Published papers

血液脳関門(BBB)は、古典的には隣接する脳血管内皮細胞間の接着に由来する物質透過性の制御機構である。近年、脳血管障害の病態を考察するツールとして提唱され広く用いられるようになったNeurovascular unit(NVU)は、ニューロンと血管内皮細胞、細胞外マトリックス、アストロサイトの機能的統合体を示す。NVUでは、BBBを内皮細胞間接着に加え、アストロサイトの足突起と血管内皮細胞、その間の基底膜細胞外マトリックスの接着を第2次バリアと考えることによって、虚血性脳損傷の更なる病態理解を進め、新しい治療法の開発につながることが期待される。(著者抄録)

ヒトの脳は生理的条件下ではD-グルコースのみをエネルギー基質とし、その酸化的代謝から得られるATPで機能活動を維持している。脳のエネルギー代謝をグルコース代謝として検討すると、CMRO2とCMRglcの実測比(CMRO2/CMRglc)は約5であり、グルコースが完全な酸化的代謝でCO2に分解された際の理論値6に近く、脳のグルコース代謝は、ほとんどがエネルギー産生のための酸化的消費である。ヒト大脳皮質ではアストロサイトの数はニューロンの約1.4倍とされる。アストロサイトはニューロンと微小血管を橋渡しするように位置し、エネルギー代謝からみてもニューロンと機能的に連動し、脳血流調節にも関与する。グルコース代謝から見たニューロンとアストロサイトのエネルギー代謝において、1)エネルギー基質としてのグルコースと乳酸の選択性(preference)、2)ニューロンの活動亢進に伴って起こるエネルギー基質の供給、3)エネルギー産生を伴わないグルコース代謝、の3点を中心に現在の脳のエネルギー代謝の知見をまとめる。(著者抄録)

OBJECTIVE: We sought to clarify risk factor profiles and current treatment of Japanese patients with stroke, myocardial infarction (MI), and nonvalvular atrial fibrillation (NVAF) using the database of the Japan Thrombosis Registry for Atrial Fibrillation, Coronary, or Cerebrovascular Events (J-TRACE). METHODS: J-TRACE is a nationwide multicenter cooperative cohort of Japanese patients with MI, stroke, and NVAF. Baseline characteristics of 8087 Japanese patients (5804 male, average age 68.7 years) with history of stroke (n=3554), MI (n=2291), or NVAF (n=2242) were analyzed. RESULTS: History of stroke (14.7%) was more frequent than history of MI (2.6%) in patients with stroke, whereas history of stroke (6.6%) was less frequent than history of MI (7.6%) in patients with MI. In patients with NVAF, history of stroke (14.3%) was far more frequent than history of MI (3.4%). Hypertension was more frequent in stroke (74.4%) than MI (62.0%) or NVAF (57.7%), whereas hypercholesterolemia, diabetes mellitus, and cigarette smoking were more prevalent in patients with MI (56.1%, 35.1%, and 33.3%, respectively) than in those with stroke (35.7%, 22.4%, and 19.7%, respectively) or NVAF (26.9%, 17.2%, and 16.1%, respectively). Alcohol consumption (34.9%) and obesity (body mass index>25) (32.8%) were most common in patients with NVAF. In all patients, nonmedication rates were higher in patients with hypercholesterolemia (29.8%) or diabetes (36.9%) than in those with hypertension (9.5%). Warfarin was used in 58.9% of patients with low-risk and 75.4% with high-risk NVAF. CONCLUSION: Risk factor profiles and their modification were not similar among patients in Japan with MI, stroke, and NVAF, although they share a high risk of thrombotic events.

