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List of Papers
Risako Fujikawa Last modified date：2023.11.28

Assistant Professor / Molecular and System Pharmacology / Department of Pharmaceutical Health Care and Sciences / Faculty of Pharmaceutical Sciences


Papers
1. Risako Fujikawa, Makoto Tsuda, The Functions and Phenotypes of Microglia in Alzheimer’s Disease, Cells, 2023.04, [URL].
2. Risako Fujikawa, Jun Yamada, Kyoko M.Iinuma, Shozo Jinno, Phytoestrogen genistein modulates neuron–microglia signaling in a mouse model of chronic social defeat stress, Neuropharmacology, 2022.03.
3. Risako Fujikawa, Shozo Jinno, Identification of hyper-ramified microglia in the CA1 region of the mouse hippocampus potentially associated with stress resilience, European Journal of Neuroscience, 10.1111/ejn.15812, 2022.10, [URL].
4. , [URL].
5. Risako Fujikawa, Jun Yamada, Shozo Jinno, Subclass imbalance of parvalbumin-expressing neurons in the hippocampus of a mouse ketamine model for schizophrenia, with reference to perineuronal nets , Schizophrenia Research, 2021.03.
6. Nogami-Hara Ai , Kubota Kaori, Takasaki Kotaro, Watanabe Takuya, Iba Hikari, Fujikawa Risako, Katsurabayashi Shutaro, Iwasaki Katsunori, Kubota Kaori, Watanabe Takuya, Iwasaki Katsunori, Egahira Nobuaki, Bolukbasi Hatip Funda, Hatip-Al-Khatib Izzettin , Extract of Yokukansan improves anxiety-like behavior and increases serum brain-derived neurotrophic factor in rats with cerebral ischemiacombinedwithamyloid-β42peptide, J Tradit Chin Med , 2019.02.
7. Ikedo T, Kataoka H, Minami M, Hayashi K, Miyata T, Nagata M, Fujikawa R, Yokode M, Imai H, Matsuda T, Miyamoto S, Sequential Inward Bending of Arterial Bifurcations is Associated with Intracranial Aneurysm Formation, World Neurosurgery , 2019.06.
8. , [URL].
9. Kotaro Takasaki, Kanako Uchida, Risako Fujikawa, Ai Nogami, Kazuya Nakamura, Chihiro Kawasaki, Kazuko Yamaguchi, Masahiko Morita, Koji Morishita, Kaori Kubota, Shutaro Katsurabayashi, Kenichi Mishima, Michihiro Fujiwara, Katsunori Iwasaki, Neuroprotective effects of citidine-5-diphosphocholine on impaired spatial memory in a rat model of cerebrovascular dementia, Journal of Pharmacological Sciences, 10.1254/jphs.11013FP, 116, 2, 232-237, 2011.06, Citidine-5-diphosphocholine or citicoline (CDP-choline) is used as a neuroprotective and memory-enhancing drug in cerebral stroke, Alzheimer's disease, and other neurovascular diseases. Non-clinical studies have demonstrated the neuroprotective effects of CDP-choline in ischemic animal models. However, the relationship between the neuroprotective effect and the memory enhancing effect of CDP-choline is still unknown. No studies have demonstrated the ameliorative effect on impaired spatial memory and the suppressive effect on neuronal cell death of CDP-choline in the same model. In this study, we examined the effect of CDP-choline on impaired spatial memory and hippocampal CA1 neuronal death in rats subjected to repeated cerebral ischemia, and we compared the mechanism of CDP-choline to that of donepezil. Seven days post administration of CDP-choline (100, 300, 1000 mg/kg per day, p.o.) or donepezil increased correct choices and reduced error choices in an eight-arm radial maze task in a dose-dependent manner. Neuronal cell death of caspase-3 protein-positive neurons in the hippocampus were reduced by repeated administration of CDP-choline at the highest dose. These results suggest that CDP-choline has ameliorative effects on the impairment of spatial memory via hippocampal neuronal cell death in a rat model of cerebral ischemia..
