Long-Term Neuroprotective Effect and Safety of Antenatal Magnesium Sulfate on Preterm Infants

전가원 대한주산의학회 2023 Perinatology Vol.34 No.3

In 2010, the American College of Obstetricians and Gynecologists (ACOG) issued a Committee Opinion regarding the administration of antenatal magnesium sulfate (MgSO4) for fetal neuroprotection based on randomized controlled trials and meta-analyses. ACOG recommends the use of antenatal MgSO4 for fetal neuroprotection. Consequently, antenatal MgSO4 is administered to pregnant women with a gestational age of less than 32 weeks to provide fetal neuroprotection and reduce the risk of cerebral palsy and neurodevelopmental impairment. Since the use of antenatal MgSO4 for fetal neuroprotection, concerns about the safety of the fetus and newborn and doubts about the long-term neuroprotective effects of antenatal MgSO4 have been raised. There is still in controversies whether antenatal MgSO4 provides short-term and long-term neuroprotection, such as decreased substantial gross motor dysfunction, cerebral palsy and cognitive dysfunction. Furthermore, the fetal and neonatal adverse effects of antenatal MgSO4, such as decreased vascular tone, blood flow of the mesenteric artery, and intestinal motility are still controversial. Therefore, preclinical studies and rigorous multicenter large cohort studies are necessary to determine the neuroprotective effects and safety of antenatal MgSO4, as well as to determine the optimal dosage and duration of treatment. It is important to administer MgSO4 to pregnant women with caution, taking into consideration the potential impact on the fetus and newborn.

Neuroprotective Effects of Ginsenoside Rg₃ against 24-OH-cholesterol-induced Cytotoxicity in Cortical Neurons

Roh, Yoon-Seok,Kim, Hyoung-Bae,Kang, Chang-Won,Kim, Bum-Seok,Nah, Seung-Yeol,Kim, Jong-Hoon The Korean Society of Ginseng 2010 Journal of Ginseng Research Vol.34 No.3

Ginsenoside $Rg_3$ ($Rg_3$), one of the active ingredients in Panax ginseng, attenuates NMDA receptor-mediated currents in vitro and antagonizes NMDA receptors through a glycine modulatory site in rat cultured hippocampal neurons. In the present study, we examined the neuroprotective effects of $Rg_3$ on 24-hydroxycholesterol (24-OH-chol)-induced cytotoxicity in vitro. The results showed that $Rg_3$ treatment significantly and dose-dependently inhibited 24-OH-chol-induced cell death in rat cultured cortical neurons, with an $IC_{50}$ value of $28.7{\pm}7.5\;{\mu}m$. Furthermore, the $Rg_3$ treatment not only significantly reduced DNA damage, but also dose-dependently attenuated 24-OH-chol-induced caspase-3 activity. To study the mechanisms underlying the in vitro neuroprotective effects of $Rg_3$ against 25-OH-chol-induced cytotoxicity, we also examined the effect of $Rg_3$ on intracellular $Ca^{2+}$ elevations in cultured neurons and found that $Rg_3$ treatment dose-dependently inhibited increases in intracellular $Ca^{2+}$, with an $IC_{50}$ value of $40.37{\pm}12.88\;{\mu}m$. Additionally, $Rg_3$ treatment dose-dependently inhibited apoptosis with an $IC_{50}$ of $47.3{\pm}14.2\;{\mu}m$. Finally, after confirming the protective effect of $Rg_3$ using a terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay, we found that $Rg_3$ is an active component in ginseng-mediated neuroprotection. These results collectively indicate that $Rg_3$-induced neuroprotection against 24-OH-chol in rat cortical neurons might be achieved via inhibition of a 24-OH-chol-mediated $Ca^{2+}$ channel. This is the first report to employ cortical neurons to study the neuroprotective effects of $Rg_3$ against 24-OH-chol. In conclusion, $Rg_3$ was effective for protecting cells against 24-OH-chol-induced cytotoxicity in rat cortical neurons. This protective ability makes $Rg_3$ a promising agent in pathologies implicating neurodegeneration such as apoptosis or neuronal cell death.

