Intranasal Insulin Prevents Anesthesia-induced Cognitive Impairments in Aged Mice

Author(s): Xing Li, Xiaoqin Run*, Zhen Wei, Kuan Zeng, Zhihou Liang, Fang Huang, Dan Ke, Qun Wang, Jian-Zhi Wang, Rong Liu, Bin Zhang*, Xiaochuan Wang*.

Journal Name: Current Alzheimer Research

Volume 16 , Issue 1 , 2019

  Journal Home
Translate in Chinese
Submit Manuscript
Submit Proposal

Abstract:

Background: Preclinical and clinical evidence suggests that elderly individuals are at increased risk of cognitive decline after general anesthesia. General anesthesia is also believed to be a risk factor for Postoperative Cognitive Dysfunction (POCD) and Alzheimer’s Disease (AD). Intranasal administration of insulin, which delivers the drug directly into the brain, improves memory and cognition in both animal studies and small clinical trials. However, how insulin treatment improves cognitive function is poorly understood.

Methods: Aged mice were pretreated with intranasal insulin or saline before anesthesia. Propofol was added intraperitoneally to the mice from 7th day of insulin/saline treatment, and general anesthesia was induced and maintained for 2 hours/day for 5 consecutive days. Mice were evaluated at 26th day when the mice were continued on insulin or saline administration for another 15 days.

Results: We found that intranasal insulin treatment prevented anesthesia-induced cognitive impairments, as measured by novel object recognition test and contextual-dependent fear conditioning test. Insulin treatment also increased the expression level of Post-synaptic Density Protein 95 (PSD95), as well as upregulated Microtubule-associated Protein-2 (MAP-2) in the dentate gyrus of the hippocampus. Furthermore, we found that insulin treatment restored insulin signaling disturbed by anesthesia via activating PI3K/PDK1/AKT pathway, and attenuated anesthesia-induced hyperphosphorylation of tau at multiple AD-associated sites. We found the attenuation of tau hyperphosphorylation occurred by increasing the level of GSK3β phosphorylated at Ser9, which leads to inactivation of GSK-3β.

Conclusion: Intranasal insulin administration might be a promising therapy to prevent anesthesiainduced cognitive deficit in elderly individuals.

Keywords: Postoperative cognitive dysfunction (POCD), insulin, propofol, tau hyperphosphorylation, cognitive impairments, memory deficit.

