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Anesthesia and Preconditioning Induced Changes in Mouse Brain [18F] FDG Uptake and Kinetics

  • Pablo BascuñanaEmail author
  • James T. Thackeray
  • M. Bankstahl
  • Frank M. Bengel
  • Jens P. Bankstahl
Research Article
  • 26 Downloads

Abstract

Purpose

2-Deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) has been widely used for imaging brain metabolism. Tracer injection in anesthetized animals is a prerequisite for performing dynamic positron emission tomography (PET) scanning. Since preconditioning, as well as anesthesia, has been described to potentially influence brain [18F] FDG levels, this study evaluated how these variables globally and regionally affect both [18F] FDG uptake and kinetics in murine brain.

Procedures

Sixty-minute dynamic [18F] FDG PET scans were performed in adult male C57BL/6 mice anesthetized with isoflurane [control (in 100 % O2), in medical air, in 100 % O2 + insulin pre-treatment, and in 100 % O2 after 18 h fasting], ketamine/xylazine, sevoflurane, and chloral hydrate. An additional group was scanned after awake uptake. Blood glucose levels were determined, and data was analyzed by comparing percent injected dose per cc tissue (%ID/cc) and glucose influx rate and metabolic rate (MRGlu) calculated by Patlak plot.

Results

Ketamine/xylazine and chloral hydrate anesthesia induced a lower whole-brain uptake of [18F] FDG (2.86 ± 0.67 %ID/cc, p < 0.001; 4.25 ± 0.28 %ID/cc, p = 0.0179, respectively) compared to isoflurane anesthesia (5.04 ± 0.19 %ID/cc). In addition, protocols affected differently distribution of [18F] FDG uptake in brain regions. Ketamine/xylazine reduced [18F] FDG influx rate in murine brain (0.0135 ± 0.0009 vs 0.0247 ± 0.0014 ml/g/min; p < 0.005) and chloral hydrate increased MRGlu (66.72 ± 3.75 vs 41.55 ± 3.06 μmol/min/100 ml; p < 0.01) compared to isoflurane. Insulin-pretreated animals showed a higher influx rate (0.0477 ± 0.0101 ml/min/g; p < 0.05) but a reduced MRGlu (21.92 ± 3.12 μmol/min/100 ml; p < 0.01). Blood glucose levels were negatively correlated to [18F] FDG uptake and influx rate, but positively correlated to MRGlu.

Conclusions

Choice of anesthesia and pre-conditioning affect not only [18F] FDG uptake but also kinetics and regional distribution in the mouse brain. Both anesthesia and pre-conditioning should be carefully considered in the interpretation of [18F] FDG studies due to its great influence on the uptake and distribution of the tracer along the brain regions.

Key words

Isoflurane Ketamine Sevoflurane Chloral hydrate Glucose 

Notes

Acknowledgments

The authors thank A. Kanwischer, S. Eilert, and P. Felsch for skillful assistance.

Funding Information

This study was partially supported by the German Research Foundation (DFG, Clinical Research Group KFO311 and grant-in-aid TH2161/1-1).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest

Supplementary material

11307_2019_1314_MOESM1_ESM.pdf (218 kb)
ESM 1 (PDF 217 kb)

