Development Of Post-ischemic Glucose Intolerance Research Articles

Retraction Note to: Honokiol suppresses the development of post-ischemic glucose intolerance and neuronal damage in mice.

This article [1] has been retracted at the request of the corresponding author because an Investigation Committee established by Kobe Gakuin University (Kobe, Japan) has found numerous discrepancies between the raw data and the data presented in Figs.6b, d. Statistical analysis of the raw data showed no significant difference between conditions. Authors S. Harada, K. Nakamoto, W. Fujita-Hamabe, H.-H. Chen, M.-H. Chan, and S. Tokuyama agree with this retraction. Authors M. Kishimoto and M. Kobayashi could not be reached for comment about this retraction.

Involvement of communication system between brain and peripheral tissues on the development of post-ischemic glucose intolerance induced by cerebral neuronal damage.

Involvement of communication system between brain and peripheral tissues on the development of post-ischemic glucose intolerance induced by cerebral neuronal damage.

Role of orexin-A-mediated communication system between brain and peripheral tissues on the development of post-ischemic glucose intolerance-induced neuronal damage

I recently found that cerebral ischemic stress per se causes hyperglycemia (i.e., post-ischemic glucose intolerance) and suppression of post-ischemic glucose intolerance might be important to improve prognosis. Here, I analyzed the efficacy of suppression of post-ischemic glucose intolerance using orexin-A (OXA) endogenous neuropeptide as a novel therapeutic strategy against cerebral ischemic neuronal damage. OXA in hypothalamus plays a role in many physiological functions including regulation of glucose metabolism. I previously found that the development of post-ischemic glucose intolerance is suppressed by OXA. Other reports have shown that the communication system between brain and peripheral tissues through the autonomic nervous system is important for maintaining glucose and energy metabolism. The aim of this study was to determine the involvement of the hepatic vagus nerve on hypothalamic OXA-mediated suppression of post-ischemic glucose intolerance and neuronal damage. Intrahypothalamic administration of OXA significantly suppressed the development of post-ischemic glucose intolerance on day 1 and of neuronal damage on day 3 after middle cerebral artery occlusion (MCAO). In the liver, MCAO-induced decrease in insulin receptors and increase in gluconeogenic enzymes on day 1 was recovered to control levels by OXA; these effects were reversed by hepatic vagotomy. In the medulla oblongata, OXA induced co-localization of the cholinergic neuronal marker choline acetyltransferase with orexin-1 receptor and c-Fos. These results suggest that the vagus nerve projecting from the medulla oblongata plays an important role in the recovery of post-ischemic glucose intolerance and mediates neuroprotection by hypothalamic OXA.

Hepatic branch vagus nerve plays a critical role in the recovery of post-ischemic glucose intolerance and mediates a neuroprotective effect by hypothalamic orexin-A.

Orexin-A (a neuropeptide in the hypothalamus) plays an important role in many physiological functions, including the regulation of glucose metabolism. We have previously found that the development of post-ischemic glucose intolerance is one of the triggers of ischemic neuronal damage, which is suppressed by hypothalamic orexin-A. Other reports have shown that the communication system between brain and peripheral tissues through the autonomic nervous system (sympathetic, parasympathetic and vagus nerve) is important for maintaining glucose and energy metabolism. The aim of this study was to determine the involvement of the hepatic vagus nerve on hypothalamic orexin-A-mediated suppression of post-ischemic glucose intolerance development and ischemic neuronal damage. Male ddY mice were subjected to middle cerebral artery occlusion (MCAO) for 2 h. Intrahypothalamic orexin-A (5 pmol/mouse) administration significantly suppressed the development of post-ischemic glucose intolerance and neuronal damage on day 1 and 3, respectively after MCAO. MCAO-induced decrease of hepatic insulin receptors and increase of hepatic gluconeogenic enzymes on day 1 after was reversed to control levels by orexin-A. This effect was reversed by intramedullary administration of the orexin-1 receptor antagonist, SB334867, or hepatic vagotomy. In the medulla oblongata, orexin-A induced the co-localization of cholin acetyltransferase (cholinergic neuronal marker used for the vagus nerve) with orexin-1 receptor and c-Fos (activated neural cells marker). These results suggest that the hepatic branch vagus nerve projecting from the medulla oblongata plays an important role in the recovery of post-ischemic glucose intolerance and mediates a neuroprotective effect by hypothalamic orexin-A.

