Paeonol alleviates brain glucose hypometabolism in streptozotocin murine model of sporadic Alzheimer’s disease using microPET imaging

Document Type : Research Paper

Authors

1 Department of Biology, School of Basic Sciences, Shahed University, Tehran, Iran

2 Neurophysiology Research Center, Shahed University, Tehran, Iran

Abstract

Background and Objective: Intracerebroventricular (ICV) injection of streptozotocin (STZ) in rodents causes a model of sporadic Alzheimer's disease (sAD) with development of insulin resistance and neuronal dysfunction. Paeonol is a phenolic agent with neuroprotective effect due to its anti-inflammatory and anti-oxidant effects. This study was conducted to assess its beneficial effect in prevention of brain glucose hypometabolism in ICV STZ rat model of sAD.
Materials and Methods: STZ (3 mg/kg) was bilaterally injected ICV on days 0 and 2 using stereotaxic surgery and paeonol was orally given at two doses of 25 (low) or 100 (high) mg/kg from day 0 (post-surgery) till day 24 post-STZ. At the end of study, positron emission tomography (PET) imaging was employed with a micro-PET scanner through tail vein injection of 18FDG and brain to background ratio (BBR) was calculated.
Results: ICV-STZ group had a significantly low BBR compared to sham group. In contrast, ICV-STZ group treated with paeonol at a dose of 100 mg/kg had a significantly higher BBR as compared to ICV-STZ group, clearly indicating attenuation of brain glucose hypometabolism. In addition, paeonol at a dose of 25 mg/kg did not significantly improve BBR in ICV-STZ group.
Conclusion: In summary, these results revealed the beneficial dose-dependent effect of paeonol in amelioration of brain glucose hypometabolism in STZ-induced model of sAD. 

