Skip to main content
SpringerLink
Log in

Prospects for the Use of Intranasally Administered Insulin and Insulin-Like Growth Factor-1 in Cerebral Ischemia

  • REVIEW
  • Published:
Biochemistry (Moscow) Aims and scope Submit manuscript

Abstract

Current approaches to the treatment of stroke have significant limitations, and neuroprotective therapy is ineffective. In view of this, searching for effective neuroprotectors and developing new neuroprotective strategies remain a pressing topic in research of cerebral ischemia. Insulin and insulin-like growth factor-1 (IGF-1) play a key role in the brain functioning by regulating the growth, differentiation, and survival of neurons, neuronal plasticity, food intake, peripheral metabolism, and endocrine functions. Insulin and IGF-1 produce multiple effects in the brain, including neuroprotective action in cerebral ischemia and stroke. Experiments in animals and cell cultures have shown that under hypoxic conditions, insulin and IGF-1 improve energy metabolism in neurons and glial cells, promote blood microcirculation in the brain, restore nerve cell functions and neurotransmission, and produce the anti-inflammatory and antiapoptotic effects on brain cells. The intranasal route of insulin and IGF-1 administration is of particular interest in the clinical practice, since it allows controlled delivery of these hormones directly to the brain, bypassing the blood–brain barrier. Intranasally administered insulin alleviated cognitive impairments in elderly people with neurodegenerative and metabolic disorders; intranasally administered insulin and IGF-1 promoted survival of animals with ischemic stroke. The review discusses the published data and results of our own studies on the mechanisms of neuroprotective action of intranasally administered insulin and IGF-1 in cerebral ischemia, as well as the prospects of using these hormones for normalization of CNS functions and reduction of neurodegenerative changes in this pathology.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.

Similar content being viewed by others

Abbreviations

BBB:

blood–brain barrier

eNOS:

endothelial NO synthase

GSK3β:

glycogen synthase kinase-3 beta

IGF-1:

insulin-like growth factor-1

IGF1R:

IGF-1 receptor

INI:

intranasally administered insulin

INSR:

insulin receptor

IRS protein:

insulin receptor substrate protein

LPO:

lipid peroxidation

MAPK:

mitogen-activated protein kinase

MCAO:

middle cerebral artery occlusion

PI3K:

phosphoinositide 3-kinase

References

  1. Soto, M., Cai, W., Konishi, M., and Kahn, C. R. (2019) Insulin signaling in the hippocampus and amygdala regulates metabolism and neurobehavior, Proc. Natl. Acad. Sci. USA, 116, 6379-6384, https://doi.org/10.1073/pnas.1817391116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Havrankova, J., Roth, J., and Brownstein, M. J. (1979) Concentrations of insulin and insulin receptors in the brain are independent of peripheral insulin levels. Studies of obese and streptozotocin-treated rodents, J. Clin. Invest., 64, 636-642, https://doi.org/10.1172/JCI109504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Rhea, E. M., and Banks, W. A. (2019) Role of the blood-brain barrier in central nervous system insulin resistance, Front. Neurosci., 13, 521, https://doi.org/10.3389/fnins.2019.00521.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Beddows, C. A., and Dodd, G. T. (2021) Insulin on the brain: The role of central insulin signalling in energy and glucose homeostasis, J. Neuroendocrinol., 33, e12947, https://doi.org/10.1111/jne.12947.

    Article  CAS  PubMed  Google Scholar 

  5. Devaskar, S. U., Giddings, S. J., Rajakumar, P. A., Carnaghi, L. R., Menon, R. K., and Zahm, D. S. (1994) Insulin gene expression and insulin synthesis in mammalian neuronal cells, J. Biol. Chem., 269, 8445-8454, https://doi.org/10.1016/S0021-9258(17)37214-9.

    Article  CAS  PubMed  Google Scholar 

  6. Devaskar, S. U., Singh, B. S., Carnaghi, L. R., Rajakumar, P. A., and Giddings, S. J. (1993) Insulin II gene expression in rat central nervous system, Regul. Pept., 48, 5563, https://doi.org/10.1016/0167-0115(93)90335-6.

    Article  Google Scholar 

  7. Schechter, R., Whitmire, J., Wheet, G.S., Beju, D., Jackson, K. W., Harlow, R., and Gavin, J. R., 3rd (1994) Immunohistochemical and in situ hybridization study of an insulin-like substance in fetal neuron cell cultures, Brain Res., 636, 9-27, https://doi.org/10.1016/0006-8993(94)90170-8.

    Article  CAS  PubMed  Google Scholar 

  8. Gerozissis, K. (2008) Brain insulin, energy and glucose homeostasis; genes, environment and metabolic pathologies, Eur. J. Pharmacol., 585, 38-49, https://doi.org/10.1016/j.ejphar.2008.01.050.

    Article  CAS  PubMed  Google Scholar 

  9. Havrankova, J., Roth, J., and Brownstein, M. (1978) Insulin receptors are widely distributed in the central nervous system of the rat, Nature, 272, 827-829, https://doi.org/10.1038/272827a0.

    Article  CAS  PubMed  Google Scholar 

  10. Escribano, O., Beneit, N., Rubio-Longás, C., López-Pastor, A. R., and Gómez-Hernández, A. (2017) The role of insulin receptor isoforms in diabetes and its metabolic and vascular complications, J. Diabetes Res., 2017, 1403206, https://doi.org/10.1155/2017/1403206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. De Meyts, P. (2008) The insulin receptor: a prototype for dimeric, allosteric membrane receptors?, Trends Biochem. Sci., 33, 376-384, https://doi.org/10.1016/j.tibs.2008.06.003.

    Article  CAS  PubMed  Google Scholar 

  12. Belfiore, A., Frasca, F., Pandini, G., Sciacca, L., and Vigneri, R. (2009) Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease, Endocr. Rev., 30, 586-623, https://doi.org/10.1210/er.2008-0047.

    Article  CAS  PubMed  Google Scholar 

  13. White, M. F., and Kahn, C. R. (2021) Insulin action at a molecular level – 100 years of progress, Mol. Metab., 52, 101304, https://doi.org/10.1016/j.molmet.2021.101304.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Copps, K. D., and White, M. F. (2012) Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2, Diabetologia, 55, 2565-2582, https://doi.org/10.1007/s00125-012-2644-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Razzini, G., Ingrosso, A., Brancaccio, A., Sciacchitano, S., Esposito, D. L., and Falasca, M. (2000) Different subcellular localization and phosphoinositides binding of insulin receptor substrate protein pleckstrin homology domains, Mol. Endocrinol., 14, 823-836, https://doi.org/10.1210/mend.14.6.0486.