[1]
Hansen MV. Chronobiology: cognitive function and depressive symptoms in surgical patients. Danish Med J 61(9): B4914. (2014).
[2]
Wang W, Wang Y, Wu H, Lei L, Xu S, Shen X, et al. Postoperative cognitive dysfunction: current developments in mechanism and prevention. Med Sci Monit 20: 1908-12. (2014).
[3]
Steinmetz J, Christensen KB, Lund T, Lohse N, Rasmussen LS, Group I. Long-term consequences of postoperative cognitive dysfunction. Anesthesiolog 110(3): 548-55. (2009).
[4]
Saniova B, Drobny M, Sulaj M. Delirium and postoperative cognitive dysfunction after general anesthesia. Med Sci Monit 15(5): CS81-7. (2009).
[5]
Fong HK, Sands LP, Leung JM. The role of postoperative analgesia in delirium and cognitive decline in elderly patients: a systematic review. Anesth Analg 102(4): 1255-66. (2006).
[6]
Banks WA, Owen JB, Erickson MA. Insulin in the brain: there and back again. Pharmacol Theraps 136(1): 82-93. (2012).
[7]
Liu Y, Liu F, Grundke-Iqbal I, Iqbal K, Gong CX. Deficient brain insulin signalling pathway in Alzheimer’s disease and diabetes. J Pathol 225(1): 54-62. (2011).
[8]
Lochhead JJ, Thorne RG. Intranasal delivery of biologics to the central nervous system. Adv Drug Deliv Rev 64(7): 614-28. (2012).
[9]
Chen Y, Run X, Liang Z, Zhao Y, Dai CL, Iqbal K, et al. Intranasal insulin prevents anesthesia-induced hyperphosphorylation of tau in 3xTg-AD mice. Front Aging Neurosci 6: 100. (2014).
[10]
Benedict C, Hallschmid M, Hatke A, Schultes B, Fehm HL, Born J, et al. Intranasal insulin improves memory in humans. Psychoneuroendocrinology 29(10): 1326-34. (2004).
[11]
Benedict C, Hallschmid M, Schmitz K, Schultes B, Ratter F, Fehm HL, et al. Intranasal insulin improves memory in humans: superiority of insulin aspart. Neuropsychopharmacology 32(1): 239-43. (2007).
[12]
Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, et al. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol 69(1): 29-38. (2012).
[13]
Run X, Liang Z, Zhang L, Iqbal K, Grundke-Iqbal I, Gong CX. Anesthesia induces phosphorylation of tau. J Alzheimers Dis 16(3): 619-26. (2009).
[14]
Le Freche H, Brouillette J, Fernandez-Gomez FJ, Patin P, Caillierez R, Zommer N, et al. Tau phosphorylation and sevoflurane anesthesia: an association to postoperative cognitive impairment. Anesthesiology 116(4): 779-87. (2012).
[15]
Zhang Y, Dai CL, Chen Y, Iqbal K, Liu F, Gong CX. Intranasal insulin prevents anesthesia-induced spatial learning and memory deficit in mice. Sci Rep 6: 21186. (2016).
[16]
Marks DR, Tucker K, Cavallin MA, Mast TG, Fadool DA. Awake intranasal insulin delivery modifies protein complexes and alters memory, anxiety, and olfactory behaviors. J Neurosci 29(20): 6734-51. (2009).
[17]
Wang X, Blanchard J, Kohlbrenner E, Clement N, Linden RM, Radu A, et al. The carboxy-terminal fragment of inhibitor-2 of protein phosphatase-2A induces Alzheimer disease pathology and cognitive impairment. FASEB J 24(11): 4420-32. (2010).
[18]
Han S, Tai C, Westenbroek RE, Yu FH, Cheah CS, Potter GB, et al. Autistic-like behaviour in Scn1a+/- mice and rescue by enhanced GABA-mediated neurotransmission. Nature 489(7416): 385-90. (2012).
[19]
Chen LM, Xiong YS, Kong FL, Qu M, Wang Q, Chen XQ, et al. Neuroglobin attenuates Alzheimer-like tau hyperphosphorylation by activating Akt signaling. J Neurochem 120(1): 157-64. (2012).
[20]
Liu X, Zeng K, Li M, Wang Q, Liu R, Zhang B, et al. Expression of P301L-hTau in mouse MEC induces hippocampus-dependent memory deficit. Sci Rep 7(1): 3914. (2017).
[21]
Chen Y, Zhao Y, Dai CL, Liang Z, Run X, Iqbal K, et al. Intranasal insulin restores insulin signaling, increases synaptic proteins, and reduces Abeta level and microglia activation in the brains of 3xTg-AD mice. Exp Neurol 261: 610-9. (2014).
[22]
Greengard P, Valtorta F, Czernik AJ, Benfenati F. Synaptic vesicle phosphoproteins and regulation of synaptic function. Science 259(5096): 780-5. (1993).
[23]
Cumming R, Burgoyne R. Neurobiology: contractile proteins in brain cells. Nature 304(5922): 118. (1983).
[24]
Gong CX, Iqbal K. Hyperphosphorylation of microtubule-associated protein tau: a promising therapeutic target for Alzheimer disease. Curr Med Chem 15(23): 2321-8. (2008).