10. A. Nogami, Kotaro Takasaki, Kaori Kubota, Kazuko Yamaguchi, Chihiro Kawasaki, Kazuya Nakamura, Risako Fujikawa, Naoki Uchida, Shutaro Katsurabayashi, Kenichi Mishima, Ryoji Nishimura, Michihiro Fujiwara, Katsunori Iwasaki, Effect of yokukansan on memory disturbance in an animal model of cerebrovascular dementia, Journal of Traditional Medicines, 10.11339/jtm.30.164, 30, 4, 164-175, 2013.01, Yokukansan (YKS) is a traditional Japanese herbal medicine, which was reported to improve the behavioral and psychological symptoms of dementia (BPSD). However, the effect of YKS on memory dysfunction remains unknown. In this study, we examined the effect of YKS on impaired spatial memory in rats subjected to repeated cerebral ischemia, a well-established animal model for cerebrovascular dementia. Additionally, we compared the effect of YKS and donepezil (DPZ) on cholinergic dysfunction and hippocampal CA1 neuronal death in rats subjected to repeated cerebral ischemia. Spatial memory, as assessed using the eight-arm radial maze task, was impaired by repeated cerebral ischemia and significantly improved following administration of YKS (100, 300, 1000 mg/kg per day, p.o. for 14 days before and after ischemia treatment. Furthermore, a significant improvement was observed following additional 7-day treatment with YKS (1000 mg/kg per day, p.o.) after ischemia. YKS treatment was comparable to DPZ (10 mg/kg per day, p.o.) after ischemia. Microdialysis studies showed that spontaneous release of acetylcholine (ACh) from the dorsal hippocampus was significantly reduced following repeated cerebral ischemia. However, treatment with YKS or DPZ increased spontaneous ACh release following repeated cerebral ischemia. In contrast, hippocampal apoptosis, which developed after repeated ischemia, was suppressed by YKS, but not by DPZ. Overall, we found that YKS improves spatial memory disturbance via its unique character of having both an increasing effect on ACh release and a neuroprotective effect, which will be useful not only for BPSD but also memory dysfunction in cerebrovascular dementia patients..
11. Masato Nakatsuji, Manabu Minami, Hiroshi Seno, Mika Yasui, Hideyuki Komekado, Sei Higuchi, Risako Fujikawa, Yuki Nakanishi, Akihisa Fukuda, Kenji Kawada, Yoshiharu Sakai, Toru Kita, Peter Libby, Hiroki Ikeuchi, Masayuki Yokode, Tsutomu Chiba, EP4 Receptor–Associated Protein in Macrophages Ameliorates Colitis and Colitis-Associated Tumorigenesis, PLoS Genetics, 10.1371/journal.pgen.1005542, 11, 10, 2015.01, Prostaglandin E2 plays important roles in the maintenance of colonic homeostasis. The recently identified prostaglandin E receptor (EP) 4–associated protein (EPRAP) is essential for an anti-inflammatory function of EP4 signaling in macrophages in vitro. To investigate the in vivo roles of EPRAP, we examined the effects of EPRAP on colitis and colitis-associated tumorigenesis. In mice, EPRAP deficiency exacerbated colitis induced by dextran sodium sulfate (DSS) treatment. Wild-type (WT) or EPRAP-deficient recipients transplanted with EPRAP-deficient bone marrow developed more severe DSS-induced colitis than WT or EPRAP-deficient recipients of WT bone marrow. In the context of colitis-associated tumorigenesis, both systemic EPRAP null mutation and EPRAP-deficiency in the bone marrow enhanced intestinal polyp formation induced by azoxymethane (AOM)/DSS treatment. Administration of an EP4-selective agonist, ONO-AE1-329, ameliorated DSS-induced colitis in WT, but not in EPRAP-deficient mice. EPRAP deficiency increased the levels of the phosphorylated forms of p105, MEK, and ERK, resulting in activation of stromal macrophages in DSS-induced colitis. Macrophages of DSS-treated EPRAP-deficient mice exhibited a marked increase in the expression of pro-inflammatory genes, relative to WT mice. By contrast, forced expression of EPRAP in macrophages ameliorated DSS-induced colitis and AOM/DSS-induced intestinal polyp formation. These data suggest that EPRAP in macrophages functions crucially in suppressing colonic inflammation. Consistently, EPRAP-positive macrophages were also accumulated in the colonic stroma of ulcerative colitis patients. Thus, EPRAP may be a potential therapeutic target for inflammatory bowel disease and associated intestinal tumorigenesis..
