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

Translational Stroke Research

Volumn 6, Issue 4, 2015, Pages 264-275

  Lioutas, Vasileios Arsenios ^a   Alfaro Martinez, Freddy ^a   Bedoya, Francisco ^a   Chung, Chen Chih ^a,b   Pimentel, Daniela A ^a   Novak, Vera ^a  

^a BETH ISRAEL DEACONESS MEDICAL CENTER   (United States)

^b TAIPEI MEDICAL UNIVERSITY   (Taiwan)

Author keywords

Acute ischemic stroke; Intranasal IGF 1; Intranasal insulin; Intranasal insulin like growth factor 1; Neuroprotection; Stroke

Indexed keywords

ANTICOAGULANT AGENT; APOPTOSIS INHIBITOR; INSULIN; INSULIN RECEPTOR; SOMATOMEDIN C; VASODILATOR AGENT; NEUROPROTECTIVE AGENT;

ANTIINFLAMMATORY ACTIVITY; BRAIN ISCHEMIA; CENTRAL NERVOUS SYSTEM; CLINICAL TRIAL (TOPIC); DRUG EFFICACY; DRUG MECHANISM; DRUG SAFETY; EXPERIMENTAL STROKE; GLUCOSE TRANSPORT; HUMAN; HYPOGLYCEMIA; INSULIN TREATMENT; METABOLIC SYNDROME X; MIDDLE CEREBRAL ARTERY OCCLUSION; NERVE CELL NECROSIS; NEUROMODULATION; NEUROPROTECTION; NONHUMAN; OXIDATIVE STRESS; PATHOPHYSIOLOGY; PRIORITY JOURNAL; PROTEIN BLOOD LEVEL; PROTEIN LOCALIZATION; RAT MODEL; REVIEW; STROKE PATIENT; TRANSPORT KINETICS; ANIMAL; COMPLICATION; DISEASE MODEL; INTRANASAL DRUG ADMINISTRATION; STROKE;

ADMINISTRATION, INTRANASAL; ANIMALS; BRAIN ISCHEMIA; DISEASE MODELS, ANIMAL; HUMANS; INSULIN; INSULIN-LIKE GROWTH FACTOR I; NEUROPROTECTIVE AGENTS; STROKE;

EID: 84933678110     PISSN: 18684483     EISSN: 1868601X     Source Type: Journal    
DOI: 10.1007/s12975-015-0409-7     Document Type: Review

References (148)

