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Long-Term Alternating Fasting Increases Interleukin-13 in the Gerbil Hippocampus, But Does Not Protect BBB and Pyramidal Neurons From Ischemia–Reperfusion Injury

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Abstract

It is questionable whether intermittent fasting (IF) protects against brain ischemic injury. This study examined whether IF increased anti-inflammatory cytokines and protected neurons from ischemia–reperfusion injury in the gerbil hippocampus. Gerbils were subjected to 1-day alternating fasting as IF for 1, 2, or 3 months and assigned to sham or 5 min of transient ischemia. We examined the changes in anti-inflammatory cytokines (IL-4 and IL-13), neurons and IgG by immunohistochemistry or immunofluorescence staining in the cornu ammonis 1 (CA1) region of the hippocampus before and after ischemia. IF increased IL-13 immunoreactivity in the CA1 region before ischemia, but did not affect IL-4 immunoreactivity. After ischemia, IL-13 and 4 immunoreactivities in the CA1 region were significantly lower in IF gerbils than in non-IF gerbils. In the IF gerbils, the CA1 pyramidal neurons were not protected from ischemic injury; in these gerbils, strong IgG immunoreactivity was seen in the CA1 parenchyma, indicating leakage of the BBB. In brief, IF increased IL-13 in the CA1 region, but these neurons were not protected from transient ischemic injury evidenced by IgG immunoreactivity in the CA1 parenchyma. This study indicates that IF increased some anti-inflammatory cytokines but did not afford neuroprotection against ischemic insults via BBB disruption.

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References

  1. Opal SM, Depalo VA (2000) Anti-inflammatory cytokines. Chest 117:1162–1172

    Article  CAS  Google Scholar 

  2. Yang M-S, Ji K-A, Jeon S-B, Jin B-K, Kim SU, Jou I, Joe E (2006) Interleukin-13 enhances cyclooxygenase-2 expression in activated rat brain microglia: implications for death of activated microglia. J Immunol 177:1323–1329

    Article  CAS  Google Scholar 

  3. Kim DW, Lee JC, Cho JH, Park JH, Ahn JH, Chen BH, Shin BN, Tae HJ, Seo JY, Kang IJ, Hong S, Kim YM, Won MH, Kim IH (2015) Neuroprotection of ischemic preconditioning is mediated by anti-inflammatory, not pro-inflammatory, cytokines in the gerbil hippocampus induced by a subsequent lethal transient cerebral ischemia. Neurochem Res 40:1984–1995

    Article  CAS  Google Scholar 

  4. Taj SH, Le Blon D, Hoornaert C, Daans J, Quarta A, Praet J, Van der Linden A, Ponsaerts P, Hoehn M (2018) Targeted intracerebral delivery of the anti-inflammatory cytokine IL13 promotes alternative activation of both microglia and macrophages after stroke. J Neuroinflamm 15:174

    Article  Google Scholar 

  5. Longo VD, Mattson MP (2014) Fasting: molecular mechanisms and clinical applications. Cell Metab 19:181–192

    Article  CAS  Google Scholar 

  6. Lee J, Seroogy KB, Mattson MP (2002) Dietary restriction enhances neurotrophin expression and neurogenesis in the hippocampus of adult mice. J Neurochem 80:539–547

    Article  CAS  Google Scholar 

  7. Randolph SA (2016) Ischemic stroke. Workplace Health Saf 64:444

    Article  Google Scholar 

  8. Kirino T (1982) Delayed neuronal death in the gerbil hippocampus following ischemia. Brain Res 239:57–69

    Article  CAS  Google Scholar 

  9. Doyle KP, Simon RP, Stenzel-Poore MP (2008) Mechanisms of ischemic brain damage. Neuropharmacology 55:310–318

    Article  CAS  Google Scholar 

  10. Yu JT, Lee CH, Yoo K-Y, Choi JH, Li H, Park OK, Yan B, Hwang IK, Kwon Y-G, Kim Y-M (2010) Maintenance of anti-inflammatory cytokines and reduction of glial activation in the ischemic hippocampal CA1 region preconditioned with lipopolysaccharide. J Neurol Sci 296:69–78

    Article  CAS  Google Scholar 

  11. Ghosh A, Birngruber T, Sattler W, Kroath T, Ratzer M, Sinner F, Pieber TR (2014) Assessment of blood–brain barrier function and the neuroinflammatory response in the rat brain by using cerebral open flow microperfusion (cOFM). PLoS One 9:e98143

    Article  Google Scholar 

  12. Jiang X, Andjelkovic AV, Zhu L, Yang T, Bennett MVL, Chen J, Keep RF, Shi Y (2018) Blood–brain barrier dysfunction and recovery after ischemic stroke. Prog Neurobiol 163–164:144–171

    Article  Google Scholar 

  13. Li L, Wang Z, Zuo Z (2013) Chronic intermittent fasting improves cognitive functions and brain structures in mice. PLoS One 8:e66069

