RETRACTED: The importance of regulation of blood glucose levels through activation of peripheral 5′-AMP-activated protein kinase on ischemic neuronal damage

Harada, Shinichi; Fujita-Hamabe, Wakako; Tokuyama, Shogo

doi:10.1016/j.brainres.2010.06.052

Cited by 42 publications

(30 citation statements)

References 22 publications

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“…As we found in our previous reports (7,8), ischemic neuronal damage could be triggered by glucose intolerance (post-ischemic glucose intolerance) that develops during the early phase of the onset of focal cerebral ischemic stress. Here, we showed that cerebral ischemic stress significantly decreased the expression levels of InsR and p-InsR in the liver but not in skeletal muscle.…”

Section: Discussionsupporting

confidence: 58%

“…Western blotting was performed as previously described (8,20) but with some modifications. Briefly, the liver and skeletal muscle were homogenized in homogenization buffer and protein samples (30 μg) were electrophoresed in 7.5% SDS-PAGE acrylamide gels and then transferred onto nitrocellulose membranes (BioRad, Hercules, CA, USA).…”

Section: Western Blot Analysismentioning

confidence: 99%

“…Clinically, cerebral ischemic neuronal damage is exacerbated in patients with a history of glucose intolerance or diabetes mellitus (6). We recently found that the cerebral ischemic stress per se causes hyperglycemia (i.e., postischemic glucose intolerance) and it may worsen ischemic neuronal damage in focal ischemic model mice (7,8). In addition, decreased insulin sensitivity after cerebral ischemic stress seems to be involved in the development of post-ischemic glucose intolerance (7).…”

Section: Introductionmentioning

confidence: 99%

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Effect of Orexin-A on Post-ischemic Glucose Intolerance and Neuronal Damage

2011

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Abstract. Orexin-A is a newly identified neuropeptide expressed in the lateral areas of the hypothalamus that plays a role in various physiological functions, including regulation of glucose metabolism. We have previously reported that the development of post-ischemic glucose intolerance is one of the triggers of ischemic neuronal damage. Therefore, the aim of this study was to determine the effects of orexin-A on the development of post-ischemic glucose intolerance and ischemic neuronal damage. Male ddY mice were subjected to middle cerebral artery occlusion (MCAO) for 2 h. Neuronal damage was estimated by histological and behavioral analysis after MCAO. Intracerebroventricular administration of orexin-A (2.5, 25, or 250 pmol/mouse) significantly and dose-dependently suppressed the development of post-ischemic glucose intolerance on day 1 after MCAO and neuronal damage on day 3 after MCAO. In the liver and skeletal muscle, the expression levels of insulin receptor were decreased, whereas those of gluconeogenic enzymes were increased on day 1 after MCAO. Furthermore, these expressions were completely recovered to normal levels by orexin-A and were reversed by the administration of SB334867, a specific orexin-1 receptor antagonist. These results suggest that regulation of post-ischemic glucose intolerance by orexin-A suppressed cerebral ischemic neuronal damage.

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Section: Discussionsupporting

confidence: 58%

Section: Western Blot Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effect of Orexin-A on Post-ischemic Glucose Intolerance and Neuronal Damage

2011

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“…The beneficial effect of metformin on blood glucose levels appears to be a result of complex multifactorial mechanisms: a) through the activation of AMPK followed by decreased hepatic gluconeogenesis leading to reduce glucose output (92); b) increased uptake of glucose by skeletal muscles and white adipocytes (93); and c) through an enhanced metabolic profile with an additional weight reduction capacity (94). As described above, we have already confirmed that the activated state of AMPK in peripheral tissue is normally conserved regardless of whether or not cerebral ischemic stress is present (67). In turn, it is possible that the peripheral activation of AMPK after ischemic stress might suppress ischemic neuronal damage by inhibiting development of post-ischemic glucose intolerance.…”

Section: Anti-diabetic Drugs (Metformin)supporting

confidence: 72%

“…In peripheral tissues, AMPK is known to regulate glucose metabolism by stimulating the translocation of GLUT4 in skeletal muscles and suppressing gluconeogenesis in the liver (66), resulting in a decrease of blood glucose levels. Although it is hypothesized that the peripheral AMPK activation cascade should be suppressed by cerebral ischemic stress, based on our findings, in liver and skeletal muscle, AMPK activation was not affected by cerebral ischemic stress (67). These results suggest that some mechanisms such as downregulation of the PPAR-α signaling pathway, (another downstream pathway of adiponectin receptor), rather than downregulation of hepatic AMPK, may be involved in the development of post-ischemic glucose intolerance (45,60).…”

Section: Interaction Between Adiponectin and Postischemic Glucose Intmentioning

confidence: 50%

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

2012

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Abstract. 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.

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