• 대한한의학회지
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• 제28권2호통권70호
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• pp.213-223
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• 2007

Objective : Alzheimer's disease (AD) is a geriatric dementia that is widespread in old age. With an aging populace, AD is a looming problem in public health service. Alzheimer's disease is characterized by specific neuronal degeneration in certain areas of the brain. Mutations and abnormal expression of several genes are associated with ${\beta}-amyloid$ deposits and Alzheimer's disease; among them APP, PS1, and PS2, SOD, free radical, ROS. Methods:We studied herbal medicines that have a relationship to brain degeneration. From pre-modern times, although a variety of oriental prescriptions of Aster tataricus have been traditionally utilized for the treatment of AD, their pharmacological effects and action mechanisms have not yet been fully elucidated. Result : Based on morphological observations by phase-contrast microscope, TUNEL assay and MTT in the culture media, $H_20_2-induced$ cell death was significantly inhibited by Aticus. We examined by ROS formation, catalase activity and GSH activity. We studied the protective effect and inhibitory effects of neurotoxicity in $H_20_2-induced$ PC-12 cells by Aticus. Findings from our experiments show that Aticus inhibits apoptosis, which has neurotoxicities and cell damage in PC-12 cells. In addition, treatment with Aticus ($>25{\mu}g/ml$ for 6hrs) partially prevented $H_20_2-induced$ cytotoxicity in PC-12 cells, and induced a protective effect. Conclusion : As the result of this study, in the Aticus group, the apoptosis in the nervous system was inhibited, protected against the degeneration of PC-12 cells by $H_20_2$. Taken together, Aticus exhibited inhibition of $H_20_2-induced$ apoptotic cell death. Aticus was found to induce protective effect on GSH and catalase in PC-12 cells. Based on these findings, Aticus may be beneficial for the treatment of AD.

• Nutrition Research and Practice
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• 제17권5호
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• pp.899-916
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• 2023

BACKGROUND/OBJECTIVES: Oxidative stress is a fundamental neurodegenerative disease trigger that damages and decimates nerve cells. Neurodegenerative diseases are chronic central nervous system disorders that progress and result from neuronal degradation and loss. Recent studies have extensively focused on neurodegenerative disease treatment and prevention using dietary compounds. Heseperetin is an aglycone hesperidin form with various physiological activities, such as anti-inflammation, antioxidant, and antitumor. However, few studies have considered hesperetin's neuroprotective effects and mechanisms; thus, our study investigated this in hydrogen peroxide (H₂O₂)-treated SH-SY5Y cells. MATERIALS/METHODS: SH-SY5Y cells were treated with H₂O₂ (400 µM) in hesperetin absence or presence (10-40 µM) for 24 h. Three-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assays detected cell viability, and 4',6-diamidino-2-phenylindole staining allowed us to observe nuclear morphology changes such as chromatin condensation and apoptotic nuclei. Reactive oxygen species (ROS) detection assays measured intracellular ROS production; Griess reaction assays assessed nitric oxide (NO) production. Western blotting and quantitative polymerase chain reactions quantified corresponding mRNA and proteins. RESULTS: Subsequent experiments utilized various non-toxic hesperetin concentrations, establishing that hesperetin notably decreased intracellular ROS and NO production in H₂O₂-treated SH-SY5Y cells (P < 0.05). Furthermore, hesperetin inhibited H₂O₂-induced inflammation-related gene expression, including interluekin-6, tumor necrosis factor-α, and nuclear factor kappa B (NF-κB) p65 activation. In addition, hesperetin inhibited NF-κB translocation into H₂O₂-treated SH-SY5Y cell nuclei and suppressed mitogen-activated protein kinase protein expression, an essential apoptotic cell death regulator. Various apoptosis hallmarks, including shrinkage and nuclear condensation in H₂O₂-treated cells, were suppressed dose-dependently. Additionally, hesperetin treatment down-regulated Bax/Bcl-2 expression ratios and activated AMP-activated protein kinase-mammalian target of rapamycin autophagy pathways. CONCLUSION: These results substantiate that hesperetin activates autophagy and inhibits apoptosis and inflammation. Hesperetin is a potentially potent dietary agent that reduces neurodegenerative disease onset, progression, and prevention.

