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01-08-2015 | Review Article

Intranasal Insulin and Insulin-Like Growth Factor 1 as Neuroprotectants in Acute Ischemic Stroke

Authors: Vasileios-Arsenios Lioutas, Freddy Alfaro-Martinez, Francisco Bedoya, Chen-Chih Chung, Daniela A. Pimentel, Vera Novak

Published in: Translational Stroke Research | Issue 4/2015

Abstract

Treatment options for stroke remain limited. Neuroprotective therapies, in particular, have invariably failed to yield the expected benefit in stroke patients, despite robust theoretical and mechanistic background and promising animal data. Insulin and insulin-like growth factor 1 (IGF-1) play a pivotal role in critical brain functions, such as energy homeostasis, neuronal growth, and differentiation. They may exhibit neuroprotective properties in acute ischemic stroke based upon their vasodilatory, anti-inflammatory and antithrombotic effects, as well as improvements of functional connectivity, neuronal metabolism, neurotransmitter regulation, and remyelination. Intranasally administered insulin has demonstrated a benefit for prevention of cognitive decline in older people, and IGF-1 has shown potential benefit to improve functional outcomes in animal models of acute ischemic stroke. The intranasal route presents a feasible, tolerable, safe, and particularly effective administration route, bypassing the blood–brain barrier and maximizing distribution to the central nervous system (CNS), without the disadvantages of systemic side effects and first-pass metabolism. This review summarizes the neuroprotective potential of intranasally administered insulin and IGF-1 in stroke patients. We present the theoretical background and pathophysiologic mechanisms, animal and human studies of intranasal insulin and IGF-1, and the safety and feasibility of intranasal route for medication administration to the CNS.

Kernan WN et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45(7):2160–236.PubMed

Lozano R et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2095–128.PubMed

Murray CJ et al. Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2197–223.PubMed

Jauch EC et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013;44(3):870–947.PubMed

Ciccone A, Valvassori L. Endovascular treatment for acute ischemic stroke. N Engl J Med. 2013;368(25):2433–4.PubMed

Broderick JP et al. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med. 2013;368(10):893–903.PubMedCentralPubMed

Kidwell CS et al. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med. 2013;368(10):914–23.PubMedCentralPubMed

Goyal M et al. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med. 2015;372(11):1019–30.PubMed

Campbell BC et al. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med. 2015;372(11):1009–18.PubMed

10.

Berkhemer OA et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med. 2015;372(1):11–20.PubMed

11.

Donnan GA et al. Penumbral selection of patients for trials of acute stroke therapy. Lancet Neurol. 2009;8(3):261–9.PubMed

12.

Ebinger M et al. Imaging the penumbra—strategies to detect tissue at risk after ischemic stroke. J Clin Neurosci. 2009;16(2):178–87.PubMed

13.

Zheng Z, Yenari MA. Post-ischemic inflammation: molecular mechanisms and therapeutic implications. Neurol Res. 2004;26(8):884–92.PubMed

14.

Ward NS, Cohen LG. Mechanisms underlying recovery of motor function after stroke. Arch Neurol. 2004;61(12):1844–8.PubMedCentralPubMed

15.

Vexler ZS, Tang XN, Yenari MA. Inflammation in adult and neonatal stroke. Clin Neurosci Res. 2006;6(5):293–313.PubMedCentralPubMed

16.

Wang Q, Tang XN, Yenari MA. The inflammatory response in stroke. J Neuroimmunol. 2007;184(1–2):53–68.PubMedCentralPubMed

17.

Hazell AS. Excitotoxic mechanisms in stroke: an update of concepts and treatment strategies. Neurochem Int. 2007;50(7–8):941–53.PubMed

18.

Moskowitz MA, Lo EH. Neurogenesis and apoptotic cell death. Stroke. 2003;34(2):324–6.PubMed

19.

Sairanen T et al. Apoptosis dominant in the periinfarct area of human ischaemic stroke–a possible target of antiapoptotic treatments. Brain. 2006;129(Pt 1):189–99.PubMed

20.

Broughton BR, Reutens DC, Sobey CG. Apoptotic mechanisms after cerebral ischemia. Stroke. 2009;40(5):e331–9.PubMed

21.