    Article  CAS  PubMed  Google Scholar 

  16. Aguirre, V., Werner, E. D., Giraud, J., Lee, Y. H., Shoelson, S. E., and White, M. F. (2002) Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action, J. Biol. Chem., 277, 1531-1537, https://doi.org/10.1074/jbc.M101521200.

    Article  CAS  PubMed  Google Scholar 

  17. Bakke, J., and Haj, F. G. (2015) Protein-tyrosine phosphatase 1B substrates and metabolic regulation, Semin. Cell Dev. Biol., 37, 58-65, https://doi.org/10.1016/j.semcdb.2014.09.020.

    Article  CAS  PubMed  Google Scholar 

  18. Dodd, G. T., Xirouchaki, C. E., Eramo, M., Mitchell, C. A., Andrews, Z. B., Henry, B. A., Cowley, M. A., and Tiganis, T. (2019) Intranasal targeting of hypothalamic PTP1B and TCPTP reinstates leptin and insulin sensitivity and promotes weight loss in obesity, Cell Rep., 28, 2905-2922.e5, https://doi.org/10.1016/j.celrep.2019.08.019.

    Article  CAS  PubMed  Google Scholar 

  19. Vanhaesebroeck, B., Guillermet-Guibert, J., Graupera, M., and Bilanges, B. (2010) The emerging mechanisms of isoform-specific PI3K signalling, Nat. Rev. Mol. Cell Biol., 11, 329-341, https://doi.org/10.1038/nrm2882.

    Article  CAS  PubMed  Google Scholar 

  20. Levenga, J., Wong, H., Milstead, R. A., LaPlante, L. E., Hoeffer, C. A. (2021) Immunohistological examination of AKT isoforms in the brain: cell-type specificity that may underlie AKT’s role in complex brain disorders and neurological disease, Cereb. Cortex Commun., 2, tgab036, https://doi.org/10.1093/texcom/tgab036.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Manning, B. D., and Toker, A. (2017) AKT/PKB signaling: navigating the network, Cell, 169, 381-405, https://doi.org/10.1016/j.cell.2017.04.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hemmings, B. A., and Restuccia, D. F. (2012) PI3K-PKB/Akt pathway, Cold Spring Harb. Perspect. Biol., 4, a011189, doi: https://doi.org/10.1101/cshperspect.a011189. Erratum in: (2015) Cold Spring Harb. Perspect. Biol., 7, a026609, doi: https://doi.org/10.1101/cshperspect.a026609.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. McCubrey, J. A., Steelman, L. S., Bertrand, F. E., Davis, N. M., Sokolosky, M., Abrams, S. L., Montalto, G., D'Assoro, A. B., Libra, M., Nicoletti, F., Maestro, R., Basecke, J., Rakus, D., Gizak, A., Demidenko, Z. N., Cocco, L., Martelli, A. M., and Cervello, M. (2014) GSK-3 as potential target for therapeutic intervention in cancer, Oncotarget, 5, 2881-2911, https://doi.org/10.18632/oncotarget.2037.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Beurel, E., Grieco, S. F., and Jope, R. S. (2015) Glycogen synthase kinase-3 (GSK3): regulation, actions, and diseases, Pharmacol. Ther., 148, 114-131, https://doi.org/10.1016/j.pharmthera.2014.11.016.

    Article  CAS  PubMed  Google Scholar 

  25. Brown, A. K., and Webb, A. E. (2018) Regulation of FOXO factors in mammalian cells, Curr. Top. Dev. Biol., 127, 165-192, https://doi.org/10.1016/bs.ctdb.2017.10.006.

    Article  CAS  PubMed  Google Scholar 

  26. Ghasemi, R., Haeri, A., Dargahi, L., Mohamed, Z., and Ahmadiani, A. (2013) Insulin in the brain: sources, localization and functions, Mol. Neurobiol., 47, 145-171, https://doi.org/10.1007/s12035-012-8339-9.

    Article  CAS  PubMed  Google Scholar 

  27. Wang, X., and Proud, C. G. (2006) The mTOR pathway in the control of protein synthesis, Physiology (Bethesda), 21, 362-369, https://doi.org/10.1152/physiol.00024.2006.

    Article  CAS  PubMed  Google Scholar 

  28. Stoica, L., Zhu, P. J., Huang, W., Zhou, H., Kozma, S. C., and Costa-Mattioli, M. (2011) Selective pharmacogenetic inhibition of mammalian target of Rapamycin complex I (mTORC1) blocks long-term synaptic plasticity and memory storage, Proc. Natl. Acad. Sci. USA, 108, 3791-3796, https://doi.org/10.1073/pnas.1014715108.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Trueba-Saiz, A., Fernandez, A. M., Nishijima, T., Mecha, M., Santi, A., Munive, V., and Aleman, I. T. (2017) Circulating insulin-like growth factor I regulates its receptor in the brain of male mice, Endocrinology, 158, 349-355, https://doi.org/10.1210/en.2016-1468.

    Article  CAS  PubMed  Google Scholar 

  30. Baker, A. M., Batchelor, D. C., Thomas, G. B., Wen, J. Y., Rafiee, M., Lin, H., and Guan, J. (2005) Central penetration and stability of N-terminal tripeptide of insulin-like growth factor-I, glycine-proline-glutamate in adult rat, Neuropeptides, 39, 81-87, https://doi.org/10.1016/j.npep.2004.11.001.

    Article  CAS  PubMed  Google Scholar 

  31. Guan, J. (2011) Insulin-like growth factor-1 (IGF-1) derived neuropeptides, a novel strategy for the development of pharmaceuticals for managing ischemic brain injury, CNS Neurosci. Ther., 17, 250-255, https://doi.org/10.1111/j.1755-5949.2009.00128.x.

