The neuroprotection of insulin on ischemic brain injury in rat hippocampus through negative regulation of JNK signaling pathway by PI3K/Akt activation

Liang, Hui; Pei, Dong; Zhang, Quan Guang; Guan, Qiu-Hua; Zhang, Guang Yi

doi:10.1016/j.brainres.2005.05.043

Cited by 114 publications

(68 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The data emerging from the present study demonstrate that the overexpression of constitutively active Akt1, the most highly diffused and expressed isoform in the brain (Hanada et al, 2004;Hui et al, 2005), induces an up-regulation of NCX1 and NCX3. Regarding NCX1 up-regulation induced by Akt1 activation, this occurs at the transcriptional level because there was an increase in NCX1 transcript and it was counteracted by CREB1 inhibition through siRNA strategy.…”

Section: Discussionsupporting

confidence: 52%

The Two Isoforms of the Na⁺/Ca²⁺Exchanger, NCX1 and NCX3, Constitute Novel Additional Targets for the Prosurvival Action of Akt/Protein Kinase B Pathway

et al. 2007

View full text Add to dashboard Cite

The proteins NCX1, NCX2, and NCX3 expressed on the plasma membrane of neurons play a crucial role in ionic regulation because they are the major bidirectional system promoting the efflux and influx of Na ϩ and Ca 2ϩ ions. Here, we demonstrate that NCX1 and NCX3 proteins are novel additional targets for the survival action of the phosphatidylinositol 3-kinase (PI3-K)/ Akt pathway. Indeed, the doxycycline-dependent overexpression of constitutively active Akt1 in tetracycline (Tet)-Off PC-12 positive mutants and the exposure of Tet-Off PC-12 wild type to nerve growth factor induced an up-regulation of NCX1 and NCX3 proteins. NCX1 up-regulation induced by Akt1 activation occurred at the transcriptional level because NCX1 mRNA increased, and it was counteracted by cAMP response element-binding protein 1 inhibition through small interfering RNA strategy. In contrast, Akt1-induced NCX3 up-regulation recognized a post-transcriptional mechanism occurring at the proteasome level because 1) NCX3 transcript did not increase and 2) the proteasome inhibitor N-benzyloxycarbonyl (Z)-Leu-Leu-leucinal (MG-132) did not further enhance NCX3 protein levels in Akt1 active mutants as it would be expected if the ubiquitin-proteasome complex was not already blocked by Akt1 pathway. As expected, in PC-12 Tet-Off wild-type cells MG-132 enhanced NCX3 protein levels. This up-regulation produced an increased activity of NCX function. Furthermore, NCX1 and NCX3 up-regulation contributed to the survival action of Akt1 during chemical hypoxia because both the silencing of NCX1 or NCX3 and the pharmacological paninhibition of NCX isoforms reduced the prosurvival property of Akt1. Together, these results indicated that NCX1 and NCX3 represent novel additional molecular targets for the prosurvival action of PI3-K/Akt pathway. with the entrance of Na ϩ ions, or in the "reverse mode" by mediating the extrusion of Na ϩ to the entrance of Ca 2ϩ ions (Blaustein and Lederer, 1999;Philipson and Nicoll, 2000;Annunziato et al., 2004). To date, three ncx genes-ncx1, ncx2, ncx3-have been identified and cloned. Whereas NCX1 is ubiquitously expressed, NCX2 and NCX3 are expressed exclusively in the brain and in the skeletal muscle (Lee et al., 1994). Specifically, NCX1, NCX2, and NCX3 are expressed in neurons, astrocytes, oligodendrocytes, and microglia (Quednau et al., 1997;Thurneysen et al., 2002;Nagano et al., ABBREVIATIONS: NCX, Na ϩ /Ca 2ϩ exchanger; PKB, protein kinase B; Tet, tetracycline; siRNA, small interfering RNA; FBS, fetal bovine serum; CREB, cAMP response element-binding; PI3-K, phosphatidylinositol 3-kinase; p-, phosphorylated; ECL, enhanced chemiluminescence; LY294002, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; HA, hemagglutinin; PI, propidium iodide; FDA, fluorescein diacetate; NGF, nerve growth factor; MG-132, N-benzyloxycarbonyl (Z)-Leu-Leu-leucinal; tTA, tetracycline-controlled transactivator; EGFP, enhanced green fluorescent protein; GSK, glycogen synthase kinase; PMCA, plasma membrane Ca 2ϩ -ATPase; RT-PCR, reverse transcr...