References

  1. 1.
    Cherry SR, Gambhir SS (2001) Use of positron emission tomography in animal research. ILAR J 42:219–232CrossRefPubMedGoogle Scholar
  2. 2.
    Deleye S, Verhaeghe J, wyffels L, Dedeurwaerdere S, Stroobants S, Staelens S (2014) Towards a reproducible protocol for repetitive and semi-quantitative rat brain imaging with 18F-FDG: exemplified in a memantine pharmacological challenge. Neuroimage 96:276–287CrossRefPubMedGoogle Scholar
  3. 3.
    Toyama H, Ichise M, Liow JS et al (2004) Absolute quantification of regional cerebral glucose utilization in mice by 18F-FDG small animal PET scanning and 2-14C-DG autoradiography. J Nucl Med 45:1398–1405PubMedGoogle Scholar
  4. 4.
    Toyama H, Ichise M, Liow JS, Vines DC, Seneca NM, Modell KJ, Seidel J, Green MV, Innis RB (2004) Evaluation of anesthesia effects on [18F] FDG uptake in mouse brain and heart using small animal PET. Nucl Med Biol 31:251–256CrossRefPubMedGoogle Scholar
  5. 5.
    Lee KH, Ko BH, Paik JY, Jung KH, Choe YS, Choi Y, Kim BT (2005) Effects of anesthetic agents and fasting duration on 18F-FDG biodistribution and insulin levels in tumor-bearing mice. J Nucl Med 46:1531–1536PubMedGoogle Scholar
  6. 6.
    Dandekar M, Tseng JR, Gambhir SS (2007) Reproducibility of 18F-FDG microPET studies in mouse tumor xenografts. J Nucl Med 48:602–607CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Eintrei C, Sokoloff L, Smith CB (1999) Effects of diazepam and ketamine administered individually or in combination on regional rates of glucose utilization in rat brain. Br J Anaesth 82:596–602CrossRefPubMedGoogle Scholar
  8. 8.
    Ito K, Sawada Y, Ishizuka H et al (1990) Measurement of cerebral glucose utilization from brain uptake of [14C]2-deoxyglucose and [3H]3-O-methylglucose in the mouse. J Pharmacol Methods 23:129–140CrossRefPubMedGoogle Scholar
  9. 9.
    Fueger BJ, Czernin J, Hildebrandt I, Tran C, Halpern BS, Stout D, Phelps ME, Weber WA (2006) Impact of animal handling on the results of 18F-FDG PET studies in mice. J Nucl Med 47:999–1006PubMedGoogle Scholar
  10. 10.
    Boellaard R (2009) Standards for PET image acquisition and quantitative data analysis. J Nucl Med 50(Suppl 1):11S–20SCrossRefPubMedGoogle Scholar
  11. 11.
    Cohade C (2010) Altered biodistribution on FDG-PET with emphasis on brown fat and insulin effect. Semin Nucl Med 40:283–293CrossRefPubMedGoogle Scholar
  12. 12.
    Schiffer WK, Mirrione MM, Dewey SL (2007) Optimizing experimental protocols for quantitative behavioral imaging with 18F-FDG in rodents. J Nucl Med 48:277–287PubMedGoogle Scholar
  13. 13.
    Wong K-P, Sha W, Zhang X, Huang S-C (2011) Effects of administration route, dietary condition, and blood glucose level on kinetics and uptake of 18F-FDG in mice. J Nucl Med 52:800–807CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Alf MF, Martic-Kehl MI, Schibli R, Kramer SD (2013) FDG kinetic modeling in small rodent brain PET: optimization of data acquisition and analysis. EJNMMI Res 3:61CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Locke LW, Berr SS, Kundu BK (2011) Image-derived input function from cardiac gated maximum a posteriori reconstructed PET images in mice. Mol Imaging Biol 13:342–347CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Tantawy MN, Peterson TE (2010) Simplified [F-18] FDG image-derived input function using the left ventricle, liver, and one venous blood sample. Mol Imaging 9:76–86CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Lanz B, Poitry-Yamate C, Gruetter R (2014) Image-derived input function from the vena cava for 18F-FDG PET studies in rats and mice. J Nucl Med 55:1380–1388CrossRefPubMedGoogle Scholar
  18. 18.
    Thackeray JT, Bankstahl JP, Bengel FM (2015) Impact of image-derived input function and fit time intervals on patlak quantification of myocardial glucose uptake in mice. J Nucl Med 56:1615–1621CrossRefPubMedGoogle Scholar
  19. 19.
    Thorn SL, deKemp RA, Dumouchel T et al (2013) Repeatable noninvasive measurement of mouse myocardial glucose uptake with 18F-FDG: evaluation of tracer kinetics in a type 1 diabetes model. J Nucl Med 54:1637–1644CrossRefPubMedGoogle Scholar
  20. 20.