12. Mika Yasui, Yukinori Tamura, Manabu Minami, Sei Higuchi, Risako Fujikawa, Taichi Ikedo, Manabu Nagata, Hidenori Arai, Toshinori Murayama, Masayuki Yokode, The prostaglandin E2 receptor EP4 regulates obesity-related inflammation and insulin sensitivity, PLoS One, 10.1371/journal.pone.0136304, 10, 8, 2015.08, With increasing body weight, macrophages accumulate in adipose tissue. There, activated macrophages secrete numerous proinflammatory cytokines and chemokines, giving rise to chronic inflammation and insulin resistance. Prostaglandin E2 suppresses macrophage activation via EP4; however, the role of EP4 signaling in insulin resistance and type 2 diabetes mellitus remains unknown. In this study, we treated db/db mice with an EP4-selective agonist, ONO-AE1-329, for 4 weeks to explore the role of EP4 signaling in obesity-related inflammation in vivo. Administration of the EP4 agonist did not affect body weight gain or food intake; however, in the EP4 agonist-treated group, glucose tolerance and insulin resistance were significantly improved over that of the vehicle-treated group. Additionally, administration of the EP4 agonist inhibited the accumulation of F4/80-positive macrophages and the formation of crown-like structures in white adipose tissue, and the adipocytes were significantly smaller. The treatment of the EP4 agonist increased the number of anti-inflammatory M2 macrophages, and in the stromal vascular fraction of white adipose tissue, which includes macrophages, it markedly decreased the levels of proinflammatory cytokines and chemokines. Further, EP4 activation increased the expression of adiponectin and peroxidase proliferator-activated receptors in white adipose tissue. Next, we examined in vitro M1/M2 polarization assay to investigate the impact of EP4 signaling on determining the functional phenotypes of macrophages. Treatment with EP4 agonist enhanced M2 polarization in wild-type peritoneal macrophages, whereas EP4-deficient macrophages were less susceptible to M2 polarization. Notably, antagonizing peroxidase proliferator-activated receptor δ activity suppressed EP4 signaling-mediated shift toward M2 macrophage polarization. Thus, our results demonstrate that EP4 signaling plays a critical role in obesity-related adipose tissue inflammation and insulin resistance by regulating macrophage recruitment and polarization. The activation of EP4 signaling holds promise for treating obesity and type 2 diabetes mellitus..
13. Ryu Fukumitsu, Manabu Minami, Kazumichi Yoshida, Manabu Nagata, Mika Yasui, Sei Higuchi, Risako Fujikawa, Taichi Ikedo, Sen Yamagata, Yasufumi Sato, Hidenori Arai, Masayuki Yokode, Susumu Miyamoto, Expression of vasohibin-1 in human carotid atherosclerotic plaque, Journal of Atherosclerosis and Thrombosis, 10.5551/jat.29074, 22, 9, 942-948, 2015.09, Aim: In patients with carotid plaque, intraplaque hemorrhage arising from ruptured neovascular vessels within the neointima is an important cause of stroke. The expression of Vasohibin-1 (VASH1), a negative feedback regulator of angiogenesis, occurs in the microvessel endothelial cells of various solid tumors and the arterial wall. However, the roles of VASH1 in the pathogenesis of atherosclerotic diseases remain unclear. The present study aimed to clarify the relevance of the VASH1 expression and plaque instability in human carotid plaques. Methods: We used quantitative real-time PCR and immunostaining to examine 12 atheromatous plaque specimens obtained via carotid endarterectomy. The distal areas of specimens lacking macroscopic atherosclerotic lesions served as controls. Results: Compared with that observed in the controls, the VASH1 gene expression increased significantly in the atheromatous plaque (p=0.018). Moreover, the VASH1 mRNA levels correlated positively with those of VEGFA, CD31 and VCAM1 (r =0.788, p=0.004; r =0.99, p＜0.001; r =0.94, p＜ 0.001, respectively). Finally, the immunohistochemical analyses revealed the VASH1 expression in the neointimal microvessel endothelial cells of carotid plaque. Conclusions: The VASH1 expression levels in atheroma reflect both enhanced neovascularization and the inflammatory burden. Therefore, the VASH1 level may be a novel biomarker for evaluating plaque instability in patients with carotid arteriosclerosis and predicting ischemic stroke..
