AD-MSC proliferation and differentiation. We initially examined the effect of zinc on stem cell proliferation at the undifferentiated stage. AD-MSCs showed high proliferation rates on day 6 in 30 M and 100 M of ZnCl. Zinc chelation inhibited AD-MSC proliferation via downregulation of ERK1/2 activity. We then assessed whether zinc was involved in cell migration and neurite outgrowth during differentiation. After three days of neuronal differentiation, TUJ-1-positive cells were observed, implying that AD-MSCs had differentiated into early neuron or neuron-like cells. Neurite outgrowth was increased in the zinc-treated group, while the CaEDTA-treated group showed diminished, shrunken neurites. Furthermore, we showed that zinc promoted neurite outgrowth via the inactivation of RhoA and led to the induction of neuronal gene expression (MAP2 and nestin) in differentiated stem cells. Taken together, zinc promoted AD-MSC proliferation and affected neuronal differentiation, mainly by increasing neurite outgrowth.
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http://dx.doi.org/10.1155/2018/5736535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5932442PMC
April 2018

Effects of Protocatechuic Acid (PCA) on Global Cerebral Ischemia-Induced Hippocampal Neuronal Death.

Int J Mol Sci 2018 May 9;19(5). Epub 2018 May 9.

Department of Physiology, College of Medicine, Hallym University, Chuncheon 24252, Korea.

Global cerebral ischemia (GCI) is one of the main causes of hippocampal neuronal death. Ischemic damage can be rescued by early blood reperfusion. However, under some circumstances reperfusion itself can trigger a cell death process that is initiated by the reintroduction of blood, followed by the production of superoxide, a blood⁻brain barrier (BBB) disruption and microglial activation. Protocatechuic acid (PCA) is a major metabolite of the antioxidant polyphenols, which have been discovered in green tea. PCA has been shown to have antioxidant effects on healthy cells and anti-proliferative effects on tumor cells. To test whether PCA can prevent ischemia-induced hippocampal neuronal death, rats were injected with PCA (30 mg/kg/day) per oral (p.o) for one week after global ischemia. To evaluate degenerating neurons, oxidative stress, microglial activation and BBB disruption, we performed Fluoro-Jade B (FJB), 4-hydroxynonenal (4HNE), CD11b, GFAP and IgG staining. In the present study, we found that PCA significantly decreased degenerating neuronal cell death, oxidative stress, microglial activation, astrocyte activation and BBB disruption compared with the vehicle-treated group after ischemia. In addition, an ischemia-induced reduction in glutathione (GSH) concentration in hippocampal neurons was recovered by PCA administration. Therefore, the administration of PCA may be further investigated as a promising tool for decreasing hippocampal neuronal death after global cerebral ischemia.
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http://dx.doi.org/10.3390/ijms19051420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983751PMC
May 2018

EAAC1 gene deletion reduces adult hippocampal neurogenesis after transient cerebral ischemia.

Sci Rep 2018 05 2;8(1):6903. Epub 2018 May 2.

Department of Physiology, Hallym University, College of Medicine, Chuncheon, 24252, South Korea.

Several studies have demonstrated that excitatory amino acid carrier-1 (EAAC1) gene deletion exacerbates hippocampal and cortical neuronal death after ischemia. However, presently there are no studies investigating the role of EAAC1 in hippocampal neurogenesis. In this study, we tested the hypothesis that reduced cysteine transport into neurons by EAAC1 knockout negatively affects adult hippocampal neurogenesis under physiological or pathological states. This study used young mice (aged 3-5 months) and aged mice (aged 11-15 months) of either the wild-type (WT) or EAAC1 genotype. Ischemia was induced through the occlusion of bilateral common carotid arteries for 30 minutes. Histological analysis was performed at 7 or 30 days after ischemia. We found that both young and aged mice with loss of the EAAC1 displayed unaltered cell proliferation and neuronal differentiation, as compared to age-matched WT mice under ischemia-free conditions. However, neurons generated from EAAC1 mice showed poor survival outcomes in both young and aged mice. In addition, deletion of EAAC1 reduced the overall level of neurogenesis, including cell proliferation, differentiation, and survival after ischemia. The present study demonstrates that EAAC1 is important for the survival of newly generated neurons in the adult brain under physiological and pathological conditions. Therefore, this study suggests that EAAC1 plays an essential role in modulating hippocampal neurogenesis.
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http://dx.doi.org/10.1038/s41598-018-25191-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5932005PMC
May 2018

Administration of placenta-derived mesenchymal stem cells counteracts a delayed anergic state following a transient induction of endogenous neurogenesis activity after global cerebral ischemia.

Brain Res 2018 06 3;1689:63-74. Epub 2018 Apr 3.

Department of Emergency Medicine, CHA University, School of Medicine, South Korea. Electronic address:

Background: Global cerebral ischemia (GCI) is a major obstacle for cardiac arrest survival. Recent studies have suggested the possibility of mesenchymal stem cell (MSC) as a novel therapeutic option for GCI, but these results were limited to the neuroprotective effects of MSCs. Therefore, we aimed to investigate specific characteristics of neurogenesis after transient GCI, and to assess the effect of MSC on these characteristics.

Methods: Adult male Sprague-Dawley rats were subjected to 7 min of transient GCI and randomized into 7 groups: baseline, MSC, and control administered groups, to be analyzed at 2, 3, and 4 weeks after GCI, respectively. The same interventions were repeated for sham operated animals. Rats were euthanized at the designated time after GCI.

Results: A comparison of GCI and sham groups without MSC treatment, showed that the counts of bromodeoxyuridine (BrdU)- and doublecortin (DCX)-positive cells were significantly increased in the GCI group at 1 week after insult, but the trend was reversed at 3 weeks after insult. The counts of BrdU-, Ki67- and DCX-positive cells and the intensity of zinc translocator 3 (ZnT3) were all significantly higher in the MSC-treated group than those in the control group at 3 weeks after GCI. The count of NeuN-positive cells in the hippocampus was significantly increased in the MSC group at 4 weeks after GCI.

Conclusions: GCI induces transient neurogenesis, followed by an anergic state. MSC may counteract this anergy of neurogenesis and result in an increase in intact neurons in later stages.
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http://dx.doi.org/10.1016/j.brainres.2018.03.033DOI Listing
June 2018