Neuroprotective Effects of Ginsenoside Rg₃ against 24-OH-cholesterol-induced Cytotoxicity in Cortical Neurons

Yoon Seok Roh,Hyoung Bae Kim,Chang-Won Kang,Bum Seok Kim,Seung-Yeol Nah,Jong-Hoon Kim 고려인삼학회 2010 Journal of Ginseng Research Vol.34 No.3

Ginsenoside Rg₃ (Rg₃), one of the active ingredients in Panax ginseng, attenuates NMDA receptor-mediated currents in vitro and antagonizes NMDA receptors through a glycine modulatory site in rat cultured hippocampal neurons. In the present study, we examined the neuroprotective effects of Rg₃ on 24-hydroxycholesterol (24-OH-chol)-induced cytotoxicity in vitro. The results showed that Rg₃ treatment significantly and dose-dependently inhibited 24-OH-chol-induced cell death in rat cultured cort ical neurons, with an IC?? value of 28.7 ± 7.5 ㎛. Furthermore, the Rg₃ treatment not only significantly reduced DNA damage, but also dose-dependently attenuated 24-OH-chol-induced caspase-3 activity. To study the mechanisms underlying the in vitro neuroprotective effects of Rg₃ against 25-OH-chol-induced cytotoxicity, we also examined the effect of Rg₃ on intracellular Ca²? elevations in cultured neurons and found that Rg₃ treatment dose-dependently inhibited increases in intracellular Ca²?, with an IC?? value of 40.37 ± 12.88 ㎛. Additionally, Rg₃ treatment dose-dependently inhibited apoptosis with an IC?? of 47.3 ± 14.2 ㎛. Finally, after confirming the protective effect of Rg₃ using a terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay, we found that Rg₃ is an active component in ginseng-mediated neuroprotection. These results collectively indicate that Rg₃-induced neuroprotection against 24-OH-chol in rat cortical neurons might be achieved via inhibition of a 24-OH-chol-mediated Ca²? channel. This is the first report to employ cortical neurons to study the neuroprotective effects of Rg₃ against 24-OH-chol. In conclusion, Rg₃ was effective for protecting cells against 24-OH-chol-induced cytotoxicity in rat cortical neurons. This protective ability makes Rg₃ a promising agent in pathologies implicating neurodegeneration such as apoptosis or neuronal cell death.

Neuroprotection in Schizophrenia and Its Therapeutic Implications

YongKu Kim,KyoungSae Na 대한신경정신의학회 2017 PSYCHIATRY INVESTIGATION Vol.14 No.4

Schizophrenia is a chronic and debilitating mental disorder. The persisting negative and cognitive symptoms that are unresponsive to pharmacotherapy reveal the impairment of neuroprotective aspects of schizophrenia. In this review, of the several neuroprotective factors, we mainly focused on neuroinflammation, neurogenesis, and oxidative stress. We conducted a narrative and selective review. Neuroinflammation is mainly mediated by pro-inflammatory cytokines and microglia. Unlike peripheral inflammatory responses, neuroinflammation has a role in various neuronal activities such as neurotransmission neurogenesis. The cross-talk between neuroinflammation and neurogenesis usually has beneficial effects in the CNS under physiological conditions. However, uncontrolled and chronic neuroinflammation exert detrimental effects such as neuronal loss, inhibited neurogenesis, and excessive oxidative stress. Neurogenesis is also a major component of neuroprotection. Adult neurogenesis mainly occurs in the hippocampal region, which has an important role in memory formation and processing. Impaired neurogenesis and an ineffective response to antipsychotics may be thought to indicate a deteriorating course of schizophrenia. Oxidative stress and excessive dopaminergic neurotransmission may create a vicious cycle and consequently disturb NMDA receptor-mediated glutamatergic neurotransmission. Based on the current evidences, several neuroprotective therapeutic approaches have been reported to be efficacious for improving psychopathology, but further longitudinal and large-sample based studies are needed.