14. Risako Fujikawa, Sei Higuchi, Masato Nakatsuji, Mika Yasui, Taichi Ikedo, Manabu Nagata, Masayuki Yokode, Manabu Minami, EP4 Receptor-Associated Protein in Microglia Promotes Inflammation in the Brain, American Journal of Pathology, 10.1016/j.ajpath.2016.04.002, 186, 8, 1982-1988, 2016.08, Microglial cells play a key role in neuronal damage in neurodegenerative disorders. Overactivated microglia induce detrimental neurotoxic effects through the excess production of proinflammatory cytokines. However, the mechanisms of microglial activation are poorly understood. We focused on prostaglandin E2 type 4 receptor-associated protein (EPRAP), which suppresses macrophage activation. We demonstrated that EPRAP exists in microglia in the brain. Furthermore, EPRAP-deficient mice displayed less microglial accumulation, and intraperitoneal administration of lipopolysaccharide (LPS) led to reduced expression of tumor necrosis factor-α and monocyte chemoattractant protein-1 mRNA in the brains of EPRAP-deficient mice. Consistently, EPRAP-deficient microglia showed a marked decrease in the production of tumor necrosis factor-α and monocyte chemoattractant protein-1 induced by LPS treatment compared with wild-type controls. In addition, EPRAP deficiency decreased microglial activation and neuronal cell death induced by intraventricular injection of kainic acid. EPRAP deficiency impaired the LPS-induced phosphorylation of c-jun N-terminal kinase and p38 mitogen-activated protein kinase in microglia. The phosphorylation levels of mitogen-activated protein kinase kinase 4—which phosphorylates c-jun N-terminal kinase and p38 mitogen-activated protein kinase—were also decreased in EPRAP-deficient microglia after LPS stimulation. Although EPRAP in macrophages plays a role in the attenuation of inflammation, EPRAP promotes proinflammatory activation of microglia through mitogen-activated protein kinase kinase 4-mediated signaling and may be key to the deteriorating neuronal damage brought on by brain inflammation..