Yuan J. Neuroprotective strategies targeting apoptotic and necrotic cell death for stroke. Apoptosis. 2009;14(4):469–77.PubMedCentralPubMed

22.

Albers GW et al. Safety, tolerability, and pharmacokinetics of the N-methyl-D-aspartate antagonist dextrorphan in patients with acute stroke. Dextrorphan Study Group. Stroke. 1995;26(2):254–8.PubMed

23.

Davis SM et al. Termination of acute stroke studies involving selfotel treatment. ASSIST Steering Committed. Lancet. 1997;349(9044):32.PubMed

24.

Lees KR. Cerestat and other NMDA antagonists in ischemic stroke. Neurology. 1997;49(5 Suppl 4):S66–9.PubMed

25.

Muir KW et al. Magnesium for acute stroke (intravenous magnesium efficacy in stroke trial): randomised controlled trial. Lancet. 2004;363(9407):439–45.PubMed

26.

Sacco RL et al. Glycine antagonist in neuroprotection for patients with acute stroke: GAIN Americas: a randomized controlled trial. JAMA. 2001;285(13):1719–28.PubMed

27.

Horn J et al. Very Early Nimodipine Use in Stroke (VENUS): a randomized, double-blind, placebo-controlled trial. Stroke. 2001;32(2):461–5.PubMed

28.

Bath PM et al. Tirilazad for acute ischaemic stroke. Cochrane Database Syst Rev. 2001;4:CD002087.PubMed

29.

Shuaib A et al. NXY-059 for the treatment of acute ischemic stroke. N Engl J Med. 2007;357(6):562–71.PubMed

30.

Lees KR et al. NXY-059 for acute ischemic stroke. N Engl J Med. 2006;354(6):588–600.PubMed

31.

Lees KR et al. Additional outcomes and subgroup analyses of NXY-059 for acute ischemic stroke in the SAINT I trial. Stroke. 2006;37(12):2970–8.PubMed

32.

Davalos A et al. Oral citicoline in acute ischemic stroke: an individual patient data pooling analysis of clinical trials. Stroke. 2002;33(12):2850–7.PubMed

33.

Davalos A et al. Citicoline in the treatment of acute ischaemic stroke: an international, randomised, multicentre, placebo-controlled study (ICTUS trial). Lancet. 2012;380(9839):349–57.PubMed

34.

Use of anti-ICAM-1 therapy in ischemic stroke: results of the enlimomab acute stroke trial. Neurology. 2001;57(8):1428–34.

35.

Taoufik E, Probert L. Ischemic neuronal damage. Curr Pharm Des. 2008;14(33):3565–73.PubMed

36.

Arundine M, Tymianski M. Molecular mechanisms of glutamate-dependent neurodegeneration in ischemia and traumatic brain injury. Cell Mol Life Sci. 2004;61(6):657–68.PubMed

37.

Chapman KZ et al. A rapid and transient peripheral inflammatory response precedes brain inflammation after experimental stroke. J Cereb Blood Flow Metab. 2009;29(11):1764–8.PubMed

38.

Danton GH, Dietrich WD. Inflammatory mechanisms after ischemia and stroke. J Neuropathol Exp Neurol. 2003;62(2):127–36.PubMed

39.

Vila N et al. Levels of anti-inflammatory cytokines and neurological worsening in acute ischemic stroke. Stroke. 2003;34(3):671–5.PubMed

40.

Mattson MP, Culmsee C, Yu ZF. Apoptotic and antiapoptotic mechanisms in stroke. Cell Tissue Res. 2000;301(1):173–87.PubMed

41.

Schulingkamp RJ et al. Insulin receptors and insulin action in the brain: review and clinical implications. Neurosci Biobehav Rev. 2000;24(8):855–72.PubMed

42.

Margolis RU, Altszuler N. Insulin in the cerebrospinal fluid. Nature. 1967;215(5108):1375–6.PubMed

43.

King GL, Johnson SM. Receptor-mediated transport of insulin across endothelial cells. Science. 1985;227(4694):1583–6.PubMed

44.

Banks WA. The source of cerebral insulin. Eur J Pharmacol. 2004;490(1–3):5–12.PubMed

45.

