Skip to main content

Advertisement

SpringerLink
Log in

Intranasal Insulin Ameliorates Cerebral Hypometabolism, Neuronal Loss, and Astrogliosis in Streptozotocin-Induced Alzheimer’s Rat Model

  • ORIGINAL ARTICLE
  • Published:
Neurotoxicity Research Aims and scope Submit manuscript

Abstract

Intracerebroventricular injection of streptozotocin (ICV-STZ) in rodents leads to cognitive impairments and several pathological changes like Alzheimer’s disease (AD). However, there is hardly any research about the effect of ICV-STZ on regional cerebral glucose metabolism in rodents. Previous studies have demonstrated that intranasal insulin improves cognition in AD patients. However, the underlying mechanism remains elusive. Here, we treated the ICV-STZ rats with daily intranasal delivery of insulin (2 U/day) for 6 consecutive weeks, then monitored 18F-fluorodeoxyglucose (18F-FDG) uptake using a high-resolution small-animal positron emission tomography (microPET) and studied the expression of neuronal nuclei (NeuN) and glial fibrillary acidic protein (GFAP) using immunohistochemical staining. We observed that 18F-FDG uptake decreased significantly at the prefrontal cortex, cingulate cortex, striatum, hippocampus, and entorhinal cortex in ICV-STZ rats as compared with the control rats. Intranasal insulin restores the cerebral glucose metabolism in prefrontal and cingulate cortex and attenuates astroglia activation and neuronal loss in the hippocampus of ICV-STZ rats. These findings provide the mechanistic basis for treating AD patients with intranasal insulin.

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
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Arnsten AF, Wang M (2016) Targeting prefrontal cortical systems for drug development: potential therapies for cognitive disorders. Annu Rev Pharmacol Toxicol 56:339–360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bedse G, Di Domenico F, Serviddio G, Cassano T (2015) Aberrant insulin signaling in Alzheimer’s disease: current knowledge. Front Neurosci 9:204

    Article  PubMed  PubMed Central  Google Scholar 

  • Benedict C, Hallschmid M, Hatke A, Schultes B, Fehm HL, Born J, Kern W (2004) Intranasal insulin improves memory in humans. Psychoneuroendocrinology 29(10):1326–1334

    Article  CAS  PubMed  Google Scholar 

  • Besson FL, La Joie R, Doeuvre L, Gaubert M, Mezenge F, Egret S, Landeau B, Barre L, Abbas A, Ibazizene M, de La Sayette V, Desgranges B, Eustache F, Chetelat G (2015) Cognitive and brain profiles associated with current neuroimaging biomarkers of preclinical Alzheimer’s disease. J Neurosci : Official J Soc Neurosci 35(29):10402–10411

    Article  CAS  Google Scholar 

  • Calvo-Ochoa E, Hernandez-Ortega K, Ferrera P, Morimoto S, Arias C (2014) Short-term high-fat-and-fructose feeding produces insulin signaling alterations accompanied by neurite and synaptic reduction and astroglial activation in the rat hippocampus. J Cereb Blood Flow Metab : Off J Int Soc Cereb Blood Flow Metab 34(6):1001–1008

    Article  CAS  Google Scholar 

  • Chen Y, Liang Z, Blanchard J, Dai CL, Sun S, Lee MH, Grundke-Iqbal I, Iqbal K, Liu F, Gong CX (2013) A non-transgenic mouse model (icv-STZ mouse) of Alzheimer’s disease: similarities to and differences from the transgenic model (3xTg-AD mouse). Mol Neurobiol 47(2):711–725

    Article  CAS  PubMed  Google Scholar 

  • Chen Y, Liang Z, Tian Z, Blanchard J, Dai CL, Chalbot S, Iqbal K, Liu F, Gong CX (2014a) Intracerebroventricular streptozotocin exacerbates Alzheimer-like changes of 3xTg-AD mice. Mol Neurobiol 49(1):547–562

    Article  CAS  PubMed  Google Scholar 

  • Chen Y, Zhang J, Zhang B, Gong CX (2016) Targeting insulin signaling for the treatment of Alzheimer’s disease. Curr Top Med Chem 16(5):485–492

    Article  CAS  PubMed  Google Scholar 

  • Chen Y, Zhao Y, Dai CL, Liang Z, Run X, Iqbal K, Liu F, Gong CX (2014b) Intranasal insulin restores insulin signaling, increases synaptic proteins, and reduces Abeta level and microglia activation in the brains of 3xTg-AD mice. Exp Neurol 261:610–619