15. Sei Higuchi, Risako Fujikawa, Taichi Ikedo, Kosuke Hayashi, Mika Yasui, Manabu Nagata, Masato Nakatsuji, Masayuki Yokode, Manabu Minami, EP4 receptor-associated protein in macrophages protects against bleomycin-induced pulmonary inflammation in mice, Journal of Immunology, 10.4049/jimmunol.1502618, 197, 11, 4436-4443, 2016.12, Excessive activation of inflammatory macrophages drives the pathogenesis of many chronic diseases. EP4 receptor-associated protein (EPRAP) has been identified as a novel, anti-inflammatory molecule in macrophages. In this study, we investigated the role of EPRAP using a murine model of bleomycin (BLM)-induced pulmonary inflammation. When compared with wild-type mice, EPRAP-deficient mice exhibited significantly higher mortality, and increased accumulation of macrophages and proinflammatory molecules in the lung 7 d post-BLM administration. Accordingly, the levels of phosphorylated p105, MEK1/2, and ERK1/2 were elevated in EPRAP-deficient alveolar macrophages following BLM administration. In contrast, macrophage-specific EPRAP overexpression decreased the production of proinflammatory cytokines and chemokines, suggesting that EPRAP in macrophages plays a key role in attenuating BLM-induced pulmonary inflammation. As EPRAP is phosphorylated after translation, we examined the role of posttranslational modifications in cellular inflammatory activation using mouse embryo fibroblasts (MEFs) expressing mutant EPRAP proteins. Expression of mutant EPRAP, in which serine-108 and serine-608 were replaced with alanine (EPRAP S108A/S608A), markedly suppressed TNF-a production in LPS-treated MEFs. Conversely, the serine phosphatase 2A (PP2A) inhibitor, cantharidic acid, increased LPS-induced TNF-α production in MEFs expressing wild-type EPRAP, but not in MEFs expressing EPRAP S108A/S608A. Immunoprecipitation analyses demonstrated that EPRAP associated with PP2A in both MEFs and alveolar macrophages from BLM-treated mice. Our data suggest that PP2A dephosphorylates EPRAP, which may be a crucial step in exertion of its anti-inflammatory properties. For these reasons, we believe the EPRAP-PP2A axis in macrophages holds the key to treating chronic inflammatory disorders..
16. Risako Fujikawa, Sei Higuchi, Masato Nakatsuji, Mika Yasui, Masayuki Yokode, Manabu Minami, EPRAP
A key regulator of inflammation, Folia Pharmacologica Japonica, 10.1254/fpj.150.114, 150, 2, 114-115, 2017.01.
17. Risako Fujikawa, Sei Higuchi, Taichi Ikedo, Manabu Nagata, Kosuke Hayashi, Tao Yang, Takeshi Miyata, Masayuki Yokode, Manabu Minami, Behavioral abnormalities and reduced norepinephrine in EP4 receptor-associated protein (EPRAP)-deficient mice, Biochemical and Biophysical Research Communications, 10.1016/j.bbrc.2017.03.095, 486, 2, 584-588, 2017.04, EP4 receptor-associated protein (EPRAP) is a newly identified molecule that regulates macrophage activation. We recently demonstrated the presence of EPRAP in the mice brain; however, little is known about the function of EPRAP in this tissue. Therefore, we investigated the role of EPRAP in behavior and emotion using behavioral analysis in mice. In this study, we subjected EPRAP-deficient (KO) mice and wild-type C57BL/6 (WT) mice to a battery of behavioral tests. EPRAP-KO mice tended to have shorter latencies to fall in the wire hang test, but had normal neuromuscular strength. EPRAP-KO mice exhibited elevated startle responses and reduced pre-pulse inhibition. Compared with WT mice, EPRAP-KO mice increased depression-like behavior in the forced swim test. These abnormal behaviors partially mimic symptoms of depression, attention deficit hyperactivity disorder (ADHD) and schizophrenia. Methylphenidate administration increased locomotor activity less in EPRAP-KO mice than in WT mice. Finally, levels of norepinephrine were reduced in the EPRAP-KO mouse brain. These behavioral abnormalities in EPRAP-KO mice may result from the dysfunction of monoamines, in particular, norepinephrine. Our results suggest that EPRAP participates in the pathogenesis of various behavioral disorders..
18. Taichi Ikedo, Manabu Minami, Hiroharu Kataoka, Kosuke Hayashi, Manabu Nagata, Risako Fujikawa, Sei Higuchi, Mika Yasui, Tomohiro Aoki, Miyuki Fukuda, Masayuki Yokode, Susumu Miyamoto, Dipeptidyl Peptidase-4 Inhibitor Anagliptin Prevents Intracranial Aneurysm Growth by Suppressing Macrophage Infiltration and Activation, Journal of the American Heart Association, 10.1161/JAHA.116.004777, 6, 6, 2017.06, BACKGROUND: Chronic inflammation plays a key role in the pathogenesis of intracranial aneurysms (IAs). DPP-4 (dipeptidyl peptidase-4) inhibitors have anti-inflammatory effects, including suppressing macrophage infiltration, in various inflammatory models. We examined whether a DPP-4 inhibitor, anagliptin, could suppress the growth of IAs in a rodent aneurysm model.