• Journal of Korean Neurosurgical Society
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• 제38권3호
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• pp.215-220
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• 2005

Objective : Many researchers believe that the hypothermia shows neuro-protective effect on brain injury. To understand the molecular mechanism of the hypothermic treatment, this study investigated its effects on the expression of cell death or survival related proteins such as p53, Bcl-2 and Bax in the rat traumatic brain injury[TBI] model. Methods : Twenty rats [Spraque Dawley, $200{\sim}250g$] were subjected to the brain injury of moderate severity [$2.4{\sim}2.6atm$] using the fluid percussion injury device and five rats were received only same surgery as controls. During 30minutes after the brain injury, the hypothermia group was maintained the body temperature around $34^{\circ}C$ while the control group were maintained that of $36^{\circ}C$. Five rats in each group were sacrificed 12h or 24h after brain injury and their brain sections was analyzed for physical damages by H-E stains and the extent of apoptosis by TUNEL assay and immunohistochemical stains. The tissue damage after TBI was mainly observed in the ipsilateral cortex and partly in the hippocampus. Results : Apoptosis was observed by TUNEL assay and the Bax protein was detected in both sample which harvested 12h and 24h after TBI. In the hypothermia treatment group, tissue damage and apoptosis were reduced in HE stains and TUNEL assay. In hypothermia treatment group rat shows more expression of the Bcl-2 protein and shows less expression of the Bax protein, at both 12h and 24h after TBI. Conclusion : These results show that the hypothermia treatment is an effective treatment after TBI, by reducing the apoptotic process. Therefore, it could be suggested that hypothermia has a high therapeutic value for treating tissue damages after TBI.

• 한국식품과학회지
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• 제44권4호
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• pp.428-433
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• 2012

본 연구팀의 선행 연구 결과, L. helveticus IDCC3801의 발효유 주정 침전물이 BACE의 활성 억제를 통한 amyloid beta($A{\beta}$) 생성 저해효과를 갖고 있음을 확인하였다(15). 이러한 결과를 바탕으로 L. helveticus IDCC3801의 발효유 주정 침전물의 산업화를 위한 공정 개선연구를 진행하였고, 대량생산을 통해 LHFM을 확보하였다. 본 연구는 LHFM의 인지기능 개선 기능성 입증 연구로써 $A{\beta}$ 저해효과 외에 신경세포 보호효과 및 기억력 개선 효능을 확인하고 어떠한 작용 기전으로 개선 효과가 나타나는지 조사한 것으로 scopolamine으로 기억 손상을 유발한 mouse에서 학습 능력과 기억력 개선 효과, 신경세포 보호 효과, AChE 저해와 ACh 증가 효과 등을 평가하였다. LHFM은 신경세포 사멸을 유도하는 고농도의 glutamate가 존재하는 환경에서 농도 의존적으로 신경세포의 사멸을 억제하여 신경세포를 보호하였다. 또한 LHFM은 in vitro에서 농도 의존적으로 강력하게 AChE의 활성을 저해하였다. 이러한 in vitro 결과들을 근거로 scopolamine으로 기억 손상을 유발한 mouse에서 Morris water maze와 Y-maze 행동 시험을 통해 LHFM의 학습능력과 기억 개선 효과를 조사하였다. LHFM은 Morris water maze에서 실험 2일째부터 escape latency시간을 유의적으로 감소 시켰으며 5일째에서는 정상 mouse와 동등한 수준으로 감소되어 우수한 학습 효과를 보였다. 실험 6일째 platform을 치운 후 시행한 probe trial에서도 platform이 있던 위치에 머무는 회수가 scopolamine을 단독으로 처리한 것보다 유의적으로 높아 장기기억의 개선에도 효과가 있었다. Y-maze 시험에서도 LHFM은 scopolamine 단독 처리군과 비교하여 뚜렷하게 변경 행동력을 증가시켜 여러 행동 시험을 통해 LHFM의 인지기능 개선 효과를 확인하였다. 행동실험 후 hippocampus를 적출하여 ACh 및 AChE의 활성을 측정한 결과, donepezil과 마찬가지로 LHFM은 AChE의 활성을 유의적으로 억제하였으며 또한 ACh 함량도 증가시켰다. 결론적으로 LHFM은 신경세포 보호 효과와 신경전달물질인 ACh의 뇌 조직 내 농도를 높여 인지기능 개선 효과를 보이는 것을 확인하였다.