show abstract

Section: Discussionsupporting

confidence: 52%

The Two Isoforms of the Na⁺/Ca²⁺Exchanger, NCX1 and NCX3, Constitute Novel Additional Targets for the Prosurvival Action of Akt/Protein Kinase B Pathway

et al. 2007

View full text Add to dashboard Cite

show abstract

“…Following the episode of hypoglycemia, the effects of chronic hyperglycemia may have been toxic to vulnerable neurons, causing increased brain damage (26,30). Since insulin has been shown to be neuroprotective in other models of brain damage, the chronic relative insulin deficiency in STZ rats may have played a role in enhanced brain damage (19,29,38,53). There is evidence that neuronal damage induced from an episode of severe hypoglycemia is actually initiated when high concentrations of glucose are infused during the recovery period (46).…”

Section: Discussionmentioning

confidence: 99%

Diabetes increases brain damage caused by severe hypoglycemia

Bree¹,

Tejera²,

Daphna-Iken³

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

107

101

View full text Add to dashboard Cite

Bree AJ, Puente EC, Daphna-Iken D, Fisher SJ. Diabetes increases brain damage caused by severe hypoglycemia. Am J Physiol Endocrinol Metab 297: E194 -E201, 2009. First published May 12, 2009 doi:10.1152/ajpendo.91041.2008.-Insulin-induced severe hypoglycemia causes brain damage. The hypothesis to be tested was that diabetes portends to more extensive brain tissue damage following an episode of severe hypoglycemia. Nine-week-old male streptozotocin-diabetic (DIAB; n ϭ 10) or vehicle-injected control (CONT; n ϭ 7) SpragueDawley rats were subjected to hyperinsulinemic (0.2 U⅐kg Ϫ1 ⅐min Ϫ1 ) severe hypoglycemic (10 -15 mg/dl) clamps while awake and unrestrained. Groups were precisely matched for depth and duration (1 h) of severe hypoglycemia (CONT 11 Ϯ 0.5 and DIAB 12 Ϯ 0.2 mg/dl, P ϭ not significant). During severe hypoglycemia, an equal number of episodes of seizure-like activity were noted in both groups. One week later, histological analysis demonstrated extensive neuronal damage in regions of the hippocampus, especially in the dentate gyrus and CA1 regions and less so in the CA3 region (P Ͻ 0.05), although total hippocampal damage was not different between groups. However, in the cortex, DIAB rats had significantly (2.3-fold) more dead neurons than CONT rats (P Ͻ 0.05). There was a strong correlation between neuronal damage and the occurrence of seizure-like activity (r 2 Ͼ 0.9). Separate studies conducted in groups of diabetic (n ϭ 5) and nondiabetic (n ϭ 5) rats not exposed to severe hypoglycemia showed no brain damage. In summary, under the conditions studied, severe hypoglycemia causes brain damage in the cortex and regions within the hippocampus, and the extent of damage is closely correlated to the presence of seizure-like activity in nonanesthetized rats. It is concluded that, in response to insulin-induced severe hypoglycemia, diabetes uniquely increases the vulnerability of specific brain areas to neuronal damage.Fluoro-Jade; insulin; seizure; streptozotocin HYPOGLYCEMIA IS THE MOST PREVALENT clinical complication in the daily management of insulin-treated people with diabetes, and hypoglycemia continues to be the limiting factor in the glycemic management of diabetes (15). Since severe hypoglycemia affects 40% of insulin-treated people with diabetes (49), concern regarding the hazardous potential for severe hypoglycemia to cause "brain damage" continues to be a very real barrier in striving to fully realize the benefits associated with intensive glycemic control (14). Animal models have unambiguously demonstrated that acute episodes of severe hypoglycemia [blood glucose (BG) Ͻ18 mg/dl] reproducibly induce neuronal damage, especially in the vulnerable neurons in the cortex and hippocampus (2,9,33,44,45,54). Deficits in learning and memory have been shown to be a direct consequence of this severe hypoglycemia-induced hippocampal neuronal damage (2,44,45). However, clincial studies in patients with diabetes have yielded variable results, since episodes of severe hypoglycemia have been shown to alter br...