『脳梗塞治療における新たな可能性を探る』 脳血管障害誘導性耐糖能異常の発現における中枢－末梢臓器間連関機構の関与

我が国の主要な死因の一つである脳卒中は，高い死亡率とは対照的に，外科的治療以外に有効な治療薬が少ない現状にある．従って，治療ウインドウの広い薬剤の開発や，新たな治療戦略の確立は急務の課題とされている．現在，脳卒中の発症に関与する因子は数多く報告されているが，その中でも，糖尿病または高血糖状態が重要な危険因子であることはよく知られている．さらに最近では，糖尿病の既往歴のない人でも，脳卒中発症後に高血糖状態を呈し，それをインスリンで厳格に制御することによって死亡率が抑制されるという報告がなされている．これらの知見は，血糖値バランスの乱れが脳卒中の発現ならびに予後に密接に影響する可能性を示唆している．しかしながら，その発現機序は未だ不明である．本総説では，①糖代謝制御に関与するインスリンシグナル系，②中枢－末梢臓器間連関に焦点を当てた脳虚血性耐糖能異常の発現機序，③インスリンやメトホルミン等の抗糖尿病薬，神経ペプチドであるorexin-Aを用いた脳虚血性耐糖能異常ならびに神経障害発現に対する影響について著者らの知見を中心に概説する．本総説を通し，中枢をターゲットとした治療だけではなく，既存の糖尿病治療薬ならびに血糖値制御因子を用いた全身性の代謝機能調節も脳卒中治療において重要であることを提唱する．

Orexin-A Suppresses Postischemic Glucose Intolerance and Neuronal Damage through Hypothalamic Brain-Derived Neurotrophic Factor

Orexin-A (a glucose-sensing neuropeptide in the hypothalamus) and brain-derived neurotrophic factor (BDNF; a member of the neurotrophin family) play roles in many physiologic functions, including regulation of glucose metabolism. We previously showed that the development of postischemic glucose intolerance is one of the triggers of ischemic neuronal damage. The aim of this study was to determine whether there was an interaction between orexin-A and BDNF functions in the hypothalamus after cerebral ischemic stress. Male ddY mice were subjected to 2 hours of middle cerebral artery occlusion (MCAO). Neuronal damage was estimated by histologic and behavioral analyses. Expression of protein levels was analyzed by Western blot. Small interfering RNA directed BDNF, orexin-A, and SB334867 [N-(2-methyl-6-benzoxazolyl)-N'-1,5-naphthyridin-4-yl urea; a specific orexin-1 receptor antagonist] were administered directly into the hypothalamus. The level of hypothalamic orexin-A, detected by immunohistochemistry, was decreased on day 1 after MCAO. Intrahypothalamic administration of orexin-A (1 or 5 pmol/mouse) significantly and dose-dependently suppressed the development of postischemic glucose intolerance on day 1 and development of neuronal damage on day 3. The MCAO-induced decrease in insulin receptor levels in the liver and skeletal muscle on day 1 was recovered to control levels by orexin-A, and this effect of orexin-A was reversed by the administration of SB334867 as well as by hypothalamic BDNF knockdown. These results suggest that suppression of postischemic glucose intolerance by orexin-A assists in the prevention of cerebral ischemic neuronal damage. In addition, hypothalamic BDNF may play an important role in this effect of orexin-A.

