Perampanel Inhibits α‐Synuclein Transmission in Parkinson's Disease Models

パーキンソン病モデルへのペランパネルの有効性を確認 --パーキンソン病の進行抑制治療への期待--. 京都大学プレスリリース. 2021-04-05.[Background]: The intercellular transmission of pathogenic proteins plays a key role in the clinicopathological progression of neurodegenerative diseases. Previous studies have demonstrated that this uptake and release process is regulated by neuronal activity. [Objective]: The objective of this study was to examine the effect of perampanel, an antiepileptic drug, on α‐synuclein transmission in cultured cells and mouse models of Parkinson's disease.Methods: Mouse primary hippocampal neurons were transduced with α‐synuclein preformed fibrils to examine the effect of perampanel on the development of α‐synuclein pathology and its mechanisms of action. An α‐synuclein preformed fibril‐injected mouse model was used to validate the effect of oral administration of perampanel on the α‐synuclein pathology in vivo. [Results]: Perampanel inhibited the development of α‐synuclein pathology in mouse hippocampal neurons transduced with α‐synuclein preformed fibrils. Interestingly, perampanel blocked the neuronal uptake of α‐synuclein preformed fibrils by inhibiting macropinocytosis in a neuronal activity‐dependent manner. We confirmed that oral administration of perampanel ameliorated the development of α‐synuclein pathology in wild‐type mice inoculated with α‐synuclein preformed fibrils.[Conclusion]: Modulation of neuronal activity could be a promising therapeutic target for Parkinson's disease, and perampanel could be a novel disease‐modifying drug for Parkinson's disease

Increased oxidative stress precedes the onset of high-fat diet-induced insulin resistance and obesity

金沢大学医薬保健研究域医学系Insulin resistance is a key pathophysiological feature of metabolic syndrome. However, the initial events triggering the development of insulin resistance and its causal relations with dysregulation of glucose and fatty acids metabolism remain unclear. We investigated biological pathways that have the potential to induce insulin resistance in mice fed a high-fat diet (HFD). We demonstrate that the pathways for reactive oxygen species (ROS) production and oxidative stress are coordinately up-regulated in both the liver and adipose tissue of mice fed an HFD before the onset of insulin resistance through discrete mechanism. In the liver, an HFD up-regulated genes involved in sterol regulatory element binding protein 1c-related fatty acid synthesis and peroxisome proliferator-activated receptor α-related fatty acid oxidation. In the adipose tissue, however, the HFD down-regulated genes involved in fatty acid synthesis and up-regulated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. Furthermore, increased ROS production preceded the elevation of tumor necrosis factor-α and free fatty acids in the plasma and liver. The ROS may be an initial key event triggering HFD-induced insulin resistance. © 2008 Elsevier Inc. All rights reserved

The hepatic circadian clock is preserved in a lipid-induced mouse model of non-alcoholic steatohepatitis

金沢大学医薬保健研究域医学系Recent studies have correlated metabolic diseases, such as metabolic syndrome and non-alcoholic fatty liver disease, with the circadian clock. However, whether such metabolic changes per se affect the circadian clock remains controversial. To address this, we investigated the daily mRNA expression profiles of clock genes in the liver of a dietary mouse model of non-alcoholic steatohepatitis (NASH) using a custom-made, high-precision DNA chip. C57BL/6J mice fed an atherogenic diet for 5 weeks developed hypercholesterolemia, oxidative stress, and NASH. DNA chip analyses revealed that the atherogenic diet had a great influence on the mRNA expression of a wide range of genes linked to mitochondrial energy production, redox regulation, and carbohydrate and lipid metabolism. However, the rhythmic mRNA expression of the clock genes in the liver remained intact. Most of the circadianly expressed genes also showed 24-h rhythmicity. These findings suggest that the biological clock is protected against such a metabolic derangement as NASH. © 2009 Elsevier Inc. All rights reserved

Olmesartan ameliorates a dietary rat model of non-alcoholic steatohepatitis through its pleiotropic effects