BACKGROUND: Clinical characteristics, including risk factors for thromboembolism, and medications differ between men and women with atrial fibrillation (AF) in Western countries. Whether such a difference exists for Japanese patients with AF is unclear, so data from J-TRACE were used to investigate this issue. METHODS AND RESULTS: A total of 2,892 patients (2,028 men, 864 women; 70.3 years old) with AF were analyzed for the respective prevalences of risk factors and medications. CHADS2 score was calculated to determine thromboembolic risk level. Women were older (P<0.001), and more frequently had heart failure (P<0.001), and hypertension (P=0.051) than men. The proportion of subjects aged 75 years or older was higher among women than among men (P<0.001). CHADS2 score was therefore significantly higher in women than in men (2.05+/-1.29 vs 1.88+/-1.33, P<0.001). Sex-related differences were not observed for the prevalence of diabetes mellitus, myocardial infarction or ischemic stroke, nor did warfarin usage differ between men and women. CONCLUSIONS: Sex-related differences were observed in the risk factor profile and medications of Japanese patients with AF. CHADS2 score was higher in women than in men.

Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists play important roles in the regulation of energy metabolism and are widely used for patients with type 2 diabetes. PPARgamma agonists reportedly reduce plasma glucose levels by recruiting glucose transporters to the cellular membrane, resulting in the enhanced uptake of glucose. However, only a limited number of studies have examined the effect of PPARgamma on cerebral glucose metabolism. In the present study, we examined the effects of a PPARgamma agonist, pioglitazone, on glucose metabolism in cultured rat neurons and astroglia. Cultures of neurons or astroglia were prepared from Sprague-Dawley rats. The cells were treated with pioglitazone (0-50 muM) for 48 hours prior to assay. Lactate released into the culture medium (an index of glycolytic glucose metabolism) and [U-(14)C]lactate or [1-(14)C]pyruvate oxidation (an index of oxidative glucose metabolism) were measured. In addition, the production of cellular reactive oxygen species (ROS) was determined utilizing an H(2)DCFDA assay. Forty-eight hours of exposure to pioglitazone (0.5 and 5 muM) resulted in dose-dependent increases in lactate release into the astroglial culture medium but not into the neuronal culture medium. [U-(14)C]lactate oxidation and [1-(14)C]pyruvate oxidation were enhanced in the neurons, but not in the astroglia. These actions of pioglitazone were not inhibited by 2-chloro-5-nitrobenzanilide (GW9662), a potent antagonist of PPARgamma, and were not mimicked by N-(2-benzoylphenyl)-O-[2-(methyl-2-pyridinylamino)ethyl]-l-tyrosine (GW1929), a non-thiazolidinedione PPARgamma agonist. Pioglitazone enhanced aerobic glycolysis and lactate release in astroglia, while the oxidative metabolism of glucose, but not glycolysis, was augmented in neurons without increasing ROS production. These results indicate that pioglitazone may enhance the efficiency of glucose metabolism in the brain.

＜ポイント＞●無症候性脳梗塞は将来の脳卒中のリスクファクターである.その進展には高血圧の関与が大きく,厳格な血圧コントロールが必要である.降圧薬として,Caチャネル遮断薬,ACE阻害薬,ARBなどが推奨される.抗血小板薬の必要性は個別に判断する.●無症候性白質病変の多くは高血圧を背景とした虚血性病変である.脳卒中,認知症への進展予防のための血圧コントロールが重要である.●無症候性脳出血はMRIのT2*強調画像で認められるmicrobleedsによって診断する.将来の脳出血のリスクが高く,抗血小板薬の投与は慎重に行う.●無症候性頸部頸動脈狭窄または閉塞に対しては,抗血小板薬やスタチンの内服に加えて,高度狭窄の場合には頸動脈内膜剥離術(CEA),ステント留置術(CAS)の適応を判断する.●無症候性頭蓋内主幹動脈狭窄または閉塞の治療についての十分なエビデンスはないが,アスピリンとシロスタゾールの併用療法により血管狭窄の改善効果が報告されている.さらに,適切な降圧は病変血管支配領域の将来の虚血性イベントを抑制する可能性が高い.(著者抄録)