• Journal of Ginseng Research
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• 제34권3호
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• pp.246-253
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• 2010

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.

• 생명과학회지
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• 제31권2호
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• pp.237-247
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• 2021

신경염증(neuroinflammation)은 여러 신경 질환의 원인 인자로 확인되고있다. 중추 신경계에 발현되는 단백질 복합체인 NLRP3 인플라마좀은 미생물, 응집되고 잘못 접힌 단백질, ATP와 같은 광범위한 외인성 및 내인성 자극에 의해 감지되고 캐스페이즈-1(capase-1)을 활성화할 수 있다. 활성을 띠는 캐스페이즈-1은 IL-1b와 IL-18과 같은 염증성 사이토카인(pro-inflammatory cytokine)을 활성화시키고 급속한 세포사멸(파이롭토시스, pyroptosis)를 야기한다. IL-1b와 IL-18, 그리고 파이롭토시스를 통해 분비된 DAMPs은 다양한 신호 전달 경로를 통해 신경염증 반응을 유도하여 신경 손상을 유발한다. 따라서 NLRP3 인플라마좀은 신경염증으로 인한 여러 가지 신경질환 발병에 중요한 역할을 할 것으로 여겨진다. 본 리뷰 에서는 NLRP3 인플라마좀의 구조와 활성화에 대해 간략히 알아 보고 다양한 형태의 신경 질환에서 NLRP3 인플라마좀의 역할에 대해 논의하고자 한다.

• 대한한의학회지
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• 제30권3호
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• pp.1-14
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• 2009

Objectives : Alzheimer's disease (AD) is characterized by neuronal loss and extracellular senile plaque. Moreover, the cellular actions of ${\beta}$-amyloid (A${\beta}$ play a causative role in the pathogenesis of AD. This study was designed to determine whether Woo-Gui-Um, a commonly used Korean herbal medicine, has the ability to protect cortical and hippocampal neurons against A${\beta}_{25-35}$ neurotoxicity Methods : In the present study, the authors investigated the preventative effects of the water extract of Woo-Gui-Um in a mouse model of AD. Memory impairment was induced by intraventricularly (i.c.v.) injecting A${\beta}_{25-35}$ peptides into mice. Woo-Gui-Um extract was then administered orally (p.o.) for 14 days. In addition, A${\beta}_{25-35}$ toxicity on the hippocampus was assessed immunohistochemically, by staining for Tau, MAP2, TUNEL, and Bax, and by performing an in vitro study in PC12 cells. Results : Woo-Gui-Um extract had an effect to improve learning ability and memory score in the water maze task. Woo-Gui-Um extract had significant neuroprotective effects in vivo against oxidative damage and apoptotic cell death of hippocampal neurons caused by i.c.v. A${\beta}_{25-35}$. In addition, Woo-Gui-Um extract was found to have a protective effect on A${\beta}_{25-35}$-induced apoptosis, and to promote neurite outgrowth of nerve growth factor (NGF)-differentiated PC12 cells. Conclusions : These results suggest that Woo-Gui-Um extract reduces memory impairment and Alzheimer's dementia via an anti-apoptotic effect and by regulating Tau and MAP2 in the hippocampus.

• Biomolecules & Therapeutics
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• 제22권1호
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• pp.17-26
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• 2014

${\alpha}$-Asarone exhibits a number of pharmacological actions including neuroprotective, anti-oxidative, anticonvulsive, and cognitive enhancing action. The present study investigated the effects of ${\alpha}$-asarone on pro-inflammatory cytokines mRNA, microglial activation, and neuronal damage in the hippocampus and on learning and memory deficits in systemic lipopolysaccharide (LPS)-treated C57BL/6 mice. Varying doses of ${\alpha}$-asarone was orally administered (7.5, 15, or 30 mg/kg) once a day for 3 days before the LPS (3 mg/kg) injection. ${\alpha}$-Asarone significantly reduced TNF-${\alpha}$ and IL-$1{\beta}$ mRNA at 4 and 24 hours after the LPS injection at dose of 30 mg/kg. At 24 hours after the LPS injection, the loss of CA1 neurons, the increase of TUNEL-labeled cells, and the up-regulation of BACE1 expression in the hippocampus were attenuated by 30 mg/kg of ${\alpha}$-asarone treatment. ${\alpha}$-Asarone significantly reduced Iba1 protein expression in the hippocampal tissue at a dose of 30 mg/kg. ${\alpha}$-Asarone did not reduce the number of Iba1-expressing microglia on immunohistochemistry but the average cell size and percentage areas of Iba1-expressing microglia in the hippocampus were significantly decreased by 30 mg/kg of ${\alpha}$-asarone treatment. In the Morris water maze test, ${\alpha}$-asarone significantly prolonged the swimming time spent in the target and peri-target zones. ${\alpha}$-Asarone also significantly increased the number of target heading and memory score in the Morris water maze. The results suggest that inhibition of pro-inflammatory cytokines and microglial activation in the hippocampus by ${\alpha}$-asarone may be one of the mechanisms for the ${\alpha}$-asarone-mediated ameliorating effect on memory deficits.