Duarte AI, Moreira PI, Oliveira CR. Insulin in central nervous system: more than just a peripheral hormone. J Aging Res. 2012;2012:384017.PubMedCentralPubMed

46.

Adamo M, Raizada MK, LeRoith D. Insulin and insulin-like growth factor receptors in the nervous system. Mol Neurobiol. 1989;3(1–2):71–100.PubMed

47.

Hopkins DF, Williams G. Insulin receptors are widely distributed in human brain and bind human and porcine insulin with equal affinity. Diabet Med. 1997;14(12):1044–50.PubMed

48.

Albrecht J, Wroblewska B, Mossakowski MJ. The binding of insulin to cerebral capillaries and astrocytes of the rat. Neurochem Res. 1982;7(4):489–94.PubMed

49.

Horsch D, Kahn CR. Region-specific mRNA expression of phosphatidylinositol 3-kinase regulatory isoforms in the central nervous system of C57BL/6J mice. J Comp Neurol. 1999;415(1):105–20.PubMed

50.

Recio-Pinto E, Rechler MM, Ishii DN. Effects of insulin, insulin-like growth factor-II, and nerve growth factor on neurite formation and survival in cultured sympathetic and sensory neurons. J Neurosci. 1986;6(5):1211–9.PubMed

51.

Reger MA et al. Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype. Neurobiol Aging. 2006;27(3):451–8.PubMed

52.

Plum L, Belgardt BF, Bruning JC. Central insulin action in energy and glucose homeostasis. J Clin Invest. 2006;116(7):1761–6.PubMedCentralPubMed

53.

Bingham EM et al. The role of insulin in human brain glucose metabolism: an 18fluoro-deoxyglucose positron emission tomography study. Diabetes. 2002;51(12):3384–90.PubMed

54.

Figlewicz DP, Benoit SC. Insulin, leptin, and food reward: update 2008. Am J Physiol Regul Integr Comp Physiol. 2009;296(1):R9–19.PubMedCentralPubMed

55.

Plitzko D, Rumpel S, Gottmann K. Insulin promotes functional induction of silent synapses in differentiating rat neocortical neurons. Eur J Neurosci. 2001;14(8):1412–5.PubMed

56.

Plum L, Schubert M, Bruning JC. The role of insulin receptor signaling in the brain. Trends Endocrinol Metab. 2005;16(2):59–65.PubMed

57.

Dandona P et al. Insulin inhibits intranuclear nuclear factor kappaB and stimulates IkappaB in mononuclear cells in obese subjects: evidence for an anti-inflammatory effect? J Clin Endocrinol Metab. 2001;86(7):3257–65.PubMed

58.

Aljada A et al. Insulin inhibits the pro-inflammatory transcription factor early growth response gene-1 (Egr)-1 expression in mononuclear cells (MNC) and reduces plasma tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) concentrations. J Clin Endocrinol Metab. 2002;87(3):1419–22.PubMed

59.

Dandona P et al. Insulin suppresses plasma concentration of vascular endothelial growth factor and matrix metalloproteinase-9. Diabetes Care. 2003;26(12):3310–4.PubMed

60.

Garg R et al. Hyperglycemia, insulin, and acute ischemic stroke: a mechanistic justification for a trial of insulin infusion therapy. Stroke. 2006;37(1):267–73.PubMed

61.

Aljada A et al. Insulin inhibits the expression of intercellular adhesion molecule-1 by human aortic endothelial cells through stimulation of nitric oxide. J Clin Endocrinol Metab. 2000;85(7):2572–5.PubMed

62.

Huang SS et al. The essential role of endothelial nitric oxide synthase activation in insulin-mediated neuroprotection against ischemic stroke in diabetes. J Vasc Surg. 2014;59(2):483–91.PubMed

63.

Philpott KL et al. Activated phosphatidylinositol 3-kinase and Akt kinase promote survival of superior cervical neurons. J Cell Biol. 1997;139(3):809–15.PubMedCentralPubMed

64.

Dimmeler S et al. Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature. 1999;399(6736):601–5.PubMed

65.