    Thackeray JT, Bankstahl JP, Wang Y, Wollert KC, Bengel FM (2015) Clinically relevant strategies for lowering cardiomyocyte glucose uptake for 18F-FDG imaging of myocardial inflammation in mice. Eur J Nucl Med Mol Imaging 42:771–780CrossRefPubMedGoogle Scholar
  21. 21.
    Mirrione MM, Schiffer WK, Fowler JS, Alexoff DL, Dewey SL, Tsirka SE (2007) A novel approach for imaging brain-behavior relationships in mice reveals unexpected metabolic patterns during seizures in the absence of tissue plasminogen activator. Neuroimage 38:34–42CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Patlak CS, Blasberg RG (1985) Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. Generalizations. J Cereb Blood Flow Metab 5:584–590CrossRefPubMedGoogle Scholar
  23. 23.
    Langen KJ, Braun U, Rota Kops E, Herzog H, Kuwert T, Nebeling B, Feinendegen LE (1993) The influence of plasma glucose levels on fluorine-18-fluorodeoxyglucose uptake in bronchial carcinomas. J Nucl Med 34:355–359PubMedGoogle Scholar
  24. 24.
    Wahl RL, Henry CA, Ethier SP (1992) Serum glucose: effects on tumor and normal tissue accumulation of 2-[F-18]-fluoro-2-deoxy-D-glucose in rodents with mammary carcinoma. Radiology 183:643–647CrossRefPubMedGoogle Scholar
  25. 25.
    Torizuka T, Clavo AC, Wahl RL (1997) Effect of hyperglycemia on in vitro tumor uptake of tritiated FDG, thymidine, L-methionine and L-leucine. J Nucl Med 38:382–386PubMedGoogle Scholar
  26. 26.
    Abdel el Motal SM, Sharp GW (1985) Inhibition of glucose-induced insulin release by xylazine. Endocrinology 116:2337–2340CrossRefPubMedGoogle Scholar
  27. 27.
    Pomplun D, Mohlig M, Spranger J, Pfeiffer AF, Ristow M (2004) Elevation of blood glucose following anaesthetic treatment in C57BL/6 mice. Horm Metab Res 36:67–69CrossRefPubMedGoogle Scholar
  28. 28.
    Rodrigues SF, de Oliveira MA, Martins JO, Sannomiya P, de Cássia Tostes R, Nigro D, Carvalho MHC, Fortes ZB (2006) Differential effects of chloral hydrate- and ketamine/xylazine-induced anesthesia by the s.c. route. Life Sci 79:1630–1637CrossRefPubMedGoogle Scholar
  29. 29.
    Jensen TL, Kiersgaard MK, Sorensen DB, Mikkelsen LF (2013) Fasting of mice: a review. Lab Anim 47:225–240CrossRefPubMedGoogle Scholar
  30. 30.
    Mizuma H, Shukuri M, Hayashi T, Watanabe Y, Onoe H (2010) Establishment of in vivo brain imaging method in conscious mice. J Nucl Med 51:1068–1075CrossRefPubMedGoogle Scholar
  31. 31.
    Prieto E, Collantes M, Delgado M, Juri C, García-García L, Molinet F, Fernández-Valle ME, Pozo MA, Gago B, Martí-Climent JM, Obeso JA, Peñuelas I (2011) Statistical parametric maps of 18F-FDG PET and 3-D autoradiography in the rat brain: a cross-validation study. Eur J Nucl Med Mol Imaging 38:2228–2237CrossRefPubMedGoogle Scholar
  32. 32.
    Yu AS, Lin HD, Huang SC, Phelps ME, Wu HM (2009) Quantification of cerebral glucose metabolic rate in mice using 18F-FDG and small-animal PET. J Nucl Med 50:966–973CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Baxter MG, Murphy KL, Taylor PM, Wolfensohn SE (2009) Chloral hydrate is not acceptable for anesthesia or euthanasia of small animals. Anesthesiology 111:209 author reply 209-210CrossRefPubMedGoogle Scholar
  34. 34.
    Spangler-Bickell MG, de Laat B, Fulton R, Bormans G, Nuyts J (2016) The effect of isoflurane on 18F-FDG uptake in the rat brain: a fully conscious dynamic PET study using motion compensation. EJNMMI Res 6:86CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Schuier F, Orzi F, Suda S, Lucignani G, Kennedy C, Sokoloff L (1990) Influence of plasma glucose concentration on lumped constant of the deoxyglucose method: effects of hyperglycemia in the rat. J Cereb Blood Flow Metab 10:765–773CrossRefPubMedGoogle Scholar
  36. 36.
    Suda S, Shinohara M, Miyaoka M, Lucignani G, Kennedy C, Sokoloff L (1990) The lumped constant of the deoxyglucose method in hypoglycemia: effects of moderate hypoglycemia on local cerebral glucose utilization in the rat. J Cereb Blood Flow Metab 10:499–509CrossRefPubMedGoogle Scholar

Copyright information

© World Molecular Imaging Society 2019

Authors and Affiliations

  1. 1.Department of Nuclear MedicineHannover Medical SchoolHannoverGermany
  2. 2.Department of PharmacologyUniversity of Veterinary Medicine HannoverHannoverGermany

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