Anti-neuroinflammatory and neuroprotective effects of the Lindera neesiana fruit in vitro

Subedi, L.,Gaire, B.P.,Do, M.H.,Lee, T.H.,Kim, S.Y. G. Fischer 2016 Phytomedicine Vol.23 No.8

<P>Background: Lindera neesiana Kurz (Lauraceae), popularly known as Siltimur in Nepal, is an aromatic and spicy plant with edible fruits. It is a traditional herbal medicine widely used for the treatment of diarrhea, tooth pain, headache, and gastric disorders and is also used as a stimulant. Purpose: The aim of the present study was to examine in vitro cytoprotective, anti-neuroinflammatory and neuroprotective potential of an aqueous extract of L. neesiana (LNE) fruit using different central nervous system (CNS) cell lines. Methods: In order to study the neuroprotective potential of LNE, we used three different types of CNS cell lines: murine microglia (BV2), rat glioma (C6), and mouse neuroblastoma (N2a). Cell viability was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reagent, and prostaglandin E-2 (PGE(2)), tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-6, and nerve growth factor (NGF) release in the culture media was determined using enzyme linked immunosorbent assay (ELISA) kits. Western blot analysis was performed to determine the protein expression of inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX2), mitogen activated protein kinase (MAPK) family proteins, Bax, B cell lymphoma (BCL)-2, and cleaved caspase 3. Neurite outgrowth was determined using the IncuCyte imaging system. Results: LNE treatment not only reduced nitric oxide (NO) production in a dose-dependent manner, but also significantly reduced proinflammatory cytokines, iNOS and COX-2 production by lipopolysaccharide (LPS) stimulated BV-2 cells. LNE increased the expression of phosphorylated (p)-extracellular signal-regulated kinase (ERK), whereas p-p38 and p- janus kinase (JNK) expression was significantly decreased in activated microglia. Furthermore, LNE increased cell viability of N2a cells, which was accompanied by decreased caspase-3 expression and the ratio of Bax/Bcl2 protein expression as well as increased NGF and neurite outgrowth, suggesting its neuroprotective potential against LPS-induced effects. Additionally, LNE substantially increased nuclear factor erythroid 2-related factor 2 (Nrf2) secretion in N2a cells and inhibited lipid dehydrogenase (LDH) release in H2O2-stimulated BV2 cells demonstrating the strong anti-inflammatory and antioxidant effects of LNE in CNS cell lines. Conclusion: Here we found that water the soluble extract of LNE has promising anti-neuroinflammation and anti-apoptotic properties and identify LNE as a potential natural candidate for neuroprotection. (C) 2016 Published by Elsevier GmbH.</P>

Soybean-Derived Phytoalexins Improve Cognitive Function through Activation of Nrf2/HO-1 Signaling Pathway

Seo, Ji Yeon,Kim, Bo Ram,Oh, Jisun,Kim, Jong-Sang MDPI 2018 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.19 No.1

<P>As soy-derived glyceollins are known to induce antioxidant enzymes in various types of cells and tissues, we hypothesized that the compounds could protect neurons from damage due to reactive oxygen species (ROS). In order to examine the neuroprotective effect of glyceollins, primary cortical neurons collected from mice and mouse hippocampal HT22 cells were challenged with glutamate. Glyceollins attenuated glutamate-induced cytotoxicity in primary cortical neuron isolated from mice carrying wild-type nuclear factor (erythroid-derived 2)-like 2 (Nrf2), but the compounds were ineffective in those isolated from Nrf2 knockout mice, suggesting the involvement of the Nrf2 signaling pathway in glyceollin-mediated neuroprotection. Furthermore, the inhibition of heme oxygenase-1 (HO-1), a major downstream enzyme of Nrf2, abolished the suppressive effect of glyceollins against glutamate-induced ROS production and cytotoxicity, confirming that activation of HO-1 by glyceollins is responsible for the neuroprotection. To examine whether glyceollins also improve cognitive ability, mice pretreated with glyceollins were challenged with scopolamine and subjected to behavioral tests. Glyceollins attenuated scopolamine-induced cognitive impairment of mice, but failed to enhance memory in Nrf2 knockout mice, suggesting that the memory-enhancing effect is also mediated by the Nrf2 signaling pathway. Overall, glyceollins showed neuroprotection against glutamate-induced damage, and attenuated scopolamine-induced memory deficits in an Nrf2-dependent manner.</P>