金沢大学大学院医学系研究科金沢大学医薬保健研究域医学系Insulin resistance is a major pathological condition associated with obesity and metabolic syndrome. Insulin resistance and the renin-angiotensin system are intimately linked. We evaluated the role of the renin-angiotensin system in the pathogenesis of insulin resistance-associated, non-alcoholic steatohepatitis by using the angiotensin II type 1 receptor blocker olmesartan medoxomil in a diabetic rat model. The effects of olmesartan on methionine- and choline-deficient (MCD) diet-induced steatohepatitis were investigated in obese, diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats and control Long-Evans Tokushima Otsuka (LETO) rats. Components of the renin-angiotensin system were up-regulated in the livers of OLETF rats, compared with LETO rats. In OLETF, but not LETO, rats, oral administration of olmesartan for 8 weeks ameliorated insulin resistance. Moreover, olmesartan suppressed MCD diet-induced hepatic steatosis and the hepatic expression of lipogenic genes (sterol regulatory element-binding protein-1c and fatty acid synthase) in OLETF, but not LETO, rats. In both OLETF and LETO rats, olmesartan inhibited hepatic oxidative stress (4-hydroxy-2-nonenal-modified protein) and expression of NADPH oxidase. Olmesartan also inhibited hepatic fibrosis, stellate cell activation, and expression of fibrogenic genes (transforming growth factor-β, α1 [I] procollagen, plasminogen activator inhibitor-1) in both OLETF and LETO rats. In conclusion, pharmacological blockade of the angiotensin II type 1 receptor slows the development of steatohepatitis in the OLETF rat model. This angiotensin II type 1 receptor blocker may exert insulin resistance-associated effects against hepatic steatosis and inflammation as well as direct effects against the generation of reactive oxygen species and fibrogenesis. © 2008 Elsevier B.V. All rights reserved

Tranilast, an antifibrogenic agent, ameliorates a dietary rat model of nonalcoholic steatohepatitis

金沢大学医薬保健研究域医学系Nonalcoholic steatohepatitis (NASH) is the progressive form of nonalcoholic fatty liver disease and is one of the most common liver diseases in the developed world. The histological findings of NASH are characterized by hepatic steatosis, inflammation, and fibrosis. However, an optimal treatment for NASH has not been established. Tranilast, N-(3′,4′-dimedioxycinnamoyl)- anthranilic acid, is an antifibrogenic agent that inhibits the action of transforming growth factor beta (TGF-β). This drug is used clinically for fibrogenesis-associated skin disorders including hypertrophic scars and scleroderma. TGF-β plays a central role in the development of hepatic fibrosis, and tranilast may thus ameliorate the pathogenesis of NASH. We investigated the effects of tranilast using an established dietary animal model of NASH, obese diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats and nondiabetic control Long-Evans Tokushima Otsuka (LETO) rats fed a methionine-deficient and choline-deficient diet. Treatment with 2% tranilast (420 mg/kg/day) for 8 weeks prevented the development of hepatic fibrosis and the activation of stellate cells, and down-regulated the expression of genes for TGF-β and TGF-β-target molecules, including α1 procollagen and plasminogen activator-1. In addition, tranilast attenuated hepatic inflammation and Kupffer cell recruitment, and down-regulated the expression of tumor necrosis factor alpha. Unexpectedly, tranilast ameliorated hepatic steatosis and up-regulated the expression of genes involved in beta-oxidation, such as peroxisome proliferator-activated receptor α and carnitine O-palmitoyltransferase-1. Most of these effects were observed in LETO rats and OLETF rats, which suggest that the action of tranilast is mediated through the insulin resistance-independent pathway. Conclusion: Our findings suggest that targeting TGF-β with tranilast represents a new mode of therapy for NASH. Copyright © 2008 by the American Association for the Study of Liver Diseases

Metformin Prevents and Reverses Inflammation in a Non-Diabetic Mouse Model of Nonalcoholic Steatohepatitis

Background: Optimal treatment for nonalcoholic steatohepatitis (NASH) has not yet been established, particularly for individuals without diabetes. We examined the effects of metformin, commonly used to treat patients with type 2 diabetes, on liver pathology in a non-diabetic NASH mouse model. Methodology/Principal Findings: Eight-week-old C57BL/6 mice were fed a methionine- and choline-deficient plus high fat (MCD+HF) diet with or without 0.1% metformin for 8 weeks. Co-administration of metformin significantly decreased fasting plasma glucose levels, but did not affect glucose tolerance or peripheral insulin sensitivity. Metformin ameliorated MCD+HF diet-induced hepatic steatosis, inflammation, and fibrosis. Furthermore, metformin significantly reversed hepatic steatosis and inflammation when administered after the development of experimental NASH. Conclusions/Significance: These histological changes were accompanied by reduced hepatic triglyceride content, suppressed hepatic stellate cell activation, and the downregulation of genes involved in fatty acid metabolism, inflammation, and fibrogenesis. Metformin prevented and reversed steatosis and inflammation of NASH in an experimental non-diabetic model without affecting peripheral insulin resistance. © 2012 Kita et al