    Article  CAS  PubMed  Google Scholar 

  32. Lewitt, M. S., and Boyd, G. W. (2019) The role of insulin-like growth factors and insulin-like growth factor-binding proteins in the nervous system, Biochem. Insights, 12, 1178626419842176, https://doi.org/10.1177/1178626419842176.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Rotwein, P., Burgess, S. K., Milbrandt, J. D., and Krause, J. E. (1988) Differential expression of insulin-like growth factor genes in rat central nervous system, Proc. Natl. Acad. Sci. USA, 85, 265-269, https://doi.org/10.1073/pnas.85.1.265.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Whittaker, J., Groth, A. V., Mynarcik, D. C., Pluzek, L., Gadsbøll, V. L., and Whittaker, L. J. (2001) Alanine scanning mutagenesis of a type 1 insulin-like growth factor receptor ligand binding site, J. Biol. Chem., 276, 43980-43986, https://doi.org/10.1074/jbc.M102863200.

    Article  CAS  PubMed  Google Scholar 

  35. Drakas, R., Tu, X., and Baserga, R. (2004) Control of cell size through phosphorylation of upstream binding factor 1 by nuclear phosphatidylinositol 3-kinase, Proc. Natl. Acad. Sci. USA, 101, 9272-9276, https://doi.org/10.1073/pnas.0403328101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Shpakov, A. O., Derkach, K. V., and Berstein, L. M. (2015) Brain signaling systems in the type 2 diabetes and metabolic syndrome: promising target to treat and prevent these diseases, Future Sci. OA, 1, FSO25, https://doi.org/10.4155/fso.15.23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Yuan, H., Chen, R., Wu, L., Chen, Q., Hu, A., Zhang, T., Wang, Z., and Zhu, X. (2015) The regulatory mechanism of neurogenesis by IGF-1 in adult mice, Mol. Neurobiol., 51, 512-522, https://doi.org/10.1007/s12035-014-8717-6.

    Article  CAS  PubMed  Google Scholar 

  38. Agis-Balboa, R. C., and Fischer, A. (2014) Generating new neurons to circumvent your fears: the role of IGF signaling, Cell Mol. Life Sci., 71, 21-42, https://doi.org/10.1007/s00018-013-1316-2.

    Article  CAS  PubMed  Google Scholar 

  39. Gubbi, S., Quipildor, G. F., Barzilai, N., Huffman, D. M., and Milman, S. (2018) 40 YEARS of IGF1: IGF1: the Jekyll and Hyde of the aging brain, J. Mol. Endocrinol., 61, T171-T185, https://doi.org/10.1530/JME-18-0093.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wrigley, S., Arafa, D., and Tropea, D. (2017) Insulin-like growth factor 1: at the crossroads of brain development and aging, Front. Cell Neurosci., 11, 14, https://doi.org/10.3389/fncel.2017.00014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Memezawa, H., Minamisawa, H., Smith, M. L., and Siesjö, B. K. (1992) Ischemic penumbra in a model of reversible middle cerebral artery occlusion in the rat, Exp. Brain Res., 89, 67-78, https://doi.org/10.1007/BF00229002.

    Article  CAS  PubMed  Google Scholar 

  42. Gidö, G., Kristián, T., and Siesjö, B. K. (1997) Extracellular potassium in a neocortical core area after transient focal ischemia, Stroke, 28, 206-210, https://doi.org/10.1161/01.str.28.1.206.

    Article  PubMed  Google Scholar 

  43. Kristián, T., Gidö, G., Kuroda, S., Schütz, A., and Siesjö, B. K. (1998) Calcium metabolism of focal and penumbral tissues in rats subjected to transient middle cerebral artery occlusion, Exp. Brain Res., 120, 503-509, https://doi.org/10.1007/s002210050424.

    Article  PubMed  Google Scholar 

  44. Dirnagl, U., Iadecola, C., and Moskowitz, M. A. (1999) Pathobiology of ischaemic stroke: an integrated view, Trends Neurosci., 22, 391-397, https://doi.org/10.1016/s0166-2236(99)01401-0.

    Article  CAS  PubMed  Google Scholar 

  45. Khoshnam, S. E., Winlow, W., Farzaneh, M., Farbood, Y., and Moghaddam, H. F. (2017) Pathogenic mechanisms following ischemic stroke, Neurol. Sci., 38, 1167-1186, https://doi.org/10.1007/s10072-017-2938-1.

    Article  PubMed  Google Scholar 

  46. George, P. M., and Steinberg, G. K. (2015) Novel stroke therapeutics: unraveling stroke pathophysiology and its impact on clinical treatments, Neuron, 87, 297-309, https://doi.org/10.1016/j.neuron.2015.05.041.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Zhang, F. X., Rubin, R., and Rooney, T. A. (1998) N-methyl-D-aspartate inhibits apoptosis through activation of phosphatidylinositol 3-kinase in cerebellar granule neurons – a role for insulin receptor substrate-1 in the neurotrophic action of N-methyl-D-aspartate and its inhibition by ethanol, J. Biol. Chem., 273, 26596-26602, https://doi.org/10.1074/jbc.273.41.26596.

    Article  CAS  PubMed  Google Scholar 

  48. Endo, H., Nito, C., Kamada, H., Nishi, T., and Chan, P. H. (2006) Activation of the Akt/GSK3beta signaling pathway mediates survival of vulnerable hippocampal neurons after transient global cerebral ischemia in rats, J. Cereb. Blood Flow Metab., 26, 1479-1489, https://doi.org/10.1038/sj.jcbfm.9600303.

    Article  CAS  PubMed  Google Scholar 

  49. Soriano, F. X., Papadia, S., Hofmann, F., Hardingham, N. R., Bading, H., and Hardingham, G. E. (2006) Preconditioning doses of NMDA promote neuroprotection by enhancing neuronal excitability, J. Neurosci., 26, 4509-4518, https://doi.org/10.1523/JNEUROSCI.0455-06.2006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Qin, C., Yang, S., Chu, Y. H., Zhang, H., Pang, X. W., Chen, L., Zhou, L. Q., Chen, M., Tian, D. S., and Wang, W. (2022) Signaling pathways involved in ischemic stroke: molecular mechanisms and therapeutic interventions, Signal Transduct. Target. Ther., 7, 215, doi: https://doi.org/10.1038/s41392-022-01064-1. Erratum in: Signal Transduct. Target. Ther., 7, 278.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Ahad, M. A., Kumaran, K. R., Ning, T., Mansor, N. I., Effendy, M. A., Damodaran, T., Lingam, K., Wahab, H. A., Nordin, N., Liao, P., Müller, C. P., and Hassan, Z. (2020) Insights into the neuropathology of cerebral ischemia and its mechanisms, Rev. Neurosci., 31, 521-538, https://doi.org/10.1515/revneuro-2019-0099.

