Post-ischemic Glucose Research Articles

Macrophage-Derived Extracellular Vesicles (EVs) Have Functional and Metabolic Effects on Cardiac Grafts in a Preclinical Model of Donation After Circulatory Death (DCD)

<h3>Purpose</h3> Donation after circulatory death (DCD) could substantially increase cardiac graft availability. Cardiac ischemia and reperfusion, as occurs during DCD, can trigger the recruitment of macrophages as well as their polarization from the M0 to M1 state, which may occur in parallel with increased glycogen turnover and pentose phosphate flux. Extracellular vesicles (EVs) can transmit the metabolic status of their parent cell to recipient cells. As post-ischemic glucose metabolism is recognized to affect the cardiac recovery, we investigated the effects of M0 and M1 macrophage-derived EV administration during reperfusion on post-ischemic functional recovery and glucose metabolism using an isolated rat heart model of DCD. <h3>Methods</h3> Hearts isolated from adult, male rats were aerobically perfused for 20 minutes, followed by 27 minutes continued perfusion or 27 minutes of warm, global ischemia, and 60 minutes aerobic reperfusion with or without the intravascular administration of EVs. Four experimental groups were examined: 1) continued perfusion, no EVs (No ISCH); 2) ischemia, no EVs (ISCH); 3) ischemia with EVs from M0 macrophages (ISCH M0); 4) ischemia with EVs from M1 macrophages (ISCH M1). Contractile and metabolic post-ischemic recovery were evaluated. Data are reported as mean ± standard deviation. <h3>Results</h3> Left ventricular (LV) work (heart rate-developed pressure product) at 60 minutes reperfusion was significantly decreased in ISCH (17 ± 3) and ISCH M1 (19 ± 3), but not in ISCH M0 (22 ± 3), compared to No ISCH (26 ± 4 mmHg*beats*min^{−1 *}10³; p<0.05 for both). Rates of glycolysis during reperfusion were not different among groups; however, glycogen content was significantly lower after 60 min reperfusion in ISCH M1 (8 ± 2) compared to ISCH M0 (17 ± 3 μmol/g dry; p<0.05). <h3>Conclusion</h3> The ischemia-induced reduction in left ventricular work was improved with M0-, but not M1-, derived EVs. M0 and M1-derived EVs also differentially affected glucose metabolism; M1-macrophage derived EVs limited glycogen content, possibly by increasing glycogen use or turnover and stimulating recipient cells to mimic parent cell metabolic phenotypes. Circulating EVs in the ex-situ perfusion of DCD hearts may be possible targets for modulating metabolic function and optimizing graft recovery following warm ischemia.

Retraction: 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

Retraction: 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

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.

Pancreatic Changes in Nerve Growth Factor/TrkA Associated with Insulin Secretion in Cerebral Ischemia.

Regulation of blood glucose levels as a therapeutic strategy for cerebral ischemia plays an important role in suppressing neuronal damage. In particular, suppression of post-ischemic glucose intolerance improves cerebral ischemia. We have reported that cerebral ischemia induces glucose intolerance and an increase in plasma insulin levels. However, the mechanism of insulin secretion after cerebral ischemia is unclear. Nerve growth factor (NGF), a member of the neurotrophin family, has high affinity for tropomyosin-related kinase A (TrkA). NGF/TrkA signaling is associated with neuronal survival, differentiation, and function. Recently, NGF/TrkA signaling has been reported to be associated with insulin synthesis and secretion. In the present study, we evaluated the insulin content and expression of NGF/TrkA by immunofluorescence and Western blotting after middle cerebral artery occlusion (MCAO) as a cerebral ischemia model. At 6, 12, and 24 h after MCAO, insulin contents were increased in MCAO mice. The expression of NGF was increased at 6, 12, and 24 h, whereas the expression of TrkA tended to decrease in pancreas after MCAO. These results suggest that NGF/TrkA signaling is an important factor in cerebral ischemia-induced insulin synthesis and secretion in the pancreas.