show abstract

“…Hui et al [297] have shown that cerebral ischemia-reperfusion increases the phosphorylation of JNK1/2 and c-jun and elevates Bcl-2 expression and caspase-3 cleavage in the rat hippocampus. In this study, insulin administration reverses all mentioned molecular changes, and so, it can be concluded that a cross-talk exist between Akt and JNK1/2 which play a role in the anti-ischemic effects of insulin [297]. Another molecular component which has been shown to be involved in ischemia-reperfusion injury is GSK-3β.…”

Section: Protective Effects Against Ischemiamentioning

confidence: 99%

Insulin in the Brain: Sources, Localization and Functions

et al. 2012

View full text Add to dashboard Cite

Historically, insulin is best known for its role in peripheral glucose homeostasis, and insulin signaling in the brain has received less attention. Insulin-independent brain glucose uptake has been the main reason for considering the brain as an insulin-insensitive organ. However, recent findings showing a high concentration of insulin in brain extracts, and expression of insulin receptors (IRs) in central nervous system tissues have gathered considerable attention over the sources, localization, and functions of insulin in the brain. This review summarizes the current status of knowledge of the peripheral and central sources of insulin in the brain, site-specific expression of IRs, and also neurophysiological functions of insulin including the regulation of food intake, weight control, reproduction, and cognition and memory formation. This review also considers the neuromodulatory and neurotrophic effects of insulin, resulting in proliferation, differentiation, and neurite outgrowth, introducing insulin as an attractive tool for neuroprotection against apoptosis, oxidative stress, beta amyloid toxicity, and brain ischemia.

show abstract

The neuroprotection of insulin on ischemic brain injury in rat hippocampus through negative regulation of JNK signaling pathway by PI3K/Akt activation

Cited by 114 publications

References 30 publications

The Two Isoforms of the Na⁺/Ca²⁺Exchanger, NCX1 and NCX3, Constitute Novel Additional Targets for the Prosurvival Action of Akt/Protein Kinase B Pathway

The Two Isoforms of the Na⁺/Ca²⁺Exchanger, NCX1 and NCX3, Constitute Novel Additional Targets for the Prosurvival Action of Akt/Protein Kinase B Pathway

Diabetes increases brain damage caused by severe hypoglycemia

Insulin in the Brain: Sources, Localization and Functions

Contact Info

Product

Resources

About

The neuroprotection of insulin on ischemic brain injury in rat hippocampus through negative regulation of JNK signaling pathway by PI3K/Akt activation

Cited by 114 publications

References 30 publications

The Two Isoforms of the Na+/Ca2+Exchanger, NCX1 and NCX3, Constitute Novel Additional Targets for the Prosurvival Action of Akt/Protein Kinase B Pathway

The Two Isoforms of the Na+/Ca2+Exchanger, NCX1 and NCX3, Constitute Novel Additional Targets for the Prosurvival Action of Akt/Protein Kinase B Pathway

Diabetes increases brain damage caused by severe hypoglycemia

Insulin in the Brain: Sources, Localization and Functions

Contact Info

Product

Resources

About

The Two Isoforms of the Na⁺/Ca²⁺Exchanger, NCX1 and NCX3, Constitute Novel Additional Targets for the Prosurvival Action of Akt/Protein Kinase B Pathway

The Two Isoforms of the Na⁺/Ca²⁺Exchanger, NCX1 and NCX3, Constitute Novel Additional Targets for the Prosurvival Action of Akt/Protein Kinase B Pathway