ニューロン(neuron)の生存に不可欠な脳循環の途絶は、ただちに脳の機能障害を起こし、時間経過とともに不可逆的損傷を起こす。脳梗塞急性期治療には、脳循環の改善という最大の治療方針に加え、可能なかぎりニューロンを救済するための併用治療が望まれる。しかし、新規治療法の確立には、ニューロンのみを対象にした虚血性細胞障害のメカニズムの基礎研究と薬剤の開発だけでは不十分である。生理的状態において、ニューロンの機能と脳循環はつねに連動しており、血管を構成する内皮細胞(endothelium)、基底膜(basal lamina)の細胞外マトリックス(extracellular matrix)とその中に存在する周皮細胞(pericyte)、さらに血管平滑筋、血管外にあってニューロンとの間に介在するアストロサイト(astrocyte)という機能ユニットの理解が必須である。これをneurovascular unit(NVU)と命名し、その包括的な研究を推進することで、脳血管障害のメカニズム解明と治療法開発のさらなる進展が期待できる。(著者抄録)

Exogenous ketone bodies (KBs), acetoacetate (AA), and beta-hydroxybutyrate (BHB) act as alternative energy substrates in neural cells under starvation. The present study examined the endogenous ketogenic capacity of astroglia under hypoxia with/without glucose and the possible roles of KBs in neuronal energy metabolism. Cultured neurons and astroglia were prepared from Sprague-Dawley rats. Palmitic acid (PAL) and l-carnitine (LC) were added to the assay medium. The 4- to 24-hr production of AA and BHB was measured using the cyclic thio-NADH method. (14)C-labeled acid-soluble products (KBs) and (14)CO2 produced from [1-(14)C]PAL were also measured. l-[U-(14)C]lactic acid ([(14)C]LAC), [1-(14)C]pyruvic acid ([(14)C]PYR), or beta-[1-(14)C]hydroxybutyric acid ([(14)C]BHB) was used to compare the oxidative metabolism of the glycolysis end products with that of the KBs. Some cells were placed in a hypoxic chamber (1% O2). PAL and LC induced a higher production of KBs in astroglia than in neurons, while the CO2 production from PAL was less than 5% of the KB production in both astroglia and neurons. KB production in astroglia was augmented by the AMP-activated protein kinase activators, AICAR and metformin, as well as hypoxia with/without glucose. Neuronal KB production increased under hypoxia in the absence of PAL and LC. In neurons, [(14)C]LAC and [(14)C]PYR oxidation decreased after 24 hr of hypoxia, while [(14)C]BHB oxidation was preserved. Astroglia responds to ischemia in vitro by enhancing KB production, and astroglia-produced KBs derived from fatty acid might serve as a neuronal energy substrate for the tricarboxylic acid cycle instead of lactate, as pyruvate dehydrogenase is susceptible to ischemia.

D-Serine is known to be essential for the activation of the N-methyl-D-aspartate (NMDA) receptor in the excitation of glutamatergic neurons, which have critical roles in long-term potentiation and memory formation. D-Serine is also thought to be involved in NMDA receptor-mediated neurotoxicity. The deletion of serine racemase (SRR), which synthesizes D-serine from L-serine, was recently reported to improve ischemic damage in mouse middle cerebral artery occlusion model. However, the cell type in which this phenomenon originates and the regulatory mechanism for D-/L-serine remain elusive. The D-/L-serine content in ischemic brain increased until 20 hours after recanalization and then leveled off gradually. The results of in vitro experiments using cultured cells suggested that D-serine is derived from neurons, while L-serine seems to be released from astroglia. Immunohistochemistry studies of brain tissue after cerebral ischemia showed that SRR is expressed in neurons, and 3-phosphoglycerate dehydrogenase (3-PGDH), which synthesizes L-serine from 3-phosphoglycerate, is located in astrocytes, supporting the results of the in vitro experiments. A western blot analysis showed that neither SRR nor 3-PGDH was upregulated after cerebral ischemia. Therefore, the increase in D-/L-serine was not related to an increase in SRR or 3-PGDH, but to an increase in the substrates of SRR and 3-PGDH.