Oral Administration of Gintonin Attenuates Cholinergic Impairments by Scopolamine, Amyloid-β Protein, and Mouse Model of Alzheimer's Disease

Kim, Hyeon-Joong,Shin, Eun-Joo,Lee, Byung-Hwan,Choi, Sun-Hye,Jung, Seok-Won,Cho, Ik-Hyun,Hwang, Sung-Hee,Kim, Joon Yong,Han, Jung-Soo,Chung, ChiHye,Jang, Choon-Gon,Rhim, Hyewon,Kim, Hyoung-Chun,Nah, S Korean Society for Molecular and Cellular Biology 2015 Molecules and cells Vol.38 No.9

Gintonin is a novel ginseng-derived lysophosphatidic acid (LPA) receptor ligand. Oral administration of gintonin ameliorates learning and memory dysfunctions in Alzheimer's disease (AD) animal models. The brain cholinergic system plays a key role in cognitive functions. The brains of AD patients show a reduction in acetylcholine concentration caused by cholinergic system impairments. However, little is known about the role of LPA in the cholinergic system. In this study, we used gintonin to investigate the effect of LPA receptor activation on the cholinergic system in vitro and in vivo using wild-type and AD animal models. Gintonin induced $[Ca^{2+}]_i $ transient in cultured mouse hippocampal neural progenitor cells (NPCs). Gintonin-mediated $[Ca^{2+}]_i $ transients were linked to stimulation of acetylcholine release through LPA receptor activation. Oral administration of gintonin-enriched fraction (25, 50, or 100 mg/kg, 3 weeks) significantly attenuated scopolamine-induced memory impairment. Oral administration of gintonin (25 or 50 mg/kg, 1 2 weeks) also significantly attenuated amyloid-${\beta}$ protein ($A{\beta}$)-induced cholinergic dysfunctions, such as decreased acetylcholine concentration, decreased choline acetyltransferase (ChAT) activity and immunoreactivity, and increased acetylcholine esterase (AChE) activity. In a transgenic AD mouse model, long-term oral administration of gintonin (25 or 50 mg/kg, 3 months) also attenuated AD-related cholinergic impairments. In this study, we showed that activation of G protein-coupled LPA receptors by gintonin is coupled to the regulation of cholinergic functions. Furthermore, this study showed that gintonin could be a novel agent for the restoration of cholinergic system damages due to $A{\beta}$ and could be utilized for AD prevention or therapy.

Oral Administration of Gintonin Attenuates Cholinergic Impairments by Scopolamine, Amyloid-β Protein, and Mouse Model of Alzheimer’s Disease

김현중,신은주,이병환,최선혜,정석원,조익현,황성희,김준용,한정수,정지혜,장춘곤,임혜원,김형춘,나승열 한국분자세포생물학회 2015 Molecules and cells Vol.38 No.9

Gintonin is a novel ginseng-derived lysophosphatidic acid (LPA) receptor ligand. Oral administration of gintonin ameliorates learning and memory dysfunctions in Alzheimer’s disease (AD) animal models. The brain cholinergic system plays a key role in cognitive functions. The brains of AD patients show a reduction in acetylcholine concentration caused by cholinergic system impairments. However, little is known about the role of LPA in the cholinergic system. In this study, we used gintonin to investigate the effect of LPA receptor activation on the cholinergic system in vitro and in vivo using wild-type and AD animal models. Gintonin induced [Ca2+]i transient in cultured mouse hippocampal neural progenitor cells (NPCs). Gintonin-mediated [Ca2+]i transients were linked to stimulation of acetylcholine release through LPA receptor activation. Oral administration of gintonin- enriched fraction (25, 50, or 100 mg/kg, 3 weeks) significantly attenuated scopolamine-induced memory impairment. Oral administration of gintonin (25 or 50 mg/kg, 1 2 weeks) also significantly attenuated amyloid-β protein (Aβ)-induced cholinergic dysfunctions, such as decreased acetylcholine concentration, decreased choline acetyltran-

Neuroimmune interactions and kidney disease

Sho Hasegawa,Tsuyoshi Inoue,Reiko Inagi 대한신장학회 2019 Kidney Research and Clinical Practice Vol.38 No.3