McKay MK, Hester RL. Role of nitric oxide, adenosine, and ATP-sensitive potassium channels in insulin-induced vasodilation. Hypertension. 1996;28(2):202–8.PubMed

66.

Duarte AI et al. Insulin neuroprotection against oxidative stress is mediated by Akt and GSK-3beta signaling pathways and changes in protein expression. Biochim Biophys Acta. 2008;1783(6):994–1002.PubMed

67.

Ueda H. Prothymosin alpha plays a key role in cell death mode-switch, a new concept for neuroprotective mechanisms in stroke. Naunyn Schmiedebergs Arch Pharmacol. 2008;377(4–6):315–23.PubMed

68.

Song J et al. Axons guided by insulin receptor in Drosophila visual system. Science. 2003;300(5618):502–5.PubMed

69.

Guyot LL et al. The effect of topical insulin on the release of excitotoxic and other amino acids from the rat cerebral cortex during streptozotocin-induced hyperglycemic ischemia. Brain Res. 2000;872(1–2):29–36.PubMed

70.

Novak V et al. Enhancement of vasoreactivity and cognition by intranasal insulin in type 2 diabetes. Diabetes Care. 2014;37(3):751–9.PubMedCentralPubMed

71.

Craft S et al. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol. 2012;69(1):29–38.PubMedCentralPubMed

72.

Zhang H, et al. Intranasal insulin enhanced resting-state functional connectivity of hippocampal regions in type 2 diabetes. Diabetes. 2014.

73.

Lochhead JJ, Thorne RG. Intranasal delivery of biologics to the central nervous system. Adv Drug Deliv Rev. 2012;64(7):614–28.PubMed

74.

Costantino HR et al. Intranasal delivery: physicochemical and therapeutic aspects. Int J Pharm. 2007;337(1–2):1–24.PubMed

75.

Migliore MM et al. Brain delivery of proteins by the intranasal route of administration: a comparison of cationic liposomes versus aqueous solution formulations. J Pharm Sci. 2010;99(4):1745–61.PubMed

76.

Liu XF et al. Intranasal administration of insulin-like growth factor-I bypasses the blood–brain barrier and protects against focal cerebral ischemic damage. J Neurol Sci. 2001;187(1–2):91–7.PubMed

77.

Hanson LR, Frey 2nd WH. Intranasal delivery bypasses the blood–brain barrier to target therapeutic agents to the central nervous system and treat neurodegenerative disease. BMC Neurosci. 2008;9 Suppl 3:S5.PubMedCentralPubMed

78.

Merkus FW, van den Berg MP. Can nasal drug delivery bypass the blood–brain barrier?: questioning the direct transport theory. Drugs R&D. 2007;8(3):133–44.

79.

Merkus P et al. Direct access of drugs to the human brain after intranasal drug administration? Neurology. 2003;60(10):1669–71.PubMed

80.

Thorne RG et al. Delivery of insulin-like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration. Neuroscience. 2004;127(2):481–96.PubMed

81.

Ross TM et al. Intranasal administration of interferon beta bypasses the blood–brain barrier to target the central nervous system and cervical lymph nodes: a non-invasive treatment strategy for multiple sclerosis. J Neuroimmunol. 2004;151(1–2):66–77.PubMed

82.

Hilsted J et al. Intranasal insulin therapy: the clinical realities. Diabetologia. 1995;38(6):680–4.PubMed

83.

Benedict C et al. Intranasal insulin improves memory in humans. Psychoneuroendocrinology. 2004;29(10):1326–34.PubMed

84.

Reger MA et al. Intranasal insulin improves cognition and modulates beta-amyloid in early AD. Neurology. 2008;70(6):440–8.PubMed

85.

Park CR et al. Intracerebroventricular insulin enhances memory in a passive-avoidance task. Physiol Behav. 2000;68(4):509–14.PubMed

86.

Benedict C et al. Intranasal insulin improves memory in humans: superiority of insulin aspart. Neuropsychopharmacology. 2007;32(1):239–43.PubMed

87.

Reger MA et al. Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-beta in memory-impaired older adults. J Alzheimers Dis. 2008;13(3):323–31.PubMedCentralPubMed

88.