[25]
Wang JZ, Liu F. Microtubule-associated protein tau in development, degeneration and protection of neurons. Prog Neurobiol 85(2): 148-75. (2008).
[26]
Maqbool M, Mobashir M, Hoda N. Pivotal role of glycogen synthase kinase-3: a therapeutic target for Alzheimer’s disease. Eur chemistry. Med Chem 107: 63-81. (2016).
[27]
Chen Y, Zhang J, Zhang B, Gong CX. Targeting insulin signaling for the treatment of Alzheimer’s disease. Curr Topics Med Chem 16(5): 485-92. (2016).
[28]
Ghasemi R, Haeri A, Dargahi L, Mohamed Z, Ahmadiani A. Insulin in the brain: sources, localization and functions. Mol Neurobiol 47(1): 145-71. (2013).
[29]
Bilotta F, Qeva E, Matot I. Anesthesia and cognitive disorders: a systematic review of the clinical evidence. Exp Rev Neurotherap 16(11): 1311-20. (2016).
[30]
Vanderweyde T, Bednar MM, Forman SA, Wolozin B. Iatrogenic risk factors for Alzheimer’s disease: surgery and anesthesia. J Alzheimers Disease 22(3): 91-104. (2010).
[31]
Tsuchiya H. Anesthetic agents of plant origin: a review of phytochemicals with anesthetic activity. Molecules 22(8): E1369. (2017).
[32]
Zhu C, Gao J, Karlsson N, Li Q, Zhang Y, Huang Z, et al. Isoflurane anesthesia induced persistent, progressive memory impairment, caused a loss of neural stem cells, and reduced neurogenesis in young, but not adult, rodents. J Cerebral Blood Flow Metabol 30(5): 1017-30. (2010).
[33]
Lin D, Cao L, Wang Z, Li J, Washington JM, Zuo Z. Lidocaine attenuates cognitive impairment after isoflurane anesthesia in old rats. Behavioural Brain Res 228(2): 319-27. (2012).
[34]
Chen Y, Dai CL, Wu Z, Iqbal K, Liu F, Zhang B, et al. Intranasal insulin prevents anesthesia-induced cognitive impairment and chronic neurobehavioral changes. Front Aging Neurosci 9: 136. (2017).
[35]
Whittington RA, Bretteville A, Dickler MF, Planel E. Anesthesia and tau pathology. Prog Neuropsychopharmacol Biol Psychiat 47: 147-55. (2013).
[36]
Run X, Liang Z, Gong CX. Anesthetics and tau protein: animal model studies. J Alzheimers Dis 22(3): 49-55. (2010).
[37]
Tang JX, Mardini F, Caltagarone BM, Garrity ST, Li RQ, Bianchi SL, et al. Anesthesia in presymptomatic Alzheimer’s disease: a study using the triple-transgenic mouse model. Alzheimers Dementia 7(5): 521-31. (2011).
[38]
Culley DJ, Baxter M, Yukhananov R, Crosby G. The memory effects of general anesthesia persist for weeks in young and aged rats. Anesthesia and analgesia 96(4): 1004-9. (2003).
[39]
Callaway JK, Jones NC, Royse AG, Royse CF. Sevoflurane anesthesia does not impair acquisition learning or memory in the Morris water maze in young adult and aged rats. Anesthesiology 117(5): 1091-101. (2012).
[40]
Lee IH, Culley DJ, Baxter MG, Xie Z, Tanzi RE, Crosby G. Spatial memory is intact in aged rats after propofol anesthesia. Anesthesia Analgesia 107(4): 1211-5. (2008).
[41]
Zhang X, Xin X, Dong Y, Zhang Y, Yu B, Mao J, et al. Surgical incision-induced nociception causes cognitive impairment and reduction in synaptic NMDA receptor 2B in mice. J Neurosci 33(45): 17737-48. (2013).
[42]
Kong F, Chen S, Cheng Y, Ma L, Lu H, Zhang H, et al. Minocycline attenuates cognitive impairment induced by isoflurane anesthesia in aged rats. PloS one 8(4): e61385. (2013).
[43]
Baranowska-Bik A, Bik W. Insulin and brain aging. Przeglad Menopauzalny Menopause Rev 16(2): 44-6. (2017).
[44]
Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R, et al. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease--is this type 3 diabetes? J Alzheimers Dis 7(1): 63-80. (2005).
[45]
Reger MA, Watson GS, Green PS, Baker LD, Cholerton B, Fishel MA, et al. Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-beta in memory-impaired older adults. J Alzheimers Dis 13(3): 323-31. (2008).
[46]
Claxton A, Baker LD, Hanson A, Trittschuh EH, Cholerton B, Morgan A, et al. Long-acting intranasal insulin detemir improves cognition for adults with mild cognitive impairment or early-stage Alzheimer’s disease dementia. J Alzheimers Dis 44(3): 897-906. (2015).


Rights & PermissionsPrintExport Cite as


Article Details

VOLUME: 16
ISSUE: 1
Year: 2019
Page: [8 - 18]
Pages: 11
DOI: 10.2174/1567205015666181031145045
Price: $58

Article Metrics

PDF: 29
HTML: 7