Pretreated fucoidan confers neuroprotection against transient global cerebral ischemic injury in the gerbil hippocampal CA1 area via reducing of glial cell activation and oxidative stress

Kim, Hyunjung,Ahn, Ji Hyeon,Song, Minah,Kim, Dae Won,Lee, Tae-Kyeong,Lee, Jae-Chul,Kim, Young-Myeong,Kim, Jong-Dai,Cho, Jun Hwi,Hwang, In Koo,Yan, Bing Chun,Won, Moo-Ho,Park, Joon Ha Elsevier 2019 BIOMEDICINE AND PHARMACOTHERAPY Vol.109 No.-

<P><B>Abstract</B></P> <P>Fucoidan is a sulfated polysaccharide derived from brown algae and possesses various beneficial activities, including antioxidant property. Previous studies have shown that fucoidan displays protective effect against ischemia-reperfusion injury in some organs. However, few studies have been reported regarding the protective effect of fucoidan against transient cerebral ischemic insults and its related mechanisms. Therefore, in this study, we examined the neuroprotective effect of fucoidan against transient global cerebral ischemia (tGCI), as well as underlying its mechanism using a gerbil model of tGCI which shows a loss of pyramidal neurons in the hippocampal cornu ammonis 1 (CA1) area after 5 min of tGCI. Fucoidan (25 and 50 mg/kg) was intraperitoneally administered once daily for 5 days before tGCI. Pretreatment with 50 mg/kg of fucoidan, not 25 mg/kg of fucoidan, attenuated tGCI-induced hyperactivity and protected CA1 pyramidal neurons from tGCI. In addition, pretreatment with 50 mg/kg of fucoidan inhibited activations of astrocytes and microglia in the ischemic CA1 area. Furthermore, pretreatment with 50 mg/kg of fucoidan significantly reduced the increased 4-hydroxy-2-noneal and superoxide anion radical production in the ischemic CA1 area and significantly increased expressions of SOD1 and SOD2 in the CA1 pyramidal neurons before and after tGCI. Additionally, treatment with diethyldithiocarbamate (an inhibitor of SODs) to the fucoidan-treated gerbils notably abolished the fucoidan-mediated neuroprotection. In brief, our present results indicate that fucoidan can effectively protect neurons from tGCI through attenuation of activated glial cells and reduction of oxidative stress via increase of SODs. Thus, we strongly suggest that fucoidan can be used as a useful preventive agent in cerebral ischemia.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Pretreatment with fucoidan protects CA1 pyramidal neurons from ischemic damage. </LI> <LI> Pretreated fucoidan inhibits activation of glial cells in ischemic CA1 area. </LI> <LI> Pretreated fucoidan attenuates oxidative stress in CA1 area after ischemic insult. </LI> <LI> Pretreated fucoidan increases SODs expressions in ischemic CA1 pyramidal neurons. </LI> <LI> Fucoidan-mediated neuroprotection is abolished by DDC (SODs inhibitor) treatment. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Dual Effects of Human Placenta-Derived Neural Cells on Neuroprotection and the Inhibition of Neuroinflammation in a Rodent Model of Parkinson’s Disease

Kim, Han Wool,Lee, Hyun-Seob,Kang, Jun Mo,Bae, Sang-Hun,Kim, Chul,Lee, Sang-Hun,Schwarz, Johannes,Kim, Gi Jin,Kim, Jin-Su,Cha, Dong Hyun,Kim, Joopyung,Chang, Sung Woon,Lee, Tae Hee,Moon, Jisook Cognizant Communication Corp. 2018 CELL TRANSPLANTATION Vol. No.