Freiherr J et al. Intranasal insulin as a treatment for Alzheimer’s disease: a review of basic research and clinical evidence. CNS Drugs. 2013;27(7):505–14.PubMedCentralPubMed

89.

Banks WA, Owen JB, Erickson MA. Insulin in the brain: there and back again. Pharmacol Ther. 2012;136(1):82–93.PubMedCentralPubMed

90.

Cholerton B, Baker LD, Craft S. Insulin, cognition, and dementia. Eur J Pharmacol. 2013;719(1–3):170–9.PubMed

91.

Cholerton B et al. Insulin and sex interactions in older adults with mild cognitive impairment. J Alzheimers Dis. 2012;31(2):401–10.PubMedCentralPubMed

92.

Schioth HB et al. Brain insulin signaling and Alzheimer’s disease: current evidence and future directions. Mol Neurobiol. 2012;46(1):4–10.PubMedCentralPubMed

93.

Benedict C et al. Immediate but not long-term intranasal administration of insulin raises blood pressure in human beings. Metabolism. 2005;54(10):1356–61.PubMed

94.

Figlewicz DP. Insulin, food intake, and reward. Semin Clin Neuropsychiatry. 2003;8(2):82–93.PubMed

95.

Farris W et al. Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci U S A. 2003;100(7):4162–7.PubMedCentralPubMed

96.

Humpel C. Chronic mild cerebrovascular dysfunction as a cause for Alzheimer’s disease? Exp Gerontol. 2011;46(4):225–32.PubMedCentralPubMed

97.

Exalto LG et al. An update on type 2 diabetes, vascular dementia and Alzheimer’s disease. Exp Gerontol. 2012;47(11):858–64.PubMed

98.

Dede DS et al. Assessment of endothelial function in Alzheimer’s disease: is Alzheimer’s disease a vascular disease? J Am Geriatr Soc. 2007;55(10):1613–7.PubMed

99.

Yang Y et al. Intranasal insulin ameliorates tau hyperphosphorylation in a rat model of type 2 diabetes. J Alzheimers Dis. 2013;33(2):329–38.PubMed

100.

Wang X et al. Insulin deficiency exacerbates cerebral amyloidosis and behavioral deficits in an Alzheimer transgenic mouse model. Mol Neurodegener. 2010;5:46.PubMedCentralPubMed

101.

Liu Y et al. Deficient brain insulin signalling pathway in Alzheimer’s disease and diabetes. J Pathol. 2011;225(1):54–62.PubMed

102.

Hoyer S. The aging brain. Changes in the neuronal insulin/insulin receptor signal transduction cascade trigger late-onset sporadic Alzheimer disease (SAD). A mini-review. J Neural Transm. 2002;109(7–8):991–1002.PubMed

103.

Jauch-Chara K et al. Intranasal insulin suppresses food intake via enhancement of brain energy levels in humans. Diabetes. 2012;61(9):2261–8.PubMedCentralPubMed

104.

Heni M et al. Nasal insulin changes peripheral insulin sensitivity simultaneously with altered activity in homeostatic and reward-related human brain regions. Diabetologia. 2012;55(6):1773–82.PubMed

105.

McInnes GT. The expanding role of angiotensin receptor blockers in the management of the elderly hypertensive. Curr Med Res Opin. 2003;19(5):452–5.PubMed

106.

Benedict C et al. Differential sensitivity of men and women to anorexigenic and memory-improving effects of intranasal insulin. J Clin Endocrinol Metab. 2008;93(4):1339–44.PubMed

107.

Dong X et al. The relationship between serum insulin-like growth factor I levels and ischemic stroke risk. PLoS One. 2014;9(4):e94845.PubMedCentralPubMed

108.

Benarroch EE. Insulin-like growth factors in the brain and their potential clinical implications. Neurology. 2012;79(21):2148–53.PubMed

109.

Kern W et al. Improving influence of insulin on cognitive functions in humans. Neuroendocrinology. 2001;74(4):270–80.PubMed

110.

Kern W et al. Central nervous system effects of intranasally administered insulin during euglycemia in men. Diabetes. 1999;48(3):557–63.PubMed

111.