    Article  CAS  PubMed  Google Scholar 

  52. Semenza, G. L. (2009) Regulation of oxygen homeostasis by hypoxia-inducible factor 1, Physiology (Bethesda), 24, 97-106, https://doi.org/10.1152/physiol.00045.2008.

    Article  CAS  PubMed  Google Scholar 

  53. Sharp, F., and Bernaudin, M. (2004) HIF1 and oxygen sensing in the brain, Nat. Rev. Neurosci., 5, 437-448, https://doi.org/10.1038/nrn1408.

    Article  CAS  PubMed  Google Scholar 

  54. Zhang, Z., Yao, L., Yang, J., Wang, Z., and Du, G. (2018) PI3K/Akt and HIF 1 signaling pathway in hypoxia ischemia (Review), Mol. Med. Rep., 18, 3547-3554, https://doi.org/10.3892/mmr.2018.9375.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Sanderson, T. H., Reynolds, C. A., Kumar, R., Przyklenk, K., and Hüttemann, M. (2013) Molecular mechanisms of ischemia-reperfusion injury in brain: pivotal role of the mitochondrial membrane potential in reactive oxygen species generation, Mol. Neurobiol., 47, 9-23, https://doi.org/10.1007/s12035-012-8344-z.

    Article  CAS  PubMed  Google Scholar 

  56. Wardlaw, J. M., Murray, V., Berge, E., and del Zoppo, G. J. (2014) Thrombolysis for acute ischaemic stroke, Cochrane Database Syst. Rev., 2014, CD000213, https://doi.org/10.1002/14651858.CD000213.pub3.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Federal Clinical Guidelines for Patient Management (2022) Ischemic stroke and transient ischemic attack in adulthood, Moscow [in Russian].

  58. Emberson, J., Lees, K. R., Lyden, P., Blackwell, L., Albers, G., Bluhmki, E., Brott, T., Cohen, G., Davis, S., Donnan, G., Grotta, J., Howard, G., Kaste, M., Koga, M., von Kummer, R., Lansberg, M., Lindley, R. I., Murray, G., Olivot, J. M., Parsons, M., Tilley, B., Toni, D., Toyoda, K., Wahlgren, N., Wardlaw, J., Whiteley, W., del Zoppo, G. J., Baigent, C., Sandercock, P., and Hacke, W. (2014) Stroke Thrombolysis Trialists’ Collaborative Group. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials, Lancet, 384, 1929-1935, https://doi.org/10.1016/S0140-6736(14)60584-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Guekht, A., Skoog, I., Edmundson, S., Zakharov, V., and Korczyn, A. D. (2017) ARTEMIDA Trial (a Randomized Trial of Efficacy, 12 Months International Double-Blind Actovegin): A randomized controlled trial to assess the efficacy of actovegin in poststroke cognitive impairment, Stroke, 48, 1262-1270, https://doi.org/10.1161/STROKEAHA.116.014321.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Zhang, C., and Yan, C. (2020) Updates of recent vinpocetine research in treating cardiovascular diseases, J. Cell Immunol., 2, 211-219, https://doi.org/10.33696/immunology.2.045.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Gusev, E. I., Skvortsova, V. I., and Chukanova, E. I. (2005) Semax in prevention of disease progress and development of exacerbations in patients with cerebrovascular insufficiency [in Russian], Zhurn. Nevrol. Psikhiatr. Im. S. S. Korsakova, 105, 35-40.

    CAS  Google Scholar 

  62. Melamed, E. (1976) Reactive hyperglycaemia in patients with acute stroke, J. Neurol. Sci., 29, 267-275, https://doi.org/10.1016/0022-510x(76)90176-3.

    Article  CAS  PubMed  Google Scholar 

  63. Capes, S. E., Hunt, D., Malmberg, K., Pathak, P., and Gerstein, H. C. (2001) Stress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients: a systematic overview, Stroke, 32, 2426-2432, https://doi.org/10.1161/hs1001.096194.

    Article  CAS  PubMed  Google Scholar 

  64. Zhang, Z., Yan, J., and Shi, H. (2013) Hyperglycemia as a risk factor of ischemic stroke, J. Drug Metab. Toxicol., 4, 153, https://doi.org/10.4172/2157-7609.1000153.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Piironen, K., Putaala, J., Rosso, C., and Samson, Y. (2012) Glucose and acute stroke: evidence for an interlude, Stroke, 43, 898-902, https://doi.org/10.1161/STROKEAHA.111.631218.

    Article  PubMed  Google Scholar 

  66. Saxena, A., Anderson, C. S., Wang, X., Sato, S., Arima, H., Chan, E., Muñoz-Venturelli, P., Delcourt, C., Robinson, T., Stapf, C., Lavados, P. M., Wang, J., Neal, B., Chalmers, J., and Heeley, E. (2016) INTERACT2 Investigators. Prognostic significance of hyperglycemia in acute intracerebral hemorrhage: The INTERACT2 study, Stroke, 47, 682-688, https://doi.org/10.1161/STROKEAHA.115.011627.

    Article  CAS  PubMed  Google Scholar 

  67. Voll, C. L., and Auer, R. N. (1988) The effect of postischemic blood glucose levels on ischemic brain damage in the rat, Ann. Neurol., 24, 638-646, https://doi.org/10.1002/ana.410240508.

    Article  CAS  PubMed  Google Scholar 

  68. Voll, C. L., Whishaw, I. Q., and Auer, R. N. (1989) Postischemic insulin reduces spatial learning deficit following transient forebrain ischemia in rats, Stroke, 20, 646-651, doi: https://doi.org/10.1161/01.str.20.5.646. Erratum in: (1989), Stroke, 20, 1118.

    Article  CAS  PubMed  Google Scholar 

  69. Hamilton, M. G., Tranmer, B. I., and Auer, R. N. (1995) Insulin reduction of cerebral infarction due to transient focal ischemia, J. Neurosurg., 82, 262-268, https://doi.org/10.3171/jns.1995.82.2.0262.

    Article  CAS  PubMed  Google Scholar 

  70. Warner, D. S., Gionet, T. X., Todd, M. M., and McAllister, A. M. (1992) Insulin-induced normoglycemia improves ischemic outcome in hyperglycemic rats, Stroke, 23, 1775-1780, discussion 1781, https://doi.org/10.1161/01.str.23.12.1775.