&lt;i&gt;Stachys sieboldii&lt;/i&gt; (Labiatae, Chorogi) Protects against Learning and Memory Dysfunction Associated with Ischemic Brain Injury

Stachys sieboldii (Labiatae; Chinese artichoke, a tuber), "chorogi" in Japanese, has been extensively used in folk medicine, and has a number of pharmacological properties, including antioxidative activity. However, few studies have examined the neuroprotective effects of S. sieboldii tuber extract (chorogi extract), and it remains unknown whether the extract can alleviate learning and memory dysfunction associated with vascular dementia or Alzheimer's disease. Therefore, in this study, we investigated the neuroprotective effects of chorogi extract, and examined its protection against learning and memory dysfunction using Ginkgo biloba leaf extract (ginkgo extract) as a positive control. Mice were subjected to bilateral carotid artery occlusion (BCAO) for 30 min. Oral administration of chorogi extract or ginkgo extract significantly reduced post-ischemic glucose intolerance on day 1 and neuronal damage including memory impairment on day 3 after BCAO, compared with the vehicle-treated group. Neither herbal medicine affected locomotor activity. Furthermore, neither significantly alleviated scopolamine-induced learning and memory impairment. In primary neurons, neuronal survival rate was significantly reduced by hydrogen peroxide treatment. This hydrogen peroxide-induced neurotoxicity was significantly suppressed by chorogi extract and ginkgo extract. Taken together, our findings suggest that chorogi extract as well as ginkgo extract can protect against learning and memory dysfunction associated with ischemic brain injury through an antioxidative mechanism.

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&amp;#65293;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.

ChemInform Abstract: Involvement of Glycemic Control in the Inhibiting Effect of Morinda citrifolia on Cerebral Ischemia‐Induced Neuronal Damage

AbstractReview: 31 refs.

Retraction: Involvement of Glycemic Control in the Inhibiting Effect of &lt;i&gt;Morinda citrifolia&lt;/i&gt; on Cerebral Ischemia-induced Neuronal Damage

Fruit juice of Morinda citrifolia (Rubiaceae, Noni juice) is a well-known healthy drink and has various pharmacological properties including antioxidant and anti-inflammatory effects. We have hitherto found the protective effect of Noni juice on neuronal damage caused by ischemic stress in mice. In addition, we have also recently reported that suppression of post-ischemic glucose intolerance might be important for good prognosis. Here, we focused on the effect of Noni juice on the development of the post-ischemic glucose intolerance as a cerebral protective mechanism. Noni juice was obtained from the mature fruit grown in Okinawa (ONJ). Male ddY mice were given 10% ONJ in drinking water for 7 d. Then, mice were subjected to 2 h of middle cerebral artery occlusion (MCAO). We found that 10% ONJ treatment suppressed the development of neuronal damage after MCAO. Interestingly, glucose intolerance observed on 1 d after MCAO completely disappeared by 10% ONJ. Furthermore, 10% ONJ treatment significantly increased serum insulin levels much further than the control group on 1 d, while serum adiponectin levels were not affected at all. These results suggest that ONJ could facilitate insulin secretion and may attenuate the development of glucose intolerance under ischemic stress. These functions may contribute to the neuronal protective effect of ONJ against ischemic stress.

Localized therapeutic hypothermia in the brain for the treatment of ischemic stroke

stroke is, according to the World Health Organization ([10][1]), the third most common cause of death in the developed countries, exceeded only by coronary heart disease and cancer. Annually, 15 million people worldwide suffer a stroke. Of these 15 million people, 5.5 million die and 5 million are

Insulin-induced improvement of postischemic recovery is abolished by inhibition of protein kinase C in rat heart

Objective We demonstrated earlier that postischemic addition of insulin improves recovery of function in isolated rat heart by phosphatidylinositol 3-kinase. Activation of phosphatidylinositol 3-kinase before ischemia improves recovery of the heart after ischemia through protein kinase C. We tested whether protein kinase C activation is required for the positive inotropic effect of insulin during reperfusion. Methods Isolated working rat hearts were perfused with Krebs-Henseleit buffer containing [2- 3H]glucose (5 mmol/L, 0.05 μCi/mL) plus oleate (0.4 mmol/L) and were subjected to 15 minutes of global ischemia followed by 35 minutes of reperfusion with or without insulin (1 mU/mL). We measured cardiac power, glucose uptake, and tissue metabolites. The protein kinase C inhibitor chelerythrine (5 μmol/L) was added either at the beginning of the experiment or together with insulin. Experiments were repeated under normoxic conditions. Results Cardiac power before ischemia was 9.63 to 12.4 mW. Insulin improved recovery of power after ischemia (96.3% ± 10.8% versus 65.7% ± 3.79%, P < .05). This effect was abolished by chelerythrine (55.3% ± 6.49%). However, chelerythrine given at reperfusion did not block insulin's effect on recovery (101.0% ± 4.25%, P < .05). Postischemic glucose uptake was not increased by insulin (3.07 ± 0.32 before, 3.45 ± 0.34 μmol/min/gdw after ischemia, not significant) and was not affected by chelerythrine (3.01 ± 0.26 before, 3.29 ± 0.32 μmol/min/gdw after ischemia, not significant). Under normoxic conditions, chelerythrine did not influence insulin's effects on glucose uptake or power. Conclusion The results suggest that (1) insulin's effect on recovery is dependent on ischemia-induced protein kinase C activation, (2) the activity of protein kinase C during reperfusion may not be important for this effect of insulin, and (3) protein kinase C plays no role in insulin's effect on glucose uptake under normoxic or postischemic conditions.