The autonomic nervous system plays critical roles in maintaining homeostasis in humans, directly regulating inflammation by altering the activity of the immune system. The cholinergic anti-inflammatory pathway is a wellstudied neuroimmune interaction involving the vagus nerve. CD4-positive T cells expressing β2 adrenergic receptors and macrophages expressing the alpha 7 subunit of the nicotinic acetylcholine receptor in the spleen receive neurotransmitters such as norepinephrine and acetylcholine and are key mediators of the cholinergic antiinflammatory pathway. Recent studies have demonstrated that vagus nerve stimulation, ultrasound, and restraint stress elicit protective effects against renal ischemia-reperfusion injury. These protective effects are induced primarily via activation of the cholinergic anti-inflammatory pathway. In addition to these immunological roles, nervous systems are directly related to homeostasis of renal physiology. Whole-kidney three-dimensional visualization using the tissue clearing technique CUBIC (clear, unobstructed brain/body imaging cocktails and computational analysis) has illustrated that renal sympathetic nerves are primarily distributed around arteries in the kidneys and denervated after ischemia-reperfusion injury. In contrast, artificial renal sympathetic denervation has a protective effect against kidney disease progression in murine models. Further studies are needed to elucidate how neural networks are involved in progression of kidney disease.

Scientific review of the aesthetic uses of botulinum toxin type A

박미영,안기영 대한두개안면성형외과학회 2021 Archives of Craniofacial Surgery Vol.22 No.1

Botulinum toxin type A (BoNT-A), onabotulinumtoxinA (Botox) was approved by the United States Food and Drug Administration for temporary improvement of glabellar lines in patients 65 years and younger in 2002, and has also been used widely for aesthetic purposes such as hyperhidrosis, body shape contouring, and other noninvasive facial procedures. BoNT-A inhibits presynaptic exocytosis of acetylcholine (ACh)-containing vesicles into the neuromuscular junction at cholinergic nerve endings of the peripheral nervous system, thereby paralyzing skeletal muscles. ACh is the most broadly used neurotransmitter in the somatic nervous system, preganglionic and postganglionic fibers of parasympathetic nerves, and preganglionic fibers or postganglionic sudomotor nerves of sympathetic nerves. The scientific basis for using BoNT-A in various cosmetic procedures is that its function goes beyond the dual role of muscle paralysis and neuromodulation by inhibiting the secretion of ACh. Although the major target organs for aesthetic procedures are facial expression muscles, skeletal body muscles, salivary glands, and sweat glands, which are innervated by the somatic or autonomic nerves of the peripheral cholinergic nerve system, few studies have attempted to directly explain the anatomy of the areas targeted for injection by addressing the neural physiology and rationale for specific aesthetic applications of BoNT-A therapy. In this article, we classify the various cosmetic uses of BoNT-A according to the relevant component of the peripheral nervous system, and describe scientific theories regarding the anatomy and physiology of the cholinergic nervous system. We also review critical physiological factors and conditions influencing the efficacy of BoNT-A for the rational aesthetic use of BoNT-A. We hope that this comprehensive review helps promote management policies to support long-term, safe, successful practice. Furthermore, based on this, we look forward to developing and expanding new advanced indications for the aesthetic use of BoNT-A in the future.

The memory-enhancing effects of 7,8,4’-trihydroxyisoflavone, a major metabolite of daidzein, are associated with activation of the cholinergic system and BDNF signaling pathway in mice

Ko, Yong-Hyun,Kwon, Seung-Hwan,Ma, Shi-Xun,Seo, Jee-Yeon,Lee, Bo-Ram,Kim, Kyungin,Kim, Sun Yeou,Lee, Seok-Yong,Jang, Choon-Gon Elsevier 2018 Brain research bulletin Vol.142 No.-

<P><B>Abstract</B></P> <P>Daidzein is one of the dietary isoflavones present in soybean-based products. After ingestion, daidzein is bioconverted into its major metabolite, 7,8,4’-trihydroxyisoflavone (THIF). Given the pharmacological importance of daidzein, 7,8,4’-THIF has also attracted the interest of researchers. However, there are no reports on the effects of 7,8,4’-THIF on cognition and memory with regard to the cholinergic system. Therefore, this study sought to evaluate the memory-enhancing effects of 7,8,4’-THIF in mice. Treatment with 7,8,4’-THIF ameliorated the cognitive impairments induced by scopolamine, a muscarinic acetylcholine receptor antagonist, in the Y-maze and passive avoidance tests. Interestingly, 7,8,4’-THIF treatment also improved cognitive function in normal mice. This treatment was also able to reverse acetylcholinesterase (AChE) and thiobarbituric acid reactive substance (TBARS) activities in the hippocampus. Finally, 7,8,4’-THIF significantly increased the expression levels of the following molecules in the hippocampus: brain-derived neurotrophic factor (BDNF); phospho extracellular signal-regulated kinase (ERK); phospho cAMP response element binding (CREB); and choline acetyltransferase (ChAT). Our data suggest that 7,8,4’-THIF, a metabolized product of daidzein, improves cognitive function by activating the cholinergic system and the BDNF/ERK/CREB signaling pathway in mice.</P> <P><B>Highlights</B></P> <P> <UL> <LI> 7,8,4’-Trihydroxyisoflavone (THIF) improved cognitive and memory function in mice. </LI> <LI> 7,8,4’-THIF restored the hippocampal cholinergic dysfunction and oxidative damage. </LI> <LI> 7,8,4’-THIF enhanced BDNF signaling pathway in the hippocampus of mice. </LI> </UL> </P>