    Article  CAS  PubMed  Google Scholar 

  • Claxton A, Baker LD, Hanson A, Trittschuh EH, Cholerton B, Morgan A, Callaghan M, Arbuckle M, Behl C, Craft S (2015) Long-acting intranasal insulin detemir improves cognition for adults with mild cognitive impairment or early-stage Alzheimer’s disease dementia. J Alzheimer's Dis : JAD 44(3):897–906

    CAS  Google Scholar 

  • Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, Arbuckle M, Callaghan M, Tsai E, Plymate SR, Green PS, Leverenz J, Cross D, Gerton B (2012) Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol 69(1):29–38

    Article  PubMed  Google Scholar 

  • Deng Y, Li B, Liu Y, Iqbal K, Grundke-Iqbal I, Gong CX (2009) Dysregulation of insulin signaling, glucose transporters, O-GlcNAcylation, and phosphorylation of tau and neurofilaments in the brain: implication for Alzheimer’s disease. Am J Pathol 175(5):2089–2098

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dhuria SV, Hanson LR, Frey WH 2nd (2010) Intranasal delivery to the central nervous system: mechanisms and experimental considerations. J Pharm Sci 99(4):1654–1673

    Article  CAS  PubMed  Google Scholar 

  • Drzezga A, Lautenschlager N, Siebner H, Riemenschneider M, Willoch F, Minoshima S, Schwaiger M, Kurz A (2003) Cerebral metabolic changes accompanying conversion of mild cognitive impairment into Alzheimer’s disease: a PET follow-up study. Eur J Nucl Med Mol Imaging 30(8):1104–1113

    Article  PubMed  Google Scholar 

  • Fletcher LC, Burke KE, Caine PL, Rinne NL, Braniff CA, Davis HR, Miles KA, Packer C (2013) Diagnosing Alzheimer’s disease: are we any nearer to useful biomarker-based, non-invasive tests? GMS Health Technol Assessment 9:Doc01

    Google Scholar 

  • Freiherr J, Hallschmid M, Frey WH 2nd, Brunner YF, Chapman CD, Holscher C, Craft S, De Felice FG, Benedict C (2013) Intranasal insulin as a treatment for Alzheimer’s disease: a review of basic research and clinical evidence. CNS drugs 27(7):505–514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gao F, Guo Y, Zhang H, Wang S, Wang J, Wu JM, Chen Z, Ding MP (2009) Anterior thalamic nucleus stimulation modulates regional cerebral metabolism: an FDG-MicroPET study in rats. Neurobiol Dis 34(3):477–483

    Article  CAS  PubMed  Google Scholar 

  • Gao F, Wang S, Guo Y, Wang J, Lou M, Wu J, Ding M, Tian M, Zhang H (2010) Protective effects of repetitive transcranial magnetic stimulation in a rat model of transient cerebral ischaemia: a microPET study. Eur J Nucl Med Mol Imaging 37(5):954–961

    Article  PubMed  Google Scholar 

  • Grieb P (2015) Intracerebroventricular streptozotocin injections as a model of Alzheimer’s disease: in search of a relevant mechanism. Mol Neurobiol 53(3):1741–1752

    Article  PubMed  PubMed Central  Google Scholar 

  • Guo Y, Gao F, Wang S, Ding Y, Zhang H, Wang J, Ding MP (2009) In vivo mapping of temporospatial changes in glucose utilization in rat brain during epileptogenesis: an 18F-fluorodeoxyglucose-small animal positron emission tomography study. Neuroscience 162(4):972–979

    Article  CAS  PubMed  Google Scholar 

  • Hanson LR, Frey WH 2nd (2008) Intranasal delivery bypasses the blood-brain barrier to target therapeutic agents to the central nervous system and treat neurodegenerative disease. BMC neuroscience 3(Suppl):S5

    Article  Google Scholar 

  • Heo JH, Lee SR, Lee ST, Lee KM, Oh JH, Jang DP, Chang KT, Cho ZH (2011) Spatial distribution of glucose hypometabolism induced by intracerebroventricular streptozotocin in monkeys. J Alzheimer's Dis : JAD 25(3):517–523