Insulin improves postischemic recovery of function through PI3K in isolated working rat heart.

Insulin improves contractile function after ischemia, but does not increase glucose uptake in the isolated working rat heart. We tested the hypothesis that the positive inotropic effect of insulin is independent of the signaling pathway responsible for insulin-stimulated glucose uptake. We inhibited this pathway at the level of phosphatidyl inositol 3-kinase (PI3K) with wortmannin. Hearts were perfused for 70 min at physiological workload with Krebs-Henseleit buffer containing [2-(3)H] glucose (5 mM, 0.05 microCi/ml) and oleate (0.4 mM, 1% BSA) in the presence (WM, n = 5) or absence (control, n = 7) of wortmannin (WM, 3 micromol/L). After 20 min, hearts were subjected to 15 min of total global ischemia followed by 35 min of reperfusion. Insulin (1 mU/ml) was added at the beginning of reperfusion (WM + insulin n = 8, insulin n = 8). Cardiac power before ischemia was 8.1 +/- 0.7 mW. Recovery of contractile function after ischemia was significantly increased in the presence of insulin (73.5 +/- 8.9% vs. 38.5 +/- 6.7%, p < 0.01). The addition of wortmannin completely abolished the effect of insulin on recovery (32.6 +/- 6.4%). Glucose uptake was 1.84 +/- 0.32 micromol/min/g dry before ischemia and was slightly elevated during reperfusion (2.68 +/- 0.35 micromol/min/g dry, n.s.). Insulin did not affect postischemic glucose uptake. In the presence of wortmannin, glucose uptake was lowest during reperfusion (n.s.). The results suggest that PI3K is involved in the insulin-induced improvement in postischemic recovery of contractile function. This effect of insulin is independent of its effect on glucose uptake.

Feeding and fasting determine postischemic glucose utilization in isolated working rat hearts

To assess the effects of endogenous substrate on glucose utilization after 15 min of ischemia, we perfused isolated working rat hearts from fed and fasted (16 h) animals with glucose and the positron-emitting glucose analogue 2-[18F]fluoro-2-deoxy-D-glucose (2-FDG). Hearts were perfused in a recirculating system with bicarbonate buffer containing glucose (10 mM) and 2-FDG (0.5 microCi/ml). Mechanical performance and 2-FDG uptake were measured on-line, and glucose and lactate metabolic rates were calculated. Fasting raised the glycogen content by 25% and the triglyceride content by 38%. Hearts in both groups recovered preischemic function. Rates of 2-FDG uptake during the preischemic period were the same in both groups. In contrast, during the postischemic period rates of 2-FDG uptake were significantly depressed in hearts of fed animals but were unchanged in hearts of fasted animals. Thus hearts of fasted animals took up more 2-FDG during the postischemic period than hearts of fed animals (P less than 0.005). The lumped constant (range, 0.38-0.40) was the same in both groups before and after ischemia. Glucose utilization was suppressed during the postischemic period in hearts of fed animals, whereas at the same time lactate utilization was significantly increased. We conclude that 1) 2-FDG accurately traces glucose utilization independent of the nutritional state or ischemic insult; 2) reversibly ischemic, viable myocardium exhibits vastly different rates of glucose utilization depending on the nutritional state of the animal before ischemia; 3) lactate derived from glycolysis suppresses utilization of exogenously supplied glucose in the early reperfusion period without affecting postischemic performance.