Keywords


  1. Arendt T, Stieler J, Ueberham U. Is sporadic Alzheimer's disease a developmental disorder? Journal of Neurochemistry 2017;143(4):396-408.
  2. Streit WJ, Khoshbouei H, Bechmann I. The Role of Microglia in Sporadic Alzheimer's Disease. Journal of Alzheimer's Disease 2021;79(3):961-8.
  3. Zhang L, Chen C, Mak MS, Lu J, Wu Z, Chen Q, et al. Advance of sporadic Alzheimer's disease animal models. Medicinal Research Reviews 2020;40(1):431-58.
  4. Shalaby MA, Nounou HA, Deif MM. The potential value of capsaicin in modulating cognitive functions in a rat model of streptozotocin-induced Alzheimer’s disease. The Egyptian Journal of Neurology, Psychiatry and Neurosurgery 2019;55(1):48.
  5. Shah K, Desilva S, Abbruscato T. The role of glucose transporters in brain disease: diabetes and Alzheimer’s Disease. International Journal of Molecular Sciences 2012;13(10):12629-55.
  6. Kamat PK. Streptozotocin induced Alzheimer's disease like changes and the underlying neural degeneration and regeneration mechanism. Neural Regeneration Research 2015;10(7):1050-2.
  7. Xu F, Xiao H, Liu R, Yang Y, Zhang M, Chen L, et al. Paeonol Ameliorates Glucose and Lipid Metabolism in Experimental Diabetes by Activating Akt. Frontiers in Pharmacology 2019;10:261.
  8. Gyawali A, Krol S, Kang Y-S. Involvement of a Novel Organic Cation Transporter in Paeonol Transport Across the Blood-Brain Barrier. Biomolecules and Therapeutics (Seoul) 2019;27(3):290-301.
  9. Bouter C, Bouter Y. (18)F-FDG-PET in Mouse Models of Alzheimer's Disease. Frontiers in Medicine (Lausanne) 2019;6:71.
  10. Chételat G, Arbizu J, Barthel H, Garibotto V, Law I, Morbelli S, et al. Amyloid-PET and (18)F-FDG-PET in the diagnostic investigation of Alzheimer's disease and other dementias. The Lancet Neurology 2020;19(11):951-62.
  11. Rubí S, Noguera A, Tarongí S, Oporto M, García A, Vico H, et al. Concordance between brain (18)F-FDG PET and cerebrospinal fluid biomarkers in diagnosing Alzheimer's disease. Revista Española de Medicina Nuclear e Imagen Molecular (Engl Ed) 2018;37(1):3-8.
  12. Chen P, Shen Z, Wang Q, Zhang B, Zhuang Z, Lin J, et al. Reduced Cerebral Glucose Uptake in an Alzheimer’s Rat Model With Glucose-Weighted Chemical Exchange Saturation Transfer Imaging. Frontiers in Aging Neuroscience 2021;13(118).
  13. Bouter C, Henniges P, Franke TN, Irwin C, Sahlmann CO, Sichler ME, et al. 18F-FDG-PET Detects Drastic Changes in Brain Metabolism in the Tg4–42 Model of Alzheimer’s Disease. Frontiers in Aging Neuroscience. 2019;10(425).
  14. Sharma Y, Garabadu D. Ruthenium red, mitochondrial calcium uniporter inhibitor, attenuates cognitive deficits in STZ-ICV challenged experimental animals. Brain Research Bulletin 2020;164:121-35.
  15. Cason E, Treglia G, Fagioli G. Leading role of 18 F-FDG-PET imaging in early diagnosis of Alzheimer's disease: an overview. Research and Reports in Nuclear Medicine 2011;Volume 1.
  16. Adki KM, Kulkarni YA. Neuroprotective effect of paeonol in streptozotocin-induced diabetes in rats. Life Sciences 2021;271:119202.
  17. Zhao Y, Fu B, Zhang X, Zhao T, Chen L, Zhang J, et al. Paeonol pretreatment attenuates cerebral ischemic injury via upregulating expression of pAkt, Nrf2, HO-1 and ameliorating BBB permeability in mice. Brain Research Bulletin 2014;109:61-7.
  18. Zhong SZ, Ge QH, Qu R, Li Q, Ma SP. Paeonol attenuates neurotoxicity and ameliorates cognitive impairment induced by d-galactose in ICR mice. Journal of the Neurological Sciences 2009;277(1-2):58-64.
  19. Liu J, Feng L, Ma D, Zhang M, Gu J, Wang S, et al. Neuroprotective effect of paeonol on cognition deficits of diabetic encephalopathy in streptozotocin-induced diabetic rat. Neuroscience Letters 2013;549:63-8.
  20. Liu J, Wang S, Feng L, Ma D, Fu Q, Song Y, et al. Hypoglycemic and antioxidant activities of paeonol and its beneficial effect on diabetic encephalopathy in streptozotocin-induced diabetic rats. Journal of Medicinal Food 2013;16(7):577-86.
  21. Xu F, Xiao H, Liu R, Yang Y, Zhang M, Chen L, et al. Paeonol Ameliorates Glucose and Lipid Metabolism in Experimental Diabetes by Activating Akt. Frontiers in Pharmacology 2019;10(261).
  22. Zhang J, Jiang M, Zhao H, Han L, Jin Y, Chen W, et al. Synthesis of Paeonol-Ozagrel Conjugate: Structure Characterization and In Vivo Anti-Ischemic Stroke potential. Frontiers in Pharmacology. 2021;11(2330).
  23. Zhu X-L, Chen J-J, Han F, Pan C, Zhuang T-T, Cai Y-F, et al. Novel antidepressant effects of Paeonol alleviate neuronal injury with concomitant alterations in BDNF, Rac1 and RhoA levels in chronic unpredictable mild stress rats. Psychopharmacology 2018;235(7):2177-91.
  24. Lin C, Lin H-Y, Chen J-H, Tseng W-P, Ko P-Y, Liu Y-S, et al. Effects of Paeonol on Anti-Neuroinflammatory Responses in Microglial Cells. International Journal of Molecular Sciences 2015;16(4):8844-60.
  25. Liu J, Feng L, Ma D, Zhang M, Gu J, Wang S, et al. Neuroprotective effect of paeonol on cognition deficits of diabetic encephalopathy in streptozotocin-induced diabetic rat. Neuroscience Letters 2013;549:63-8.
  26. Su S-Y, Cheng C-Y, Tsai T-H, Hsieh C-L. Paeonol Protects Memory after Ischemic Stroke via Inhibiting β-Secretase and Apoptosis. Evidence-Based Complementary and Alternative Medicine 2012;2012:932823.