1. 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.
2. 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.
3. 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.
4. 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.
5. Ciccone A, Valvassori L. Endovascular treatment for acute ischemic stroke. N Engl J Med. 2013;368(25):2433–4.
6. 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.
7. Kidwell CS et al. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med. 2013;368(10):914–23.
8. Goyal M et al. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med. 2015;372(11):1019–30.
9. Campbell BC et al. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med. 2015;372(11):1009–18.
10. Berkhemer OA et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med. 2015;372(1):11–20.
11. Donnan GA et al. Penumbral selection of patients for trials of acute stroke therapy. Lancet Neurol. 2009;8(3):261–9.
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.
13. Zheng Z, Yenari MA. Post-ischemic inflammation: molecular mechanisms and therapeutic implications. Neurol Res. 2004;26(8):884–92.
14. Ward NS, Cohen LG. Mechanisms underlying recovery of motor function after stroke. Arch Neurol. 2004;61(12):1844–8.
15. Vexler ZS, Tang XN, Yenari MA. Inflammation in adult and neonatal stroke. Clin Neurosci Res. 2006;6(5):293–313.
16. Wang Q, Tang XN, Yenari MA. The inflammatory response in stroke. J Neuroimmunol. 2007;184(1–2):53–68.
17. Hazell AS. Excitotoxic mechanisms in stroke: an update of concepts and treatment strategies. Neurochem Int. 2007;50(7–8):941–53.
18. Moskowitz MA, Lo EH. Neurogenesis and apoptotic cell death. Stroke. 2003;34(2):324–6.
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.
20. Broughton BR, Reutens DC, Sobey CG. Apoptotic mechanisms after cerebral ischemia. Stroke. 2009;40(5):e331–9.
21. Yuan J. Neuroprotective strategies targeting apoptotic and necrotic cell death for stroke. Apoptosis. 2009;14(4):469–77.
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.
23. Davis SM et al. Termination of acute stroke studies involving selfotel treatment. ASSIST Steering Committed. Lancet. 1997;349(9044):32.
24. Lees KR. Cerestat and other NMDA antagonists in ischemic stroke. Neurology. 1997;49(5 Suppl 4):S66–9.
25. Muir KW et al. Magnesium for acute stroke (intravenous magnesium efficacy in stroke trial): randomised controlled trial. Lancet. 2004;363(9407):439–45.
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.
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.
28. Bath PM et al. Tirilazad for acute ischaemic stroke. Cochrane Database Syst Rev. 2001;4:CD002087.
29. Shuaib A et al. NXY-059 for the treatment of acute ischemic stroke. N Engl J Med. 2007;357(6):562–71.
30. Lees KR et al. NXY-059 for acute ischemic stroke. N Engl J Med. 2006;354(6):588–600.
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.
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.
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.
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.
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.
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.
38. Danton GH, Dietrich WD. Inflammatory mechanisms after ischemia and stroke. J Neuropathol Exp Neurol. 2003;62(2):127–36.
39. Vila N et al. Levels of anti-inflammatory cytokines and neurological worsening in acute ischemic stroke. Stroke. 2003;34(3):671–5.
40. Mattson MP, Culmsee C, Yu ZF. Apoptotic and antiapoptotic mechanisms in stroke. Cell Tissue Res. 2000;301(1):173–87.
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.
42. Margolis RU, Altszuler N. Insulin in the cerebrospinal fluid. Nature. 1967;215(5108):1375–6.
43. King GL, Johnson SM. Receptor-mediated transport of insulin across endothelial cells. Science. 1985;227(4694):1583–6.
44. Banks WA. The source of cerebral insulin. Eur J Pharmacol. 2004;490(1–3):5–12.
45. Duarte AI, Moreira PI, Oliveira CR. Insulin in central nervous system: more than just a peripheral hormone. J Aging Res. 2012;2012:384017.
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.
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.
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.
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.
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.
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.
52. Plum L, Belgardt BF, Bruning JC. Central insulin action in energy and glucose homeostasis. J Clin Invest. 2006;116(7):1761–6.
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.
54. Figlewicz DP, Benoit SC. Insulin, leptin, and food reward: update 2008. Am J Physiol Regul Integr Comp Physiol. 2009;296(1):R9–19.
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.
56. Plum L, Schubert M, Bruning JC. The role of insulin receptor signaling in the brain. Trends Endocrinol Metab. 2005;16(2):59–65.
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.
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.
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.
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.
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.
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.
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.
64. Dimmeler S et al. Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature. 1999;399(6736):601–5.
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.
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.
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.
68. Song J et al. Axons guided by insulin receptor in Drosophila visual system. Science. 2003;300(5618):502–5.
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.
70. Novak V et al. Enhancement of vasoreactivity and cognition by intranasal insulin in type 2 diabetes. Diabetes Care. 2014;37(3):751–9.
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.
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.
74. Costantino HR et al. Intranasal delivery: physicochemical and therapeutic aspects. Int J Pharm. 2007;337(1–2):1–24.
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.
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.
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.
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.
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.
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.
82. Hilsted J et al. Intranasal insulin therapy: the clinical realities. Diabetologia. 1995;38(6):680–4.
83. Benedict C et al. Intranasal insulin improves memory in humans. Psychoneuroendocrinology. 2004;29(10):1326–34.
84. Reger MA et al. Intranasal insulin improves cognition and modulates beta-amyloid in early AD. Neurology. 2008;70(6):440–8.
85. Park CR et al. Intracerebroventricular insulin enhances memory in a passive-avoidance task. Physiol Behav. 2000;68(4):509–14.
86. Benedict C et al. Intranasal insulin improves memory in humans: superiority of insulin aspart. Neuropsychopharmacology. 2007;32(1):239–43.
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.
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.
89. Banks WA, Owen JB, Erickson MA. Insulin in the brain: there and back again. Pharmacol Ther. 2012;136(1):82–93.
90. Cholerton B, Baker LD, Craft S. Insulin, cognition, and dementia. Eur J Pharmacol. 2013;719(1–3):170–9.
91. Cholerton B et al. Insulin and sex interactions in older adults with mild cognitive impairment. J Alzheimers Dis. 2012;31(2):401–10.
92. Schioth HB et al. Brain insulin signaling and Alzheimer’s disease: current evidence and future directions. Mol Neurobiol. 2012;46(1):4–10.
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.
94. Figlewicz DP. Insulin, food intake, and reward. Semin Clin Neuropsychiatry. 2003;8(2):82–93.
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.
96. Humpel C. Chronic mild cerebrovascular dysfunction as a cause for Alzheimer’s disease? Exp Gerontol. 2011;46(4):225–32.
97. Exalto LG et al. An update on type 2 diabetes, vascular dementia and Alzheimer’s disease. Exp Gerontol. 2012;47(11):858–64.
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.
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.
100. Wang X et al. Insulin deficiency exacerbates cerebral amyloidosis and behavioral deficits in an Alzheimer transgenic mouse model. Mol Neurodegener. 2010;5:46.
101. Liu Y et al. Deficient brain insulin signalling pathway in Alzheimer’s disease and diabetes. J Pathol. 2011;225(1):54–62.
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.
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.
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.
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.
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.
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.
108. Benarroch EE. Insulin-like growth factors in the brain and their potential clinical implications. Neurology. 2012;79(21):2148–53.
109. Kern W et al. Improving influence of insulin on cognitive functions in humans. Neuroendocrinology. 2001;74(4):270–80.
110. Kern W et al. Central nervous system effects of intranasally administered insulin during euglycemia in men. Diabetes. 1999;48(3):557–63.
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.
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.
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.
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.
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.
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.
117. Frauman AG et al. Long-term use of intranasal insulin in insulin-dependent diabetic patients. Diabetes Care. 1987;10(5):573–8.
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.
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.
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.
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.
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.
123. Vincent AM et al. IGF-I prevents glutamate-induced motor neuron programmed cell death. Neurobiol Dis. 2004;16(2):407–16.
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.
125. Russo VC et al. The insulin-like growth factor system and its pleiotropic functions in brain. Endocr Rev. 2005;26(7):916–43.
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.
127. Torres Aleman I. Role of insulin-like growth factors in neuronal plasticity and neuroprotection. Adv Exp Med Biol. 2005;567:243–58.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
144. Yang JP et al. The dose-effectiveness of intranasal VEGF in treatment of experimental stroke. Neurosci Lett. 2009;461(3):212–6.
145. Di Lazzaro V et al. Motor cortex plasticity predicts recovery in acute stroke. Cereb Cortex. 2010;20(7):1523–8.
146. Witsch J et al. Hypoglycemic encephalopathy: a case series and literature review on outcome determination. J Neurol. 2012;259(10):2172–81.
147. Fujioka M et al. Specific changes in human brain after hypoglycemic injury. Stroke. 1997;28(3):584–7.
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.