    Article  CAS  PubMed  Google Scholar 

  71. Guyot, L. L., Diaz, F. G., O’Regan, M. H., Ren, J., and Phillis, J. W. (2000) The effect of intravenous insulin on accumulation of excitotoxic and other amino acids in the ischemic rat cerebral cortex, Neurosci. Lett., 288, 61-65, https://doi.org/10.1016/s0304-3940(00)01168-x.

    Article  CAS  PubMed  Google Scholar 

  72. Fukuoka, S., Yeh, H., Mandybur, T. I., and Tew, J. M. Jr. (1989) Effect of insulin on acute experimental cerebral ischemia in gerbils, Stroke, 20, 396-399, https://doi.org/10.1161/01.str.20.3.396.

    Article  CAS  PubMed  Google Scholar 

  73. Meden, P., Andersen, M., Overgaard, K., Rasmussen, R. S., and Boysen, G. (2002) The effects of early insulin treatment combined with thrombolysis in rat embolic stroke, Neurol. Res., 24, 399-404, https://doi.org/10.1179/016164102101200096.

    Article  CAS  PubMed  Google Scholar 

  74. Huang, S. S., Lu, Y. J., Huang, J. P., Wu, Y. T., Day, Y. J., and Hung, L. M. J. (2014) The essential role of endothelial nitric oxide synthase activation in insulin-mediated neuroprotection against ischemic stroke in diabetes, Vasc. Surg., 59, 483-491, https://doi.org/10.1016/j.jvs.2013.03.023.

    Article  Google Scholar 

  75. Izumi, Y., Pinard, E., Roussel, S., and Seylaz, J. (1992) Insulin protects brain tissue against focal ischemia in rats, Neurosci. Lett., 144, 121-123, https://doi.org/10.1016/0304-3940(92)90730-u.

    Article  CAS  PubMed  Google Scholar 

  76. Fanne, R. A., Nassar, T., Heyman, S. N., Hijazi, N., and Higazi, A. A. (2011) Insulin and glucagon share the same mechanism of neuroprotection in diabetic rats: role of glutamate, Am. J. Physiol. Regul. Integr. Comp. Physiol., 301, R668-R673, https://doi.org/10.1152/ajpregu.00058.2011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Voll, C. L., and Auer, R. N. (1991) Insulin attenuates ischemic brain damage independent of its hypoglycemic effect, J. Cereb. Blood Flow Metab., 11, 1006-1014, https://doi.org/10.1038/jcbfm.1991.168.

    Article  CAS  PubMed  Google Scholar 

  78. Guan, J., Williams, C., Gunning, M., Mallard, C., and Gluckman, P. (1993) The effects of IGF-1 treatment after hypoxic-ischemic brain injury in adult rats, J. Cereb. Blood Flow Metab., 13, 609-616, https://doi.org/10.1038/jcbfm.1993.79.

    Article  CAS  PubMed  Google Scholar 

  79. Zhu, C. Z., and Auer, R. N. (1994) Intraventricular administration of insulin and IGF-1 in transient forebrain ischemia, J. Cereb. Blood Flow Metab., 14, 237-242, https://doi.org/10.1038/jcbfm.1994.30.

    Article  CAS  PubMed  Google Scholar 

  80. Russo, V., Candeloro, P., Malara, N., Perozziello, G., Iannone, M., Scicchitano, M., Mollace, R., Musolino, V., Gliozzi, M., Carresi, C., Morittu, V. M., Gratteri, S., Palma, E., Muscoli, C., Di Fabrizio, E., and Mollace, V. (2019) Key role of cytochrome C for apoptosis detection using Raman microimaging in an animal model of brain ischemia with insulin treatment, Appl. Spectrosc., 73, 1208-1217, https://doi.org/10.1177/0003702819858671.

    Article  CAS  PubMed  Google Scholar 

  81. Sanderson, T. H., Kumar, R., Sullivan, J. M., and Krause, G. S. (2008) Insulin blocks cytochrome c release in the reperfused brain through PI3-K signaling and by promoting Bax/Bcl-XL binding, J. Neurochem., 106, 1248-1258, https://doi.org/10.1111/j.1471-4159.2008.05473.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Sanderson, T. H., Kumar, R., Murariu-Dobrin, A. C., Page, A. B., Krause, G. S., and Sullivan, J. M. (2009) Insulin activates the PI3K-Akt survival pathway in vulnerable neurons following global brain ischemia, Neurol. Res., 31, 947-958, https://doi.org/10.1179/174313209X382449.

    Article  CAS  PubMed  Google Scholar 

  83. Sanderson, T. H., Mahapatra, G., Pecina, P., Ji, Q., Yu, K., Sinkler, C., Varughese, A., Kumar, R., Bukowski, M. J., Tousignant, R. N., Salomon, A. R., Lee, I., and Hüttemann, M. (2013) Cytochrome C is tyrosine 97 phosphorylated by neuroprotective insulin treatment, PLoS One, 8, e78627, https://doi.org/10.1371/journal.pone.0078627.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Duarte, A. I., Santos, P., Oliveira, C. R., Santos, M. S., and Rego, A. C. (2008) Insulin neuroprotection against oxidative stress is mediated by Akt and GSK-3beta signaling pathways and changes in protein expression, Biochim. Biophys. Acta, 1783, 994-1002, https://doi.org/10.1016/j.bbamcr.2008.02.016.

    Article  CAS  PubMed  Google Scholar 

  85. Duarte, A. I., Moreira, P. I., and Oliveira, C. R. (2012) Insulin in central nervous system: more than just a peripheral hormone, J. Aging Res., 2012, 384017, https://doi.org/10.1155/2012/384017.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Hughes, T. M., and Craft, S. (2016) The role of insulin in the vascular contributions to age-related dementia, Biochim. Biophys. Acta, 1862, 983-991, https://doi.org/10.1016/j.bbadis.2015.11.013.

    Article  CAS  PubMed  Google Scholar 

  87. Muniyappa, R., and Yavuz, S. (2013) Metabolic actions of angiotensin II and insulin: a microvascular endothelial balancing act, Mol. Cell Endocrinol., 378, 59-69, https://doi.org/10.1016/j.mce.2012.05.017.

    Article  CAS  PubMed  Google Scholar 

  88. McKay, M. K., and Hester, R. L. (1996) Role of nitric oxide, adenosine, and ATP-sensitive potassium channels in insulin-induced vasodilation, Hypertension, 28, 202-208, https://doi.org/10.1161/01.hyp.28.2.202.