Kalmijn S et al. A prospective study on circulating insulin-like growth factor I (IGF-I), IGF-binding proteins, and cognitive function in the elderly. J Clin Endocrinol Metab. 2000;85(12):4551–5.PubMed

112.

Fernandez AM, Torres-Aleman I. The many faces of insulin-like peptide signalling in the brain. Nat Rev Neurosci. 2012;13(4):225–39.PubMed

113.

Frauman AG, Jerums G, Louis WJ. Effects of intranasal insulin in non-obese type II diabetics. Diabetes Res Clin Pract. 1987;3(4):197–202.PubMed

114.

Hallschmid M et al. Towards the therapeutic use of intranasal neuropeptide administration in metabolic and cognitive disorders. Regul Pept. 2008;149(1–3):79–83.PubMed

115.

Schilling TM et al. Intranasal insulin increases regional cerebral blood flow in the insular cortex in men independently of cortisol manipulation. Hum Brain Mapp. 2014;35(5):1944–56.PubMed

116.

Lalej-Bennis D et al. Six month administration of gelified intranasal insulin in 16 type 1 diabetic patients under multiple injections: efficacy vs subcutaneous injections and local tolerance. Diabetes Metab. 2001;27(3):372–7.PubMed

117.

Frauman AG et al. Long-term use of intranasal insulin in insulin-dependent diabetic patients. Diabetes Care. 1987;10(5):573–8.PubMed

118.

Lalej-Bennis D et al. Efficacy and tolerance of intranasal insulin administered during 4 months in severely hyperglycaemic Type 2 diabetic patients with oral drug failure: a cross-over study. Diabet Med. 2001;18(8):614–8.PubMed

119.

Chesik D, De Keyser J, Wilczak N. Insulin-like growth factor system regulates oligodendroglial cell behavior: therapeutic potential in CNS. J Mol Neurosci. 2008;35(1):81–90.PubMed

120.

Espinosa-Jeffrey A et al. Transferrin regulates transcription of the MBP gene and its action synergizes with IGF-1 to enhance myelinogenesis in the md rat. Dev Neurosci. 2002;24(2–3):227–41.PubMed

121.

Heck S et al. Insulin-like growth factor-1-mediated neuroprotection against oxidative stress is associated with activation of nuclear factor kappaB. J Biol Chem. 1999;274(14):9828–35.PubMed

122.

Matsuzaki H et al. Activation of Akt kinase inhibits apoptosis and changes in Bcl-2 and Bax expression induced by nitric oxide in primary hippocampal neurons. J Neurochem. 1999;73(5):2037–46.PubMed

123.

Vincent AM et al. IGF-I prevents glutamate-induced motor neuron programmed cell death. Neurobiol Dis. 2004;16(2):407–16.PubMed

124.

Johnston BM et al. Insulin-like growth factor-1 is a potent neuronal rescue agent after hypoxic-ischemic injury in fetal lambs. J Clin Invest. 1996;97(2):300–8.PubMedCentralPubMed

125.

Russo VC et al. The insulin-like growth factor system and its pleiotropic functions in brain. Endocr Rev. 2005;26(7):916–43.PubMed

126.

Torres-Aleman I. Insulin-like growth factors as mediators of functional plasticity in the adult brain. Horm Metab Res. 1999;31(2–3):114–9.PubMed

127.

Torres Aleman I. Role of insulin-like growth factors in neuronal plasticity and neuroprotection. Adv Exp Med Biol. 2005;567:243–58.PubMed

128.

Johnsen SP et al. Insulin-like growth factor (IGF) I, −II, and IGF binding protein-3 and risk of ischemic stroke. J Clin Endocrinol Metab. 2005;90(11):5937–41.PubMed

129.

Aberg D et al. Serum IGF-I levels correlate to improvement of functional outcome after ischemic stroke. J Clin Endocrinol Metab. 2011;96(7):E1055–64.PubMed

130.

Denti L et al. Insulin-like growth factor 1 as a predictor of ischemic stroke outcome in the elderly. Am J Med. 2004;117(5):312–7.PubMed

131.

Schabitz WR et al. Delayed neuroprotective effect of insulin-like growth factor-i after experimental transient focal cerebral ischemia monitored with MRI. Stroke. 2001;32(5):1226–33.PubMed

132.