    Google Scholar 

  • Herholz K, Carter SF, Jones M (2007) Positron emission tomography imaging in dementia. Br J radiol 80(Spec No2):S160–S167

    Article  PubMed  Google Scholar 

  • Kalafatakis K, Zarros A (2014) Intracerebroventricular administration of streptozotocin as an experimental approach to Alzheimer’s disease. Int J neurosci 124(12):944–946

    Article  CAS  PubMed  Google Scholar 

  • Kamat PK, Kalani A, Rai S, Tota SK, Kumar A, Ahmad AS (2015) Streptozotocin intracerebroventricular-induced neurotoxicity and brain insulin resistance: a therapeutic intervention for treatment of sporadic Alzheimer’s disease (sAD)-like pathology. Mol Neurobiol 53(7):4548–4562

    Article  PubMed  Google Scholar 

  • Kato T, Inui Y, Nakamura A, Ito K (2016) Brain fluorodeoxyglucose (FDG) PET in dementia. Ageing Res Rev 30:73–84

    Article  PubMed  Google Scholar 

  • Kumar A, Singh A, Ekavali (2015) A review on Alzheimer’s disease pathophysiology and its management: an update. Pharmacol Rep : PR 67(2):195–203

    Article  CAS  PubMed  Google Scholar 

  • Lenzen S (2008) The mechanisms of alloxan- and streptozotocin-induced diabetes. Diabetologia 51(2):216–226

    Article  CAS  PubMed  Google Scholar 

  • Lu Y, Ren J, Cui S, Chen J, Huang Y, Tang C, Shan B, Nie B, Xinsheng L (2015) Cerebral glucose metabolism assessment in rat models of Alzheimer’s disease: an 18F-FDG-PET study. Am J Alzheimer's Dis Other Dement 31(4):333–340

    Article  CAS  Google Scholar 

  • Macdonald IR, DeBay DR, Reid GA, O’Leary TP, Jollymore CT, Mawko G, Burrell S, Martin E, Bowen CV, Brown RE, Darvesh S (2014) Early detection of cerebral glucose uptake changes in the 5XFAD mouse. Curr Alzheimer Res 11(5):450–460

    Article  CAS  PubMed  Google Scholar 

  • Mao YF, Guo Z, Zheng T, Jiang Y, Yan Y, Yin X, Chen Y, Zhang B (2016) Intranasal insulin alleviates cognitive deficits and amyloid pathology in young adult APPswe/PS1dE9 mice. Aging Cell 15(5):893–902

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marks DR, Tucker K, Cavallin MA, Mast TG, Fadool DA (2009) Awake intranasal insulin delivery modifies protein complexes and alters memory, anxiety, and olfactory behaviors. J Neurosci : Off J Soc Neurosci 29(20):6734–6751

    Article  CAS  Google Scholar 

  • Mosconi L (2005) Brain glucose metabolism in the early and specific diagnosis of Alzheimer’s disease. FDG-PET studies in MCI and AD. Eur J Nucl Med Mol Imaging 32(4):486–510

    Article  CAS  PubMed  Google Scholar 

  • Mrak RE, Griffin WS (2001) Interleukin-1, neuroinflammation, and Alzheimer’s disease. Neurobiol Aging 22(6):903–908

    Article  CAS  PubMed  Google Scholar 

  • Poisnel G, Herard AS, Tannir E, Tayara N, Bourrin E, Volk A, Kober F, Delatour B, Delzescaux T, Debeir T, Rooney T, Benavides J, Hantraye P, Dhenain M (2012) Increased regional cerebral glucose uptake in an APP/PS1 model of Alzheimer’s disease. Neurobiol Aging 33(9):1995–2005

    Article  CAS  PubMed  Google Scholar 

  • Prickaerts J, Fahrig T, Blokland A (1999) Cognitive performance and biochemical markers in septum, hippocampus and striatum of rats after an i.c.v. injection of streptozotocin: a correlation analysis. Behav Brain Res 102(1–2):73–88

    Article  CAS  PubMed  Google Scholar 

  • Reger MA, Watson GS, Green PS, Baker LD, Cholerton B, Fishel MA, Plymate SR, Cherrier MM, Schellenberg GD, Frey WH 2nd, Craft S (2008) Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-beta in memory-impaired older adults. J Alzheimer's Dis : JAD 13(3):323–331