    Article  CAS  PubMed  Google Scholar 

  89. Hung, L. M., Huang, J. P., Liao, J. M., Yang, M. H., Li, D. E., Day, Y. J., and Huang, S. S. (2014) Insulin renders diabetic rats resistant to acute ischemic stroke by arresting nitric oxide reaction with superoxide to form peroxynitrite, J. Biomed. Sci., 21, 92, https://doi.org/10.1186/s12929-014-0092-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Beilharz, E. J., Russo, V. C., Butler, G., Baker, N. L., Connor, B., Sirimanne, E. S., Dragunow, M., Werther, G. A., Gluckman, P. D., Williams, C. E., and Scheepens, A. (1998) Co-ordinated and cellular specific induction of the components of the IGF/IGFBP axis in the rat brain following hypoxic-ischemic injury, Brain Res. Mol. Brain Res., 59, 119-134, https://doi.org/10.1016/s0169-328x(98)00122-3.

    Article  CAS  PubMed  Google Scholar 

  91. Schober, M. E., Ke, X., Xing, B., Block, B. P., Requena, D. F., McKnight, R., and Lane, R. H. (2012) Traumatic brain injury increased IGF-1B mRNA and altered IGF-1 exon 5 and promoter region epigenetic characteristics in the rat pup hippocampus, J. Neurotrauma, 29, 2075-2085, https://doi.org/10.1089/neu.2011.2276.

    Article  PubMed  Google Scholar 

  92. Åberg, D., Jood, K., Blomstrand, C., Jern, C., Nilsson, M., Isgaard, J., and Aberg, N. D. (2011) Serum IGF-I levels correlate to improvement of functional outcome after ischemic stroke, J. Clin. Endocrinol. Metab., 96, E1055-E1064, https://doi.org/10.1210/jc.2010-2802.

    Article  PubMed  Google Scholar 

  93. Brywe, K. G., Mallard, C., Gustavsson, M., Hedtjärn, M., Leverin, A. L., Wang, X., Blomgren, K., Isgaard, J., and Hagberg, H. (2005) IGF-I neuroprotection in the immature brain after hypoxia-ischemia, involvement of Akt and GSK3beta?, Eur. J. Neurosci., 21, 1489-1502, https://doi.org/10.1111/j.1460-9568.2005.03982.x.

    Article  PubMed  Google Scholar 

  94. Rizk, N. N., Rafols, J. A., and Dunbar, J. C. (2006) Cerebral ischemia-induced apoptosis and necrosis in normal and diabetic rats: effects of insulin and C-peptide, Brain Res., 1096, 204-212, https://doi.org/10.1016/j.brainres.2006.04.060.

    Article  CAS  PubMed  Google Scholar 

  95. Lin, S., Fan, L. W., Rhodes, P. G., and Cai, Z. (2009) Intranasal administration of IGF-1 attenuates hypoxic-ischemic brain injury in neonatal rats, Exp. Neurol., 217, 361-370, https://doi.org/10.1016/j.expneurol.2009.03.021.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Nishiyama, A., Komitova, M., Suzuki, R., and Zhu, X. (2009) Polydendrocytes (NG2 cells): multifunctional cells with lineage plasticity, Nat. Rev. Neurosci., 10, 9-22, https://doi.org/10.1038/nrn2495.

    Article  CAS  PubMed  Google Scholar 

  97. Storm-Mathisen, J., Danbolt, N. C., Rothe, F., Torp, R., Zhang, N., Aas, J. E., Kanner, B. I., Langmoen, I., and Ottersen, O. P. (1992) Ultrastructural immunocytochemical observations on the localization, metabolism and transport of glutamate in normal and ischemic brain tissue, Prog. Brain Res., 94, 225-241, https://doi.org/10.1016/s0079-6123(08)61753-7.

    Article  CAS  PubMed  Google Scholar 

  98. Prabhu, D., Khan, S. M., Blackburn, K., Marshall, J. P., and Ashpole, N. M. (2019) Loss of insulin-like growth factor-1 signaling in astrocytes disrupts glutamate handling, J. Neurochem., 151, 689-702, https://doi.org/10.1111/jnc.14879.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Logan, S., Pharaoh, G. A., Marlin, M. C., Masser, D. R., Matsuzaki, S., Wronowski, B., Yeganeh, A., Parks, E. E., Premkumar, P., Farley, J. A., Owen, D. B., Humphries, K. M., Kinter, M., Freeman, W. M., Szweda, L. I., Van Remmen, H. , and Sonntag, W. E. (2018) Insulin-like growth factor receptor signaling regulates working memory, mitochondrial metabolism, and amyloid-β uptake in astrocytes, Mol. Metab., 9, 141-155, https://doi.org/10.1016/j.molmet.2018.01.013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Grinberg, Y. Y., Dibbern, M. E., Levasseur, V. A., and Kraig, R. P. (2013) Insulin-like growth factor-1 abrogates microglial oxidative stress and TNF-α responses to spreading depression, J. Neurochem., 126, 662-672, https://doi.org/10.1111/jnc.12267.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Lee, C. C., Huang, C. C., and Hsu, K. S. (2011) Insulin promotes dendritic spine and synapse formation by the PI3K/Akt/mTOR and Rac1 signaling pathways, Neuropharmacology, 61, 867-879, https://doi.org/10.1016/j.neuropharm.2011.06.003.

    Article  CAS  PubMed  Google Scholar 

  102. Lioutas, V. A., Alfaro-Martinez, F., Bedoya, F., Chung, C. C., Pimentel, D. A., and Novak, V. (2015) Intranasal insulin and insulin-like growth factor 1 as neuroprotectants in acute ischemic stzroke, Transl. Stroke Res., 6, 264-275, https://doi.org/10.1007/s12975-015-0409-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Yu, L. Y., and Pei, Y. (2015) Insulin neuroprotection and the mechanisms, Chin. Med. J. (Engl.), 128, 976-981, https://doi.org/10.4103/0366-6999.154323.

    Article  CAS  PubMed  Google Scholar 

  104. Lioutas, V. A., and Novak, V. (2016) Intranasal insulin neuroprotection in ischemic stroke, Neural Regen. Res., 11, 400-401, https://doi.org/10.4103/1673-5374.179040.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Romanova, I. V., Derkach, K. V., Mikhrina, A. L., Sukhov, I. B., Mikhailova, E. V., and Shpakov, A. O. (2018) The leptin, dopamine and serotonin receptors in hypothalamic POMC-neurons of normal and obese rodents, Neurochem. Res., 43, 821-837, https://doi.org/10.1007/s11064-018-2485-z.