    Article  CAS  Google Scholar 

  14. Jeong JH, Yu KS, Bak DH, Lee JH, Lee NS, Jeong YG, Kim DK, Kim JJ, Han SY (2016) Intermittent fasting is neuroprotective in focal cerebral ischemia by minimizing autophagic flux disturbance and inhibiting apoptosis. Exp Ther Med 12:3021–3028

    Article  CAS  Google Scholar 

  15. Tajes M, Gutierrez-Cuesta J, Folch J, Ortuño-Sahagun D, Verdaguer E, Jiménez A, Junyent F, Lau A, Camins A, Pallàs M (2010) Neuroprotective role of intermittent fasting in senescence-accelerated mice P8 (SAMP8). Exp Gerontol 45:702–710

    Article  CAS  Google Scholar 

  16. Candelario-Jalil E, Alvarez D, Merino N, León OS (2003) Delayed treatment with nimesulide reduces measures of oxidative stress following global ischemic brain injury in gerbils. Neurosci Res 47:245–253

    Article  CAS  Google Scholar 

  17. Lee T-K, Park JH, Ahn JH, Shin MC, Cho JH, Bae EJ, Kim Y-M, Won M-H, Lee C-H (2016) Pretreated duloxetine protects hippocampal CA1 pyramidal neurons from ischemia–reperfusion injury through decreases of glial activation and oxidative stress. J Neurol Sci 370:229–236

    Article  CAS  Google Scholar 

  18. Schmued LC, Hopkins KJ (2000) Fluoro-Jade B: a high affinity fluorescent marker for the localization of neuronal degeneration. Brain Res 874:123–130

    Article  CAS  Google Scholar 

  19. Fann DY, Ng GY, Poh L, Arumugam TV (2017) Positive effects of intermittent fasting in ischemic stroke. Exp Gerontol 89:93–102

    Article  Google Scholar 

  20. Manzanero S, Gelderblom M, Magnus T, Arumugam TV (2011) Calorie restriction and stroke. Exp Transl Stroke Med 3:8

    Article  CAS  Google Scholar 

  21. McEwen BR, Paterson PG (2010) Caloric restriction provided after global ischemia does not reduce hippocampal cornu ammonis injury or improve functional recovery. Neuroscience 166:263–270

    Article  CAS  Google Scholar 

  22. Wang Q, Tang XN, Yenari MA (2007) The inflammatory response in stroke. J Neuroimmunol 184:53–68

    Article  CAS  Google Scholar 

  23. Pahan K, Khan M, Singh I (2000) Interleukin-10 and interleukin-13 inhibit proinflammatory cytokine-induced ceramide production through the activation of phosphatidylinositol 3-kinase. J Neurochem 75:576–582

    Article  CAS  Google Scholar 

  24. Maleki SN, Aboutaleb N, Souri F (2018) Berberine confers neuroprotection in coping with focal cerebral ischemia by targeting inflammatory cytokines. J Chem Neuroanat 87:54–59

    Article  CAS  Google Scholar 

  25. Park JH, Park O, Cho JH, Chen BH, Kim IH, Ahn JH, Lee JC, Yan BC, Yoo KY, Lee CH, Hwang IK, Kwon SH, Lee YL, Won MH, Choi JH (2014) Anti-inflammatory effect of tanshinone I in neuroprotection against cerebral ischemia–reperfusion injury in the gerbil hippocampus. Neurochem Res 39:1300–1312

    Article  CAS  Google Scholar 

  26. Manzanero S, Erion JR, Santro T, Steyn FJ, Chen C, Arumugam TV, Stranahan AM (2014) Intermittent fasting attenuates increases in neurogenesis after ischemia and reperfusion and improves recovery. J Cereb Blood Flow Metab 34:897–905

    Article  CAS  Google Scholar 

  27. Ahn JH, Noh Y, Shin BN, Kim SS, Park JH, Lee TK, Song M, Kim H, Lee JC, Yong JH, Kang IJ, Lee YL, Won MH, Kim JD (2018) Intermittent fasting increases SOD2 and catalase immunoreactivities in the hippocampus but does not protect from neuronal death following transient ischemia in gerbils. Mol Med Rep 18:4802–4812

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Buiatti de Araujo FL, Bertolino G, Rodrigues Funayama CA, Coimbra NC, Eduardo de Araujo J (2008) Influence of treadmill training on motor performance and organization of exploratory behavior in Merionesunguiculatus with unilateral ischemic stroke: histological correlates in hippocampal CA1 region and the neostriatum. Neurosci Lett 431:179–183

    Article  CAS  Google Scholar 

  29. Min D, Mao X, Wu K, Cao Y, Guo F, Zhu S, Xie N, Wang L, Chen T, Shaw C, Cai J (2012) Donepezil attenuates hippocampal neuronal damage and cognitive deficits after global cerebral ischemia in gerbils. Neurosci Lett 510:29–33

    Article  CAS  Google Scholar 

  30. ElAli A, Doeppner TR, Zechariah A, Hermann DM (2011) Increased blood–brain barrier permeability and brain edema after focal cerebral ischemia induced by hyperlipidemia: role of lipid peroxidation and calpain-1/2, matrix metalloproteinase-2/9, and RhoA overactivation. Stroke 42:3238–3244