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・家族人員数は平均4.2人であり, 家族構成は親と子が半数で祖父母と同居している者が約40%であった。・使用米の購入は,全体的にみておよそ60%が業者からで, 購入量は20～29kgが44%, 30kg以上が33.7%であった。・使用米の種類は, 精白米を使用している家庭が77%あり, 1kg当たりの価格は, 350～600円であった。品質はIA・IB, IIA・IIBが半数を占めており, 標準価格米は12.9%であった。・食味の官能検査においては, 標準価格米はIIBシルバーよりやや劣り, 価格の高い米の方がわずかにおいしいという結果が得られた。・食事状況については, 休日は朝昼兼用で二食にしている者が多く, 朝・昼・夕とも平日より「家庭で作る」者は少ない。・米を主食とする者は, 朝食・昼食では60%夕食では80%あり, 全体的にみると主食の種類は米 : パン : 麺の割合が7 : 2 : 1であった。主食に米を食する者の割合は, 昭和57年の本学学生を対象にした調査よりわずかに増加した。・米飯料理にうち1/4が白飯以外の米飯料理であった。種類は35種類で, その順位はすし・炊き込みごはん・カレーライスの順で, すしはどの季節にも多く, 炊き込みごはんは春秋に多く食べられていた。・1人1日当たりの摂取量は平均110.6gで, 1食当たりの摂取量は63.4gであった。1食当たりの摂取量を米飯料理の種類別にみると白飯では57.8gであり, 白飯以外はいずれも多く1.2～1.4倍であった。・若者の米離れがいわれているが, やはり今回の調査でも, 昭和57年の調査に比べて, 摂取量においてはかなりの減少がみられた。米飯嗜好の点からみると米は決して嫌われているわけではなく, 朝食を手軽にするということからパン食になったり, 米飯が適している弁当を持参する者が少なくなったり, また飽食の時代となって, 副食が多く主食の少ない食事傾向になるなど, 米の摂取量を減らしているのは嗜好より他の要因によるのではないかと考えられる

Selenoprotein P as a diabetes-associated hepatokine that impairs angiogenesis by inducing VEGF resistance in vascular endothelial cells

Aims/hypothesis Impaired angiogenesis induced by vascular endothelial growth factor (VEGF) resistance is a hallmark of vascular complications in type 2 diabetes; however, its molecular mechanism is not fully understood. We have previously identified selenoprotein P (SeP, encoded by the SEPP1 gene in humans) as a liver-derived secretory protein that induces insulin resistance. Levels of serum SeP and hepatic expression of SEPP1 are elevated in type 2 diabetes. Here, we investigated the effects of SeP on VEGF signalling and angiogenesis. Methods We assessed the action of glucose on Sepp1 expression in cultured hepatocytes. We examined the actions of SeP on VEGF signalling and VEGF-induced angiogenesis in HUVECs. We assessed wound healing in mice with hepatic SeP overexpression or SeP deletion. The blood flow recovery after ischaemia was also examined by using hindlimb ischaemia model with Sepp1-heterozygous-knockout mice. Results Treatment with glucose increased gene expression and transcriptional activity for Sepp1 in H4IIEC hepatocytes. Physiological concentrations of SeP inhibited VEGF-stimulated cell proliferation, tubule formation and migration in HUVECs. SeP suppressed VEGF-induced reactive oxygen species (ROS) generation and phosphorylation of VEGF receptor 2 (VEGFR2) and extracellular signal-regulated kinase 1/2 (ERK1/2) in HUVECs. Wound closure was impaired in the mice overexpressing Sepp1, whereas it was improved in SeP-/-mice. SeP+/-mice showed an increase in blood flow recovery and vascular endothelial cells after hindlimb ischaemia. Conclusions/interpretation The hepatokine SeP may be a novel therapeutic target for impaired angiogenesis in type 2 diabetes. © 2014 Springer-Verlag Berlin Heidelberg

LECT2 functions as a hepatokine that links obesity to skeletal muscle insulin resistance

Recent articles have reported an association between fatty liver disease and systemic insulin resistance in humans, but the causal relationship remains unclear. The liver may contribute to muscle insulin resistance by releasing secretory proteins called hepatokines. Here we demonstrate that leukocyte cell-derived chemotaxin 2 (LECT2), an energy-sensing hepatokine, is a link between obesity and skeletal muscle insulin resistance. Circulating LECT2 positively correlated with the severity of both obesity and insulin resistance in humans. LECT2 expression was negatively regulated by starvation-sensing kinase adenosine monophosphate-activated protein kinase in H4IIEC hepatocytes. Genetic deletion of LECT2 in mice increased insulin sensitivity in the skeletal muscle. Treatment with recombinant LECT2 protein impaired insulin signaling via phosphorylation of Jun NH2-terminal kinase in C2C12 myocytes. These results demonstrate the involvement of LECT2 in glucose metabolism and suggest that LECT2 may be a therapeutic target for obesity-associated insulin resistance. © 2014 by the American Diabetes Association