    Article  CAS  PubMed  Google Scholar 

  106. Derkach, K., Zakharova, I., Zorina, I., Bakhtyukov, A., Romanova, I., Bayunova, L., and Shpakov, A. (2019) The evidence of metabolic-improving effect of metformin in Ay/a mice with genetically-induced melanocortin obesity and the contribution of hypothalamic mechanisms to this effect, PLoS One, 14, e0213779, https://doi.org/10.1371/journal.pone.0213779.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Gänger, S., and Schindowski, K. (2018) Tailoring formulations for intranasal nose-to-brain delivery: a review on architecture, physico-chemical characteristics and mucociliary clearance of the nasal olfactory mucosa, Pharmaceutics, 10, 116, https://doi.org/10.3390/pharmaceutics10030116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Craft, S., Baker, L. D., Montine, T. J., Minoshima, S., Watson, G. S., Claxton, A., Arbuckle, M., Callaghan, M., Tsai, E., Plymate, S. R., Green, P. S., Leverenz, J., Cross, D., and Gerton, B. (2012) Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial, Arch. Neurol., 69, 29-38, https://doi.org/10.1001/archneurol.2011.233.

    Article  PubMed  Google Scholar 

  109. Kooijman, R., Sarre, S., Michotte, Y., and De Keyser, J. (2009) Insulin-like growth factor I: a potential neuroprotective compound for the treatment of acute ischemic stroke?, Stroke, 40, e83-e88, https://doi.org/10.1161/STROKEAHA.108.528356.

    Article  PubMed  Google Scholar 

  110. Fan, L. W., Carter, K., Bhatt, A., and Pang, Y. (2019) Rapid transport of insulin to the brain following intranasal administration in rats, Neural Regen. Res., 14, 1046-1051, https://doi.org/10.4103/1673-5374.250624.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Picone, P., Sabatino, M. A., Ditta, L. A., Amato, A., San Biagio, P. L., Mulè, F., Giacomazza, D., Dispenza, C., and Di Carlo, M. (2018) Nose-to-brain delivery of insulin enhanced by a nanogel carrier, J. Control Release, 270, 23-36, https://doi.org/10.1016/j.jconrel.2017.11.040.

    Article  CAS  PubMed  Google Scholar 

  112. Lochhead, J. J., Kellohen, K. L., Ronaldson, P. T., and Davis, T. P. (2019) Distribution of insulin in trigeminal nerve and brain after intranasal administration, Sci. Rep., 9, 2621, https://doi.org/10.1038/s41598-019-39191-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Liu, X. F., Fawcett, J. R., Thorne, R. G., DeFor, T. A., and Frey, W. H. 2nd (2001) Intranasal administration of insulin-like growth factor-I bypasses the blood-brain barrier and protects against focal cerebral ischemic damage, J. Neurol. Sci., 187, 91-97, https://doi.org/10.1016/s0022-510x(01)00532-9.

    Article  CAS  PubMed  Google Scholar 

  114. Liu, X. F., Fawcett, J. R., Thorne, R. G., and Frey, W. H. 2nd (2001) Non-invasive intranasal insulin-like growth factor-I reduces infarct volume and improves neurologic function in rats following middle cerebral artery occlusion, Neurosci. Lett., 308, 91-94, https://doi.org/10.1016/s0304-3940(01)01982-6.

    Article  CAS  PubMed  Google Scholar 

  115. Fletcher, L., Kohli, S., Sprague, S. M., Scranton, R. A., Lipton, S. A., Parra, A., Jimenez, D. F., and Digicaylioglu, M. (2009) Intranasal delivery of erythropoietin plus insulin-like growth factor-I for acute neuroprotection in stroke. Laboratory investigation, J. Neurosurg., 111, 164-170, https://doi.org/10.3171/2009.2.JNS081199.

    Article  CAS  PubMed  Google Scholar 

  116. Lin, S., Rhodes, P. G., and Cai, Z. (2011) Whole body hypothermia broadens the therapeutic window of intranasally administered IGF-1 in a neonatal rat model of cerebral hypoxia-ischemia, Brain Res., 1385, 246-256, https://doi.org/10.1016/j.brainres.2011.02.013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Shen, H., Gu, X., Wei, Z. Z., Wu, A., Liu, X., and Wei, L. (2021) Combinatorial intranasal delivery of bone marrow mesenchymal stem cells and insulin-like growth factor-1 improves neurovascularization and functional outcomes following focal cerebral ischemia in mice, Exp. Neurol., 337, 113542, https://doi.org/10.1016/j.expneurol.2020.113542.

    Article  CAS  PubMed  Google Scholar 

  118. Liu, X. F., Fawcett, J. R., Hanson, L. R., and Frey, W. H. 2nd (2004) 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., 13, 16-23, https://doi.org/10.1016/j.jstrokecerebrovasdis.2004.01.005.

    Article  PubMed  Google Scholar 

  119. Saber, H., Himali, J. J., Beiser, A. S., Shoamanesh, A., Pikula, A., Roubenoff, R., Romero, J. R., Kase, C. S., Vasan, R. S., and Seshadri, S. (2017) Serum insulin-like growth factor 1 and the risk of ischemic stroke: The framingham study, Stroke, 48, 1760-1765, https://doi.org/10.1161/STROKEAHA.116.016563.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Iravanpour, F., Dargahi, L., Rezaei, M., Haghani, M., Heidari, R., Valian, N., and Ahmadiani, A. (2021) Intranasal insulin improves mitochondrial function and attenuates motor deficits in a rat 6-OHDA model of Parkinson’s disease, CNS Neurosci. Ther., 27, 308-319, https://doi.org/10.1111/cns.13609.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Kim, B. H., Kelschenbach, J., Borjabad, A., Hadas, E., He, H., Potash, M. J., Nedelcovych, M. T., Rais, R., Haughey, N. J., McArthur, J. C., Slusher, B. S., and Volsky, D. J. (2019) Intranasal insulin therapy reverses hippocampal dendritic injury and cognitive impairment in a model of HIV-associated neurocognitive disorders in EcoHIV-infected mice, AIDS, 33, 973-984, https://doi.org/10.1097/QAD.0000000000002150.