<P>Parkinson’s disease (PD) is the second most common age-related neurodegenerative disease in the elderly and the patients suffer from uncontrolled movement disorders due to loss of dopaminergic (DA) neurons on substantia nigra pars compacta (SNpc). We previously reported that transplantation of human fetal midbrain-derived neural precursor cells restored the functional deficits of a 6-hydroxy dopamine (6-OHDA)-treated rodent model of PD but its low viability and ethical issues still remain to be solved. Albeit immune privilege and neural differentiation potentials suggest mesenchymal stem cells (MSCs) from various tissues including human placenta MSCs (hpMSCs) for an alternative source, our understanding of their therapeutic mechanisms is still limited. To expand our knowledge on the MSC-mediated PD treatment, we here investigated the therapeutic mechanism of hpMSCs and hpMSC-derived neural phenotype cells (hpNPCs) using a PD rat model. Whereas both hpMSCs and hpNPCs protected DA neurons in the SNpc at comparable levels, the hpNPC transplantation into 6-OHDA treated rats exhibited longer lasting recovery in motor deficits than either the saline or the hpMSC treated rats. The injected hpNPCs induced delta-like ligand (DLL)1 and neurotrophic factors, and influenced environments prone to neuroprotection. Compared with hpMSCs, co-cultured hpNPCs more efficiently protected primary neural precursor cells from midbrain against 6-OHDA as well as induced their differentiation into DA neurons. Further experiments with conditioned media from hpNPCs revealed that the secreted factors from hpNPCs modulated immune responses and neural protection. Taken together, both DLL1-mediated contact signals and paracrine factors play critical roles in hpNPC-mediated improvement. First showing here that hpMSCs and their neural derivative hpNPCs were able to restore the PD-associated deficits via dual mechanisms, neuroprotection and immunosuppression, this study expanded our knowledge of therapeutic mechanisms in PD and other age-related diseases.</P>

Lithium-Pilocarpine으로 중첩경련을 유발한 흰쥐에서 칼슘 통로 길항제가 해마에 미치는 영향

한시령,김영인,김범생 대한신경과학회 1997 대한신경과학회지 Vol.15 No.6

Neuroprotective effects of erythropoietin against hypoxic injury via modulation of the mitogen-activated protein kinase pathway and apoptosis

정지은,박재현,김천수,이상락,정혜리,김우택,이은주 대한소아청소년과학회 2017 Clinical and Experimental Pediatrics (CEP) Vol.60 No.6

Purpose: Hypoxic-ischemic encephalopathy is a significant cause of neonatal morbidity and mortality. Erythropoietin (EPO) is emerging as a therapeutic candidate for neuroprotection. Therefore, this study was designed to determine the neuroprotective role of recombinant human EPO (rHuEPO) and the possible mechanisms by which mitogen-activated protein kinase (MAPK) signaling pathway including extracellular signal-regulated kinase (ERK1/2), JNK, and p38 MAPK is modulated in cultured cortical neuronal cells and astrocytes. Methods: Primary neuronal cells and astrocytes were prepared from cortices of ICR mouse embryos and divided into the normoxic, hypoxia (H), and hypoxia-pretreated with EPO (H+EPO) groups. The phosphorylation of MAPK pathway was quantified using western blot, and the apoptosis was assessed by caspase-3 measurement and terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Results: All MAPK pathway signals were activated by hypoxia in the neuronal cells and astrocytes (P<0.05). In the neuronal cells, phosphorylation of ERK-1/-2 and apoptosis were significantly decreased in the H+EPO group at 15 hours after hypoxia (P<0.05). In the astrocytes, phosphorylation of ERK-1/-2, p38 MAPK, and apoptosis was reduced in the H+EPO group at 15 hours after hypoxia (P<0.05). Conclusion: Pretreatment with rHuEPO exerts neuroprotective effects against hypoxic injury reducing apoptosis by caspase-dependent mechanisms. Pathologic, persistent ERK activation after hypoxic injury may be attenuateed by pretreatment with EPO supporting that EPO may regulate apoptosis by affecting ERK pathways.