Insulin Preferentially Regulates the Activity of Parasympathetic Preganglionic Neurons over Sympathetic Preganglionic Neurons

손종우,Uisu Hyun,권윤영 대한내분비학회 2023 Endocrinology and metabolism Vol.38 No.5

Background: Insulin is a peptide hormone that regulates post-prandial physiology, and it is well known that insulin controls homeostasis at least in part via the central nervous system. In particular, insulin alters the activity of neurons within the autonomic nervous system. However, currently available data are mostly from unidentified brainstem neurons of the dorsal motor nucleus of the vagus nerve (DMV). Methods: In this study, we used several genetically engineered mouse models to label distinct populations of neurons within the brainstem and the spinal cord for whole-cell patch clamp recordings and to assess several in vivo metabolic functions. Results: We first confirmed that insulin directly inhibited cholinergic (parasympathetic preganglionic) neurons in the DMV. We also found inhibitory effects of insulin on both the excitatory and inhibitory postsynaptic currents recorded in DMV cholinergic neurons. In addition, GABAergic neurons of the DMV and nucleus tractus solitarius were inhibited by insulin. However, insulin had no effects on the cholinergic sympathetic preganglionic neurons of the spinal cord. Finally, we obtained results suggesting that the insulininduced inhibition of parasympathetic preganglionic neurons may not play a critical role in the regulation of glucose homeostasis and gastrointestinal motility. Conclusion: Our results demonstrate that insulin inhibits parasympathetic neuronal circuitry in the brainstem, while not affecting sympathetic neuronal activity in the spinal cord.

The Aqueous Extract of Humulus japonicus Ameliorates Cognitive Dysfunction in Alzheimer's Disease Models via Modulating the Cholinergic System

Chang Muk Kang,Joon Seok Bang,Seung Yeon Park,Tae Woo Jung,Hyoung-Chun Kim,Yoon Hee Chung,Ji Hoon Jeong 한국식품영양과학회 2022 Journal of medicinal food Vol.25 No.10

Humulus japonicus (HJ) is an herbal medicine, which has been reported as being antioxidative and anti-inflammatory. The present study aimed to investigate the effect of oral administration of HJ water extract (HJW) on cognitive function through the cholinergic system in Alzheimer's disease (AD) mouse models. Institute of Cancer Research mice injected with beta-amyloid (Aβ) (1-42) (i.c.v.) and APP/PS1 transgenic (TG) mice were orally administered with HJW at 500 mg/kg/day for 3 weeks. Aβ-injected mice and APP/PS1 TG mice showed cognitive dysfunction, which was evaluated by various behavioral tests. HJW treatment significantly attenuated memory impairments in Aβ-injected mice and APP/PS1 TG mice. Aβ injection decreased acetylcholine (ACh) concentrations and choline acetyltransferase (ChAT) activity, and increased acetylcholinesterase (AChE) activity. These cholinergic impairments were also found in APP/PS1 TG mice. HJW significantly attenuated cholinergic alterations in Aβ-injected mice and TG mice. In addition, HJW significantly decreased Aβ plaque deposition in the cerebral cortex and hippocampus of TG mice. Therefore, the present study demonstrated that HJW protected against AD-related memory impairments via enhancing the cholinergic system and inhibiting Aβ plaque deposition.