    Article  CAS  PubMed  Google Scholar 

  122. Zhu, Y., Huang, Y., Yang, J., Tu, R., Zhang, X., He, W. W., Hou, C. Y., Wang, X. M., Yu, J. M., and Jiang, G. H. (2022) Intranasal insulin ameliorates neurological impairment after intracerebral hemorrhage in mice, Neural Regen. Res., 17, 210-216, https://doi.org/10.4103/1673-5374.314320.

    Article  CAS  PubMed  Google Scholar 

  123. Zorina, I. I., Saveleva, L. O., Bakhtyukov, A. A., and Shpakov, A. O. (2018) Intranasal insulin administration normalizes the gene expression of antioxidant enzymes in the two-vessel ischemia and reperfusion in the rat brain, in BIOMEMBRANES 2018: International Conference 1-5 October 2018 Book of Abstracts, J. Bioenerg. Biomembr., 50, 467-603, https://doi.org/10.1007/s10863-018-9775-7.

    Article  Google Scholar 

  124. Zorina, I. I., Zakharova, I. O., Bayunova, L. V., and Avrova, N. F. (2018) Insulin administration prevents accumulation of conjugated dienes and trienes and inactivation of Na+, K+-ATPase in the rat cerebral cortex during two-vessel forebrain ischemia and reperfusion, J. Evol. Biochem. Phys., 54, 246-249, https://doi.org/10.1134/S0022093018030109.

    Article  CAS  Google Scholar 

  125. Zorina, I. I., Galkina, O. V., Bayunova, L. V., and Zakharova, I. O. (2019) Effect of insulin on lipid peroxidation and glutathione levels in a two-vessel occlusion model of rat forebrain ischemia followed by reperfusion, J. Evol. Biochem. Phys., 55, 333-335, https://doi.org/10.1134/S0022093019040094.

    Article  Google Scholar 

  126. Zakharova, I. O., Bayunova, L. V., Zorina, I. I., Sokolova, T. V., Shpakov, A. O., and Avrova, N. F. (2021) Insulin and α-tocopherol enhance the protective effect of each other on brain cortical neurons under oxidative stress conditions and in rat two-vessel forebrain ischemia/reperfusion injury, Int. J. Mol. Sci., 22, 11768, https://doi.org/10.3390/ijms222111768.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Zakharova, I. O., Bayunova, L. V., Zorina, I. I., Shpakov, A. O., and Avrova, N. F. (2022) Insulin and brain gangliosides prevent metabolic disorders caused by activation of free radical reactions after two-vessel ischemia-reperfusion injury to the rat forebrain, J. Evol. Biochem. Phys., 58, 279-291, https://doi.org/10.1134/S0022093022010240.

    Article  CAS  Google Scholar 

  128. Duarte, A. I., Santos, M. S., Oliveira, C. R., and Rego, A. C. (2005) Insulin neuroprotection against oxidative stress in cortical neurons – involvement of uric acid and glutathione antioxidant defenses, Free Radic. Biol. Med., 39, 876-889, https://doi.org/10.1016/j.freeradbiomed.2005.05.002.

    Article  CAS  PubMed  Google Scholar 

  129. Derkach, K. V., Bogush, I. V., Berstein, L. M., and Shpakov, A. O. (2015) The influence of intranasal insulin on hypothalamic-pituitary-thyroid axis in normal and diabetic rats, Horm. Metab. Res., 47, 916-924, https://doi.org/10.1055/s-0035-1547236.

    Article  CAS  PubMed  Google Scholar 

  130. Derkach, K. V., Bondareva, V. M., and Shpakov, A. O. (2019) Regulatory effects of intranasal C-peptide and insulin on thyroid and androgenic status of male rats with moderate type 1 diabetes mellitus, J. Evol. Biochem. Physiol., 55, 493-496, https://doi.org/10.1134/S0022093019060073.

    Article  Google Scholar 

  131. Sukhov, I. B., Derkach, K. V., Chistyakova, O. V., Bondareva, V. M., and Shpakov, A. O. (2016) Functional state of hypothalamic signaling systems in rats with type 2 diabetes mellitus treated with intranasal insulin, J. Evol. Biochem. Physiol., 52, 204-216, https://doi.org/10.1134/S0022093016030030.

    Article  CAS  Google Scholar 

  132. Derkach, K. V., Ivantsov, A. O., Chistyakova, O. V., Sukhov, I. B., Buzanakov, D. M., Kulikova, A. A., and Shpakov, A. O. (2017) Intranasal insulin restores metabolic parameters and insulin sensitivity in rats with metabolic syndrome, Bull. Exp. Biol. Med., 163, 184-189, https://doi.org/10.1007/s10517-017-3762-6.

    Article  CAS  PubMed  Google Scholar 

  133. Albers, G. W., Goldstein, L. B., Hess, D. C., Wechsler, L. R., Furie, K. L., Gorelick, P. B., Hurn, P., Liebeskind, D. S., Nogueira, R. G., and Saver, J. L. (2011) STAIR VII Consortium. 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, 42, 2645-2650, https://doi.org/10.1161/STROKEAHA.111.618850.

    Article  PubMed  Google Scholar 

Download references

Funding

The study was supported by the State budget of the Ministry of Science and Higher Education of the Russian Federation according to the state order No. 075-00967-23-00 (Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences).

Author information

Authors and Affiliations

  1. Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, 194223, Saint-Petersburg, Russia

    Inna I. Zorina, Natalia F. Avrova, Irina O. Zakharova & Alexander O. Shpakov

Authors
  1. Inna I. Zorina
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Natalia F. Avrova
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Irina O. Zakharova
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alexander O. Shpakov
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

I. I. Z. and I. O. Z. analyzed publications, wrote the manuscript, and prepared illustrations; A. O. Sh. and N. F. A. developed the concept and edited the manuscript.

Corresponding author

Correspondence to Inna I. Zorina.

Ethics declarations

The authors declare no conflict of interest. No description of studies with human subjects or animals performed by any of the authors is provided in the paper.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zorina, I.I., Avrova, N.F., Zakharova, I.O. et al. Prospects for the Use of Intranasally Administered Insulin and Insulin-Like Growth Factor-1 in Cerebral Ischemia. Biochemistry Moscow 88, 374–391 (2023). https://doi.org/10.1134/S0006297923030070

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S0006297923030070

Keywords

Search

Navigation