    Article  CAS  Google Scholar 

  31. Marchi N, Granata T, Ghosh C, Janigro D (2012) Blood–brain barrier dysfunction and epilepsy: pathophysiologic role and therapeutic approaches. Epilepsia 53:1877–1886

    Article  Google Scholar 

  32. Zhang H, Park JH, Maharjan S, Park JA, Choi KS, Park H, Jeong Y, Ahn JH, Kim IH, Lee JC, Cho JH, Lee IK, Lee CH, Hwang IK, Kim YM, Suh YG, Won MH, Kwon YG (2017) Sac-1004, a vascular leakage blocker, reduces cerebral ischemia–reperfusion injury by suppressing blood–brain barrier disruption and inflammation. J Neuroinflamm 14:122

    Article  Google Scholar 

  33. Ha Park J, Yoo KY, Hye Kim I, Cho JH, Lee JC, Hyeon Ahn J, Jin Tae H, Chun Yan B, Won Kim D, Kyu Park O, Kwon SH, Her S, Su Kim J, Hoon Choi J, Hyun Lee C, Koo Hwang I, Youl Cho J, Hwi Cho J, Kwon YG, Ryoo S, Kim YM, Won MH, Jun Kang I (2016) Hydroquinone strongly alleviates focal ischemic brain injury via blockage of blood–brain barrier disruption in rats. Toxicol Sci Off J Soc Toxicol 154:430–441

    Article  Google Scholar 

  34. Thrippleton MJ, Backes WH, Sourbron S, Ingrisch M, van Osch MJP, Dichgans M, Fazekas F, Ropele S, Frayne R, van Oostenbrugge RJ, Smith EE, Wardlaw JM (2019) Quantifying blood–brain barrier leakage in small vessel disease: review and consensus recommendations. Alzheimer’s Dement J Alzheimer’s Assoc 15:840–858

    Article  Google Scholar 

  35. Ahn JH, Chen BH, Park JH, Shin BN, Lee TK, Cho JH, Lee JC, Park JR, Yang SR, Ryoo S, Shin MC, Kang IJ, Lee CH, Hwang IK, Kim YM, Won MH (2018) Early IV-injected human dermis-derived mesenchymal stem cells after transient global cerebral ischemia do not pass through damaged blood–brain barrier. J Tissue Eng Regen Med 12:1646–1657

    Article  CAS  Google Scholar 

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Funding

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2016R1D1A1B01011790), (NRF-2018R1D1A1B07049453) and (NRF-2017R1D1A1B03032409).

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Author notes

  1. Tae-Kyeong Lee and Yoonsoo Park contributed equally to this article.

Authors and Affiliations

  1. Department of Biomedical Science and Research Institute for Bioscience and Biotechnology, Hallym University, Chuncheon, Gangwon, 24252, Republic of Korea

    Tae-Kyeong Lee & Ji Hyeon Ahn

  2. Department of Emergency Medicine, and Institute of Medical Sciences, Kangwon National University Hospital, School of Medicine, Kangwon National University, Chuncheon, Gangwon, 24341, Republic of Korea

    Yoonsoo Park, Myoung Cheol Shin, Taek Geun Ohk, Chan Woo Park & Jun Hwi Cho

  3. Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, Gangwon, 24341, Republic of Korea

    Bora Kim, Jae-Chul Lee, Moo-Ho Won & Ji Hyeon Ahn

  4. Department of Anatomy, College of Oriental Medicine, Dongguk University-Gyeongju, Gyeongju, Gyeongbuk, 38066, Republic of Korea

    Joon Ha Park

  5. Department of Pharmacy, College of Pharmacy, Dankook University, Cheonan, Chungnam, 31116, Republic of Korea

    Choong Hyun Lee

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  1. Tae-Kyeong Lee
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Contributions

YP, TL, MW and JA were responsible for experimental design, data analysis and manuscript review. YP, TL wrote the draft manuscript. DK, BK, CP, MS and TO carried out experiments and data collection. JL, CP, JM, JC, JP and CL performed data analysis and critical comments on the whole process of this work.

Corresponding authors

Correspondence to Moo-Ho Won or Ji Hyeon Ahn.

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Conflict of interest

The authors have declared that there are no competing interests.

Ethical Approval

The process of handling and caring animals conformed to the guidelines from the current international laws and policies in the “NIH Guide for the Care and Use of Laboratory Animals” (The National Academies Press, 8th Ed., 2011). The protocol of this experiment was approved (Approval No. KW-180124-1) by the Institutional Animal Care and Use Committee (IACUC) at Kangwon National University.

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Lee, TK., Park, Y., Kim, B. et al. Long-Term Alternating Fasting Increases Interleukin-13 in the Gerbil Hippocampus, But Does Not Protect BBB and Pyramidal Neurons From Ischemia–Reperfusion Injury. Neurochem Res 45, 2352–2363 (2020). https://doi.org/10.1007/s11064-020-03094-z

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  • DOI: https://doi.org/10.1007/s11064-020-03094-z

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