RETRACTED ARTICLE: Honokiol suppresses the development of post-ischemic glucose intolerance and neuronal damage in mice

Honokiol, a constituent of Magnolia obovata, has various pharmacological effects, including protection against cerebral ischemia. However, few studies have been conducted to evaluate the possible neuroprotective effects of honokiol against cerebral ischemia. We recently reported that cerebral ischemic neuronal damage could be triggered by glucose intolerance that develops after the onset of ischemic stress (i.e., post-ischemic glucose intolerance). In addition, suppression of post-ischemic glucose intolerance significantly ameliorated ischemic neuronal damage. Here, we investigated the effects of honokiol on the development of post-ischemic glucose intolerance and neuronal damage. Mice were subjected to middle cerebral artery occlusion (MCAO) for 2h. The development of post-ischemic glucose intolerance on day 1 and neuronal damage on day 3 after MCAO were significantly reduced by intraperitoneal administration of honokiol (10mg/kg) compared with the vehicle-treated group. Honokiol did not affect serum insulin or adiponectin levels. However, honokiol significantly decreased the expression of phosphoenolpyruvate carboxykinase and increased the expression of 5'-AMP-activated protein kinase (AMPK) on day 1 after MCAO, compared with the vehicle-treated MCAO group. The results of this study suggest that honokiol could prevent post-ischemic glucose intolerance in an AMPK-dependent manner, which may be involved in the neuroprotective effects of honokiol against cerebral ischemia.

Ischemic Stroke and Glucose Intolerance: a Review of the Evidence and Exploration of Novel Therapeutic Targets

Stroke is one of the leading causes of death and disability worldwide. It is well known that hyperglycemia and/or diabetes potentially exacerbate the neuronal damage observed following ischemic stroke. Recent reports have shown that hyperglycemia/glucose intolerance may be induced by cerebral ischemic stress, and that normalization of blood glucose levels during the first 48 h of hospitalization appears to confer greater survival outcomes in stroke patients. However, the mechanisms underlying post-ischemic glucose intolerance remain unclear. Here, we review research to date on the mechanisms through which ischemic neuronal damage develops and on the role of post-ischemic glucose intolerance focusing on insulin and adiponectin signaling and communication between the brain and peripheral tissues. The relationship between ischemic neuronal damage and post-ischemic glucose intolerance is also discussed. With respect to therapeutic options, in addition to traditional post-stroke therapies, we also discuss the effect of anti-diabetic drugs and glucose-sensing neuropeptides on the development of the post-ischemic glucose intolerance and neuronal damage. In conclusion, we support the idea for focusing research on the development of post-ischemic glucose intolerance as a new therapeutic target for the stroke patients.

ChemInform Abstract: Effectiveness of Metformin in Prevention of Development of Hyperglycemia and Neuronal Damage Caused by Ischemic Stress

AbstractReview: 13 refs.

Effectiveness of Metformin in Prevention of Development of Hyperglycemia and Neuronal Damage Caused by Ischemic Stress

Hyperglycemia is a known exacerbating factor in ischemic stroke. It has been reported that hyperglycemia and post-ischemic glucose intolerance can develop after stroke and be involved in the development of neuronal damage, as we described previously. Here, we focus on the effectiveness of metformin, a hypoglycemic drug, in preventing the development of neuronal damage using the middle cerebral artery occlusion (MCAO) model mice. 5'-AMP-activated protein kinase (AMPK) is a serine/threonine kinase that plays a key role in the hypoglycemic effects of metformin. Recently, it has been reported that centrally activated AMPK is involved in the development of ischemic neuronal damage, while the effect of peripherally activated AMPK on ischemic neuronal damage is not known. In the liver, AMPK activity was not affected by MCAO, while the administration of intraperitoneal metformin (250 mg/kg), an AMPK activator, significantly activated hepatic AMPK and suppressed both the development of post-ischemic glucose intolerance and ischemic neuronal damage without alteration of central AMPK activity. On the other hand, the administration of intracerebroventricular metformin (100 µg/mouse) significantly exacerbated the development of neuronal damage observed on day 1 after MCAO. These effects were significantly blocked by compound C, a specific AMPK inhibitor. These results suggest that central AMPK is activated by ischemic stress per se, although peripheral AMPK is not altered. Furthermore, the regulation of post-ischemic glucose intolerance by metformin-induced activation of peripheral AMPK contributes to the reduction of cerebral ischemic neuronal damage.