• 생명과학회지
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• 제26권7호
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• pp.812-818
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• 2016

본 연구는 칼슘 배합 비율에 따른 초석잠이 scopolamine 치매유도 흰쥐의 기억손상 개선효과에 대하여 연구하였다. 칼슘 배합 비율별(S, 1CS, 5CS군)로 군을 나누어 Y자 미로와 수중미로를 통한 행동실험을 실시한 결과, Y자 미로 실험에서 5CS군이 N군과 비교하였을 때 유사한 수치를 보이며 공간 인지기능을 개선시켰고, 수중미로 실험 또한 CS군의 escape latency가 감소하여 N군과 유사한 수치를 보여 기억력 및 학습능력 개선에 효과적이라는 것을 알 수 있었다. 또한 아세틸콜린 함량과 아세틸콜린에스테라제의 활성을 측정한 결과, CS군은 아세틸콜린에스테라제의 활성을 저해함으로써 뇌 조직 내 신경전달물질인 아세틸콜린의 함량을 증가시켜 뇌 신경세포 활성화 효과를 통해 인지기능 개선 효과를 유도할 수 있을 것으로 사료된다. 해마를 병리조직학적으로 관찰한 결과, 앞선 결과와 유사하게 손상 정도가 심하여 많은 수의 응축된 신경세포가 관찰된 C군에 비하여 CS군은 응축된 신경세포 수가 현저하게 감소하여 신경세포 손상을 억제한 것으로 보인다. 따라서 칼슘 배합 비율에 따른 초석잠은 scopolamine 치매유도 흰쥐모델에서 기억력, 학습능력 및 인지능력 개선에 효과적으로 작용하는 천연물 유래 기능성 소재로 이용될 수 있을 것으로 사료된다.

• Biomolecules & Therapeutics
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• 제27권3호
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• pp.327-335
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• 2019

As the elderly population is increasing, Alzheimer's disease (AD) has become a global issue and many clinical trials have been conducted to evaluate treatments for AD. As these clinical trials have been conducted and have failed, the development of new theraphies for AD with fewer adverse effects remains a challenge. In this study, we examined the effects of Theracurmin on cognitive decline using 5XFAD mice, an AD mouse model. Theracurmin is more bioavailable form of curcumin, generated with submicron colloidal dispersion. Mice were treated with Theracurmin (100, 300 and 1,000 mg/kg) for 12 weeks and were subjected to the novel object recognition test and the Barnes maze test. Theracurmin-treated mice showed significant amelioration in recognition and spatial memories compared those of the vehicle-treated controls. In addition, the antioxidant activities of Theracurmin were investigated by measuring the superoxide dismutase (SOD) activity, malondialdehyde (MDA) and glutathione (GSH) levels. The increased MDA level and decreased SOD and GSH levels in the vehicle-treated 5XFAD mice were significantly reversed by the administration of Theracurmin. Moreover, we observed that Theracurmin administration elevated the expression levels of synaptic components, including synaptophysin and post synaptic density protein 95, and decreased the expression levels of ionized calcium-binding adapter molecule 1 (Iba-1), a marker of activated microglia. These results suggest that Theracurmin ameliorates cognitive function by increasing the expression of synaptic components and by preventing neuronal cell damage from oxidative stress or from the activation of microglia. Thus, Theracurmin would be useful for treating the cognitive dysfunctions observed in AD.