METHODS AND RESULTS: IAs were surgically induced in 7-week-old male Sprague Dawley rats, followed by oral administration of 300 mg/kg anagliptin. We measured the morphologic parameters of aneurysms over time and their local inflammatory responses. To investigate the molecular mechanisms, we used lipopolysaccharide-treated RAW264.7 macrophages. In the anagliptin-treated group, aneurysms were significantly smaller 2 to 4 weeks after IA induction. Anagliptin inhibited the accumulation of macrophages in IAs, reduced the expression of MCP-1 (monocyte chemotactic protein 1), and suppressed the phosphorylation of p65. In lipopolysaccharide-stimulated RAW264.7 cells, anagliptin treatment significantly reduced the production of tumor necrosis factor α, MCP-1, and IL-6 (interleukin 6) independent of GLP-1 (glucagon-like peptide 1), the key mediator in the antidiabetic effects of DPP-4 inhibitors. Notably, anagliptin activated ERK5 (extracellular signal-regulated kinase 5), which mediates the anti-inflammatory effects of statins, in RAW264.7 macrophages. Preadministration with an ERK5 inhibitor blocked the inhibitory effect of anagliptin on MCP-1 and IL-6 expression. Accordingly, the ERK5 inhibitor also counteracted the suppression of p65 phosphorylation in vitro.
CONCLUSIONS: A DPP-4 inhibitor, anagliptin, prevents the growth of IAs via its anti-inflammatory effects on macrophages..
19. Risako Fujikawa, Sei Higuchi, Masato Nakatsuji, Mika Yasui, Taichi Ikedo, Manabu Nagata, Kosuke Hayashi, Masayuki Yokode, Manabu Minami, Deficiency in EP4 Receptor–Associated Protein Ameliorates Abnormal Anxiety-Like Behavior and Brain Inflammation in a Mouse Model of Alzheimer Disease, American Journal of Pathology, 10.1016/j.ajpath.2017.04.010, 187, 8, 1848-1854, 2017.08, Microglia are thought to play key roles in the progression of Alzheimer disease (AD). Overactivated microglia produce proinflammatory cytokines, such as tumor necrosis factor-α, which appear to contribute to disease progression. Previously, we reported that prostaglandin E2 type 4 receptor–associated protein (EPRAP) promotes microglial activation. We crossed human amyloid precursor protein transgenic mice from strain J20+/− onto an EPRAP-deficient background to determine the role of EPRAP in AD. Behavioral tests were performed in 5-month-old male J20+/−EPRAP+/+ and J20+/−EPRAP−/− mice. EPRAP deficiency reversed the reduced anxiety of J20+/− mice but did not affect hyperactivity. No differences in spatial memory were observed between J20+/−EPRAP+/+ and J20+/−EPRAP−/− mice. In comparison with J20+/−EPRAP+/+, J20+/−EPRAP−/− mice exhibited less microglial accumulation and reductions in the Cd68 and tumor necrosis factor-α mRNAs in the prefrontal cortex and hippocampus. No significant differences were found between the two types of mice in the amount of amyloid-β 40 or 42 in the cortex and hippocampus. J20+/−EPRAP−/− mice reversed the reduced anxiety-like behavior and had reduced microglial activation compared with J20+/−EPRAP+/+ mice. Further research is required to identify the role of EPRAP in AD, but our results indicate that EPRAP may be related to behavioral and psychological symptoms of dementia and inflammation in patients with AD..