Rizk NN et al. Insulin like growth factor-1 (IGF-1) decreases ischemia-reperfusion induced apoptosis and necrosis in diabetic rats. Endocrine. 2007;31(1):66–71.PubMed

133.

Shirakura M et al. Postischemic administration of Sendai virus vector carrying neurotrophic factor genes prevents delayed neuronal death in gerbils. Gene Ther. 2004;11(9):784–90.PubMed

134.

Wang JM et al. Reduction of ischemic brain injury by topical application of insulin-like growth factor-I after transient middle cerebral artery occlusion in rats. Brain Res. 2000;859(2):381–5.PubMed

135.

Liu XF et al. The window of opportunity for treatment of focal cerebral ischemic damage with noninvasive intranasal insulin-like growth factor-I in rats. J Stroke Cerebrovasc Dis. 2004;13(1):16–23.PubMed

136.

Liu XF et al. Non-invasive intranasal insulin-like growth factor-I reduces infarct volume and improves neurologic function in rats following middle cerebral artery occlusion. Neurosci Lett. 2001;308(2):91–4.PubMed

137.

Rizk NN, Rafols J, Dunbar JC. Cerebral ischemia induced apoptosis and necrosis in normal and diabetic rats. Brain Res. 2005;1053(1–2):1–9.PubMed

138.

Rizk NN, Rafols JA, Dunbar JC. Cerebral ischemia-induced apoptosis and necrosis in normal and diabetic rats: effects of insulin and C-peptide. Brain Res. 2006;1096(1):204–12.PubMed

139.

Kooijman R et al. Insulin-like growth factor I: a potential neuroprotective compound for the treatment of acute ischemic stroke? Stroke. 2009;40(4):e83–8.PubMed

140.

Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke. 1999;30(12):2752–8.

141.

Hanson LR et al. Intranasal deferoxamine provides increased brain exposure and significant protection in rat ischemic stroke. J Pharmacol Exp Ther. 2009;330(3):679–86.PubMedCentralPubMed

142.

Akpan N et al. Intranasal delivery of caspase-9 inhibitor reduces caspase-6-dependent axon/neuron loss and improves neurological function after stroke. J Neurosci. 2011;31(24):8894–904.PubMedCentralPubMed

143.

Fletcher L et al. Intranasal delivery of erythropoietin plus insulin-like growth factor-I for acute neuroprotection in stroke. Laboratory investigation. J Neurosurg. 2009;111(1):164–70.PubMed

144.

Yang JP et al. The dose-effectiveness of intranasal VEGF in treatment of experimental stroke. Neurosci Lett. 2009;461(3):212–6.PubMed

145.

Di Lazzaro V et al. Motor cortex plasticity predicts recovery in acute stroke. Cereb Cortex. 2010;20(7):1523–8.PubMed

146.

Witsch J et al. Hypoglycemic encephalopathy: a case series and literature review on outcome determination. J Neurol. 2012;259(10):2172–81.PubMed

147.

Fujioka M et al. Specific changes in human brain after hypoglycemic injury. Stroke. 1997;28(3):584–7.PubMed

148.

Albers GW et al. Stroke Treatment Academic Industry Roundtable (STAIR) recommendations for maximizing the use of intravenous thrombolytics and expanding treatment options with intra-arterial and neuroprotective therapies. Stroke. 2011;42(9):2645–50.PubMed

Title: Intranasal Insulin and Insulin-Like Growth Factor 1 as Neuroprotectants in Acute Ischemic Stroke
Authors: Vasileios-Arsenios Lioutas
Freddy Alfaro-Martinez
Francisco Bedoya
Chen-Chih Chung
Daniela A. Pimentel
Vera Novak
Publication date: 01-08-2015
Publisher: Springer US
Published in: Translational Stroke Research / Issue 4/2015
Print ISSN: 1868-4483
Electronic ISSN: 1868-601X
DOI: https://doi.org/10.1007/s12975-015-0409-7

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Intranasal Insulin and Insulin-Like Growth Factor 1 as Neuroprotectants in Acute Ischemic Stroke

Abstract

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

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