Upregulated expression of neuronal nitric oxide synthase by insulin in both neurons and astrocytes

Yuan, Zhong Rui; Liu, Bao-yi; Zhang, Ye; Yuan, Lan; Muteliefu, Gulinuer; Lu, Jingfen

doi:10.1016/j.brainres.2004.01.076

Cited by 15 publications

(10 citation statements)

References 50 publications

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“…Consequently, insulin might limit free radical formation and protect the integrity of the BBB. Insulin also increases nitric oxide by upregulating nitric oxide synthase [107] and has platelet antiaggregant, anticoagulant, and pro-fibrinolytic effects [6,108,109] that could protect the flow in the microcirculation and enhance brain perfusion.…”

Section: Neuroprotective Properties Of Insulinmentioning

confidence: 99%

Treating Hyperglycemia in Neurocritical Patients: Benefits and Perils

Godoy

Napoli²,

Rabinstein

2010

Neurocrit Care

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There is growing debate over the value of intensive insulin therapy (IIT) in critically ill patients. Available trials have been performed in general medical or surgical intensive care units, and the results may not be directly applicable to patients with severe acute brain disease because these patients may have heightened susceptibility to hyperglycemia (HyperG) and hypoglycemia. Our objective was to review the pathophysiology and effects of HyperG and hypoglycemia in neurocritical patients and to analyze the potential role of IIT in this population. Source data were obtained from a PubMed search of the medical literature combining the terms HyperG, hypoglycemia, insulin, stroke, intracerebral hemorrhage (ICH), subarachnoid hemorrhage (SAH), traumatic brain injury (TBI), spinal cord injury (SCI), and related diagnoses. Brain metabolism is highly dependent on constant supply of glucose. As a consequence, the acutely injured brain is particularly sensitive to hypoglycemia, which can induce a state of energy failure (metabolic crisis). Meanwhile, neurocritical patients have a high prevalence of HyperG, and its occurrence is associated with poor outcome after acute ischemic stroke, ICH, SAH, and TBI. It is unclear whether this association is due to direct detrimental effects exerted by HyperG or simply represents a marker of severe brain injury. Insulin has been shown to have various potentially pleiotropic neuroprotective properties in experimental models. However, the safety and efficacy of IIT in patients with critical brain disease have not been well studied. Available results do not support the use of IIT to maintain strict normoglycemia in this population. Patients with critical brain disease should have frequent glucose monitoring because severe HyperG and even modest hypoglycemia may be detrimental. Careful use of insulin infusion protocols appears advisable, but maintenance of strict normoglycemia cannot be recommended. Rigorous studies must be conducted to assess the value of insulin therapy and to determine the optimal blood glucose targets in patients with the most common acute vascular and traumatic brain insults.

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Section: Neuroprotective Properties Of Insulinmentioning

confidence: 99%

Treating Hyperglycemia in Neurocritical Patients: Benefits and Perils

Godoy

Napoli²,

Rabinstein

2010

Neurocrit Care

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“…Briefly, 100 ng total RNA, in a final volume of 25 ll was used for RT into cDNA and further amplification. Sequences of oligonucleotide primers specific for nNOS were chosen according to Yuan et al (2004). The primers sequences for b-actin were as follows: fwd 5 0 -GTCACCCACACTGTGCCCATCT-3 0 and rev (5 0 -GAG-GACTCGCGTTCATGAGACA-3 0 ) to generate a 539-bp fragment.…”

Section: Determination Of Nnos By Semiquantitative Rt-pcrmentioning

confidence: 99%

Bilirubin as an endogenous modulator of neurotrophin redox signaling

Mancuso¹,

Capone

Ranieri

et al. 2008

J of Neuroscience Research

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Bilirubin is neurotoxic upon excess accumulation in the brain, but it also plays important physiological roles related to its antioxidant properties. Here we report that exposure of PC12 and primary rat cerebellar granule neurons to bilirubin (0.5-10 microM) drastically decreases nerve growth factor (NGF)/brain-derived neurotrophic factor signaling to Akt and extracellular signal-regulated kinases (ERKs), indicating a direct interference of the molecule with crucial prosurvival signaling pathways. This effect likely involves the scavenging capacity of bilirubin, the latter being able to inhibit, in PC12 cells, accumulation of intracellular reactive oxygen species and phosphorylation of Akt and ERKs in response to extracellular hydrogen peroxide. Interestingly, in the absence of exogenous growth factor, bilirubin elicited the phosphorylation of ERKs and of the cAMP responsive element binding (CREB) transcription factor, a signature of NGF-dependent survival signaling. These growth factor-like signaling effects were paralleled by the induction of the neuronal nitric oxide synthase (nNOS) and generation of nitric oxide (NO). Pharmacological dissection of the signaling cascade triggered by bilirubin revealed that phosphorylation of ERKs requires NO signaling through soluble guanylyl cyclase, and, further upstream, influx of extracellular calcium is necessary for nNOS induction and NO release, likely through calcium-dependent phosphorylation of CREB. Importantly, the cascade elicited by bilirubin through NO and ERK is cytoprotective, as revealed by exacerbated bilirubin toxicity in cultures treated by either NOS or MEK inhibitors. Taken together, these observations indicate an important action of bilirubin on redox signaling by neurotrophins, with either inhibitory or agonistic effects based on growth factor availability.

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“…52,53 Insulin was also recently shown to increase the expression of neuronal NOS in astrocytes as well as neurons. 54 Generation of NO would potentially help in vasodilatation and improved blood flow to the penumbra but also result in decreased production of ICAM-1. In addition, insulin has a direct inhibitory effect on platelet aggregation, mediated through the NO-guanylate cyclase-cGMP pathway activated by NO generated by NOS in platelets.…”

Section: Insulin Treatment Of Acute Strokementioning

confidence: 99%

Hyperglycemia, Insulin, and Acute Ischemic Stroke

Garg

Chaudhuri

Munschauer

et al. 2006

Stroke

209

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Background and Purpose-Hyperglycemia is associated with increased mortality and morbidity in acute ischemic stroke. Summary of Review-Hyperglycemia induces a pro-oxidative and proinflammatory state that can cause direct neuronal toxicity. Hyperglycemia-mediated increase in matrix metalloproteinase-9 can cause neuronal damage by an increase in cerebral edema. Moreover, hyperglycemia may be responsible for a procoagulant state that can further compromise blood supply to the penumbral areas in acute ischemic stroke. Insulin infusion has an effect that is opposite to that of hyperglycemia. It not only lowers blood glucose levels but also exerts an antioxidant and anti-inflammatory effect. Insulin also improves NO production and results in improved blood circulation to the ischemic areas. This article focuses on the potential mechanisms underlying the injurious effects of glucose and the beneficial effects of insulin. Conclusions-In the absence of other potential beneficial therapies, there is an urgency to institute trials with insulin infusion in acute ischemic stroke. (Stroke. 2006;37:267-273.)

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Upregulated expression of neuronal nitric oxide synthase by insulin in both neurons and astrocytes

Cited by 15 publications

References 50 publications

Treating Hyperglycemia in Neurocritical Patients: Benefits and Perils

Treating Hyperglycemia in Neurocritical Patients: Benefits and Perils

Bilirubin as an endogenous modulator of neurotrophin redox signaling

Hyperglycemia, Insulin, and Acute Ischemic Stroke

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