20. Taichi Ikedo, Manabu Minami, Hiroharu Kataoka, Kosuke Hayashi, Manabu Nagata, Risako Fujikawa, Fumiyoshi Yamazaki, Mitsutoshi Setou, Masayuki Yokode, Susumu Miyamoto, Imaging mass spectroscopy delineates the thinned and thickened walls of intracranial aneurysms, Biochemical and Biophysical Research Communications, 10.1016/j.bbrc.2017.10.133, 495, 1, 332-338, 2018.01, Object The wall thickness of intracranial aneurysms (IAs) is heterogeneous. Although thinning of the IA wall is thought to contribute to IA rupture, the underlying mechanism remains poorly understood. Recently, imaging mass spectroscopy (IMS) has been used to reveal the distribution of phospholipids in vascular diseases. To investigate the feature of phospholipid composition of IA walls, we conducted IMS in a rat model of experimentally induced IA. Material and methods IAs were surgically induced in 7-week-old male rats and analyzed by IMS in negative-ion mode. Results A molecule at m/z 885.5 was more abundant in the thickened wall than in the thinned wall (P = 0.03). Multiple-stage mass spectroscopy revealed the molecule to be phosphatidylinositol containing stearic acid and arachidonic acid (PI 18:0/20:4). Immunohistochemistry indicated that vascular smooth muscle cells (SMCs) in the thickened wall had dedifferentiated phenotypes. To investigate the relationship between accumulation of PI (18:0/20:4) and phenotypic changes in SMCs, we subjected primary mouse aortic SMCs to liquid chromatography–tandem mass spectrometry. Notably, dedifferentiated SMCs had 1.3-fold more PI (18:0/20:4) than partly differentiated SMCs. Conclusions Our study demonstrated the heterogeneity in phospholipid composition of the aneurysmal walls using experimentally induced IAs. PI (18:0/20:4) accumulated at high levels in the thickened aneurysmal wall where synthetic dedifferentiated SMCs exist, suggesting that this phospholipid may be involved in the phenotypic switching of medial SMCs in the IA wall..
21. Ai Nogami-Hara, Masaki Nagao, Kotaro Takasaki, Nobuaki Egashira, Risako Fujikawa, Kaori Kubota, Takuya Watanabe, Shutaro Katsurabayashi, Funda Bolukbasi Hatip, Izzettin Hatip-Al-Khatib, Katsunori Iwasaki, The Japanese Angelica acutiloba root and yokukansan increase hippocampal acetylcholine level, prevent apoptosis and improve memory in a rat model of repeated cerebral ischemia, Journal of Ethnopharmacology, 10.1016/j.jep.2017.12.025, 214, 190-196, 2018.03, Ethnopharmacological relevance Japanese Angelica acutiloba root (Angelica root) is included in several Kampo medicines including Yokukansan (YKS). Angelica root and YKS are used for the treatment of a variety of psychological and neurodegenerative disorders. Development of safe and effective therapeutic agents against cerebrovascular disorders will improve the treatment of patients with dementia. Aim of the study The effect of Angelica root and YKS on ischemia-impaired memory has not yet been fully investigated. The present study investigated whether Angelica root is also involved in memory improving and neuroprotective effect of YKS in a model of cerebrovascular ischemia. Materials and methods Male Wistar rats grouped into sham rats received saline, and other three groups subjected to repeated cerebral ischemia induced by 4-vessel occlusion (4-VO), received a 7-day oral administration of either saline, Angelica root or YKS. Memory was evaluated by eight-arm radial maze task. Acetylcholine release (ACh) in the dorsal hippocampus was investigated by microdialysis-HPLC. Apoptosis was determined by terminal deoxynucleotidyl transferase (TdT)-mediated fluorescein-deoxyuridine triphosphate (dUTP) nick-end labeling. Results Ischemia induced apoptosis, reduced release of ACh, and impaired the memory (increased error choices and decreased correct choices). Angelica root and YKS improved the memory deficits, upregulated the release of ACh and prevented 4-VO-induced hippocampal apoptosis. Conclusion The dual ACh-increasing and neuroprotective effect of Angelica root could make it a promising therapeutic agent useful for the treatment of symptoms of cerebrovascular dementia. Angelica root could be one of the components contributing to the memory-improving and neuroprotective effects of YKS..


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