Korean Red Pine (Pinus densiflora) Bark Extract Attenuates Aβ-Induced Cognitive Impairment by Regulating Cholinergic Dysfunction and Neuroinflammation

Go Min Ji,Kim Jong Min,Kang Jin Yong,Park Seon Kyeong,Lee Chang Jun,Kim Min Ji,Lee Hyo Rim,Kim Tae Yoon,Joo Seung Gyum,김대옥,허호진 한국미생물·생명공학회 2022 Journal of microbiology and biotechnology Vol.32 No.9

In this study, we investigated the anti-amnesic effect of Korean red pine (Pinus densiflora) bark extract (KRPBE) against amyloid beta1-42 (Aβ1-42)-induced neurotoxicity. We found that treatment with KRPBE improved the behavioral function in Aβ-induced mice, and also boosted the antioxidant system in mice by decreasing malondialdehyde (MDA) content, increasing superoxide dismutase (SOD) activities, and reducing glutathione (GSH) levels. In addition, KRPBE improved the cholinergic system by suppressing reduced acetylcholine (ACh) content while also activating acetylcholinesterase (AChE), regulating the expression of choline acetyltransferase (ChAT), postsynaptic density protein-95 (PSD-95), and synaptophysin. KRPBE also showed an ameliorating effect on cerebral mitochondrial deficit by regulating reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and ATP levels. Moreover, KRPBE modulated the expression levels of neurotoxicity indicators Aβ and phosphorylated tau (p-tau) and inflammatory cytokines TNF-α, p- IκB-α, and IL-1β. Furthermore, we found that KRPBE improved the expression levels of neuronal apoptosis-related markers BAX and BCl-2 and increased the expression levels of BDNF and p-CREB. Therefore, this study suggests that KRPBE treatment has an anti-amnestic effect by modulating cholinergic system dysfunction and neuroinflammation in Aβ1-42-induced cognitive impairment in mice.

Protein Hydrolysate of Silkworm Pupa Prevents Memory Impairment Induced by Oxidative Stress in Scopolamine-Induced Mice via Modulating the Cholinergic Nervous System and Antioxidant Defense System

Seung Yeon Baek,Fu Yi Li,Jong Hoon Kim,Changwon Ahn,Hun Jung Kim,Mee Ree Kim 한국식품영양과학회 2020 Preventive Nutrition and Food Science Vol.25 No.4

Silkworm pupae (Bombyx mori) is an edible insect that has been reported to contain high-quality proteins, lipids, minerals, and vitamins, and to possess high antioxidant activity. However, there have been no studies on the neuroprotective effects of silkworm pupae. Therefore, we investigated a water extract of silkworm pupae with protease (WSP) as a functional and therapeutic candidate for neurodegenerative disorders. First, we evaluated the effect of WSP on oxidative stress-induced mouse hippocampal neuronal cells (HT-22 cells). Cell viability diminished by addition of glutamate but was significantly recovered by WSP treatment. Furthermore, WSP significantly decreased the release of lactate dehydrogenase and generation of intracellular reactive oxygen species in oxidative stress-induced cells. In addition, in scopolamine-treated mice, WSP attenuated memory impairment, as demonstrated in the Morris water maze and passive avoidance tests, indicating protection of neuronal cells against oxidative damage. Moreover, WSP prevented scopolamine-induced increases in acetylcholinesterase activity and decreases in choline-acetyltransferase activity. Finally, treatment with WSP enhanced the antioxidant defense system by regulating the activities of antioxidant enzymes. Overall, this study showed that WSP exerted antioxidant and memory enhancing action against oxidative stress.

스코폴아민을 이용한 치매 동물 모델 연구

윤은정,최윤서,박동선 한국교원대학교 뇌기반교육연구소 2022 Brain, Digital, & Learning Vol.12 No.1

This study aimed to determine dose of scopolamine to induce cognitive and memory dysfunction in rat. Six-week-old male rats (n=20) were randomly divided four groups. Scopolamine bromide (0, 0.5, 1.0 and 2.0 mg/kg) was intraperitoneally injected for 7 days. From 4-7 days after injection, the rats were performed memory test by water maze and passive avoidance test. On the 8th day, the rats were sacrificed, then acetylcholinesterase (AChE) activity, cholinergic proteins and inflammatory mediators were analyzed from their brain tissue. In the memory test and AChE activity, the group of scopolamine treatment (0.5 mg/kg) showed no significant difference compared to the control group (0 mg/kg). But, they showed significant differences compared to the control group in expression of choline transporter, choline acetyltransferase, and vesicular acetylcholine transporter protein and nuclear factor kappa B, tumor necrosis factor-α, interLeukin-6, inducible nitric oxide synthase, and cyclooxygenase2 mRNA. Also, the groups of scopolamine treatment (1.0 and 2.0 mg/kg) showed significant differences compared to the control group in memory test, AChE activity, expression of cholinergic proteins and inflammatory mediators mRNA. Therefore, it was suggested that 1.0 mg/kg of scopolamine is adequate dose to induce cognitive and memory dysfunction in rats.