    Article  CAS  Google Scholar 

  • Schiffer WK, Mirrione MM, Dewey SL (2007) Optimizing experimental protocols for quantitative behavioral imaging with 18F-FDG in rodents. J Nucl Med : Off Publ Soc Nucl Med 48(2):277–287

    CAS  Google Scholar 

  • Silverman DH, Small GW, Chang CY, Lu CS, Kung De Aburto MA, Chen W, Czernin J, Rapoport SI, Pietrini P, Alexander GE, Schapiro MB, Jagust WJ, Hoffman JM, Welsh-Bohmer KA, Alavi A, Clark CM, Salmon E, de Leon MJ, Mielke R, Cummings JL, Kowell AP, Gambhir SS, Hoh CK, Phelps ME (2001) Positron emission tomography in evaluation of dementia: regional brain metabolism and long-term outcome. JAMA 286(17):2120–2127

    Article  CAS  PubMed  Google Scholar 

  • Simpson IA, Chundu KR, Davies-Hill T, Honer WG, Davies P (1994) Decreased concentrations of GLUT1 and GLUT3 glucose transporters in the brains of patients with Alzheimer’s disease. Ann Neurol 35(5):546–551

    Article  CAS  PubMed  Google Scholar 

  • Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R, Xu XJ, Wands JR, de la Monte SM (2005) Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease—is this type 3 diabetes? J Alzheimer's Dis : JAD 7(1):63–80

    Article  CAS  Google Scholar 

  • Sutphen CL, Jasielec MS, Shah AR, Macy EM, Xiong C, Vlassenko AG, Benzinger TL, Stoops EE, Vanderstichele HM, Brix B, Darby HD, Vandijck ML, Ladenson JH, Morris JC, Holtzman DM, Fagan AM (2015) Longitudinal cerebrospinal fluid biomarker changes in preclinical Alzheimer disease during middle age. JAMA Neurol 72(9):1029–1042

    Article  PubMed  PubMed Central  Google Scholar 

  • Villemagne VL, Burnham S, Bourgeat P, Brown B, Ellis KA, Salvado O, Szoeke C, Macaulay SL, Martins R, Maruff P, Ames D, Rowe CC, Masters CL, Australian Imaging B, Lifestyle Research G (2013) Amyloid beta deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer’s disease: a prospective cohort study. Lancet Neurol 12(4):357–367

    Article  CAS  PubMed  Google Scholar 

  • Willette AA, Bendlin BB, Starks EJ, Birdsill AC, Johnson SC, Christian BT, Okonkwo OC, La Rue A, Hermann BP, Koscik RL, Jonaitis EM, Sager MA, Asthana S (2015) Association of insulin resistance with cerebral glucose uptake in late middle-aged adults at risk for Alzheimer disease. JAMA Neurol 72(9):1013–1020

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhang L, Guo Y, Hu H, Wang J, Liu Z, Gao F (2015) FDG-PET and NeuN-GFAP immunohistochemistry of hippocampus at different phases of the pilocarpine model of temporal lobe epilepsy. Int J Med Sci 12(3):288–294

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the National 973 Project [grant numbers 2013CB530904], the National Nature Science Foundation of China [grant numbers 81400866], and the Zhejiang Provincial Natural Science Foundation of China [grant numbers LQ15H09000].

Author information

Author notes

  1. Yanxing Chen and Zhangyu Guo contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, No.88 Jiefang Road, Zhejiang, Hangzhou, 310009, China

    Yanxing Chen, Zhangyu Guo, Tingting Zheng & Baorong Zhang

  2. Department of Neurology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Zhejiang, Hangzhou, 310016, China

    Yan-Fang Mao

Authors
  1. Yanxing Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhangyu Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yan-Fang Mao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tingting Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Baorong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Baorong Zhang.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

The use and care of the animal is complied with the National Institute of Health Guide for the Care and Use of Laboratory Animals (NIH Publications No. 80-23) revised 1996, and protocols were approved by the Institutional Animal Care and Use Committee of Zhejiang University.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, Y., Guo, Z., Mao, YF. et al. Intranasal Insulin Ameliorates Cerebral Hypometabolism, Neuronal Loss, and Astrogliosis in Streptozotocin-Induced Alzheimer’s Rat Model. Neurotox Res 33, 716–724 (2018). https://doi.org/10.1007/s12640-017-9809-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12640-017-9809-7

Keywords

Search

Navigation