Skip to main content
SpringerLink
Log in

Neuroprotective effects of ivermectin against transient cerebral ischemia-reperfusion in rats

  • Original Article
  • Published:
Metabolic Brain Disease Aims and scope Submit manuscript

Abstract

Stroke is a leading cause of disability and death worldwide. Ivermectin is a broad-spectrum anti-parasitic agent with potential anti-bacterial, anti-viral, and anti-cancer effects. However, the effects of ivermectin on the brain are poorly described. This study examined the effects of ivermectin on cerebral ischemia-reperfusion (IR) in rats. A rat model of transient global IR was induced by bilateral carotid artery occlusion for 20 min. Rats received ivermectin (2 mg/kg/day, ip) one hour after inducing cerebral IR for three consecutive days at 24-h intervals. Next, we examined the effects of ivermectin on brain infarction, histopathology, malondialdehyde levels, myeloperoxidase activity, spatial learning and memory, and phospho-AMPK protein levels. The results showed that ivermectin reduced brain infarct size (P < 0.001) and histopathological changes such as cerebral leukocyte accumulation and edema (P < 0.05) compared to untreated rats with IR. Treatment with ivermectin also decreased myeloperoxidase activity (P < 0.01) and malondialdehyde levels (P < 0.05) while increasing AMPK activity (P < 0.001), memory, and learning compared to the untreated IR group. Overall, we show for the first time that ivermectin conferred neuroprotective effects in a rat model of cerebral IR. Our results indicate that three days of treatment with ivermectin reduced brain infarct size, lipid peroxidation, and myeloperoxidase activity and improved memory and learning in rats with cerebral IR. These effects likely occurred via AMPK-dependent mechanisms.

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
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Data availability

All data generated or analyzed during this study are included in this published article and further datasets are available from the corresponding author on reasonable request.

References

  • Azarbaijani M, Kian M, Soraya H (2021) Anti-inflammatory effects of memantine in carrageenan-induced paw edema model in rats. J Rep Pharm Sci 10(1):60–65

    Article  CAS  Google Scholar 

  • Bhat R, Axtell R, Mitra A, Miranda M, Lock C, Tsien RW, Steinman L (2010) Inhibitory role for GABA in autoimmune inflammation. Proc Natl Acad Sci U S A 107(6):2580–2585

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bradley PP, Priebat DA, Christensen RD, Rothstein G (1982) Measurement of cutaneous inflammation: estimation of neutrophil content with an enzyme marker. J Invest Dermatol 78(3):206–209

    Article  CAS  PubMed  Google Scholar 

  • Camarata PJ, Heros RC, Latchaw RE (1994) Brain attack: the rationale for treating stroke as a medical emergency. Neurosurgery 34(1):144–157

    CAS  PubMed  Google Scholar 

  • Carling D (2017) AMPK signalling in health and disease. Curr Opin Cell Biol 45:31–37

    Article  CAS  PubMed  Google Scholar 

  • Cassidy JM, Cramer SC (2017) Spontaneous and therapeutic-induced mechanisms of functional recovery after stroke. Transl Stroke Res 8(1):33–46

    Article  CAS  PubMed  Google Scholar 

  • Chan SJ, Love C, Spector M, Cool SM, Nurcombe V, Lo EH (2017) Endogenous regeneration: engineering growth factors for stroke. Neurochem Int 107:57–65

    Article  CAS  PubMed  Google Scholar 

  • Chen S, Chen H, Du Q, Shen J (2020) Targeting myeloperoxidase (MPO) mediated oxidative stress and inflammation for reducing Brain Ischemia Injury: potential application of Natural Compounds. Front Physiol 11:433

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen C, Zhou X, He J, Xie Z, Xia S, Lu G (2019) The roles of GABA in Ischemia-Reperfusion injury in the central nervous system and peripheral organs. Oxid Med Cell Longev 2019:4028394

    Article  PubMed  PubMed Central  Google Scholar 

  • Ci X, Li H, Yu Q, Zhang X, Yu L, Chen N, Song Y, Deng X (2009) Avermectin exerts anti-inflammatory effect by downregulating the nuclear transcription factor kappa-B and mitogen-activated protein kinase activation pathway. Fundam Clin Pharmacol 23(4):449–455

    Article  CAS  PubMed  Google Scholar 

  • Crump A (2017) Ivermectin: enigmatic multifaceted ‘wonder’drug continues to surprise and exceed expectations. J Antibiot (Tokyo) 70(5):495–505

    Article  CAS  PubMed  Google Scholar 

  • Eklöf B, Siesjö BK (1972) The effect of bilateral carotid artery ligation upon the blood flow and the energy state of the rat brain. Acta Physiol Scand 86(2):155–165

    Article  PubMed  Google Scholar 

  • Fan J, Liu Y, Yin J, Li Q, Li Y, Gu J, Cai W, Yin G (2016) Oxygen-Glucose-deprivation/reoxygenation-induced autophagic cell death depends on JNK-Mediated phosphorylation of Bcl-2. Cell Physiol Biochem 38(3):1063–1074

    Article  CAS  PubMed  Google Scholar 

  • Hosseini Omshi FS, Abbasalipourkabir R, Abbasalipourkabir M, Nabyan S, Bashiri A, Ghafourikhosroshahi A (2018) Effect of vitamin A and vitamin C on attenuation of ivermectin-induced toxicity in male Wistar rats. Environ Sci Pollut Res Int 25(29):29408–29417

    Article  CAS  PubMed  Google Scholar 

  • Hussein SZ, Mohd Yusoff K, Makpol S, Mohd Yusof YA (2013) Gelam honey attenuates carrageenan-induced rat paw inflammation via NF-κB pathway. PLoS One 8(8):e72365

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang SLT, Ji T, Yi W, Yang Z, Wang S, Yang Y, Gu C (2018) AMPK: potential therapeutic target for ischemic stroke. Theranostics 8(16):4535–4551

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jin Z, Mendu SK, Birnir B (2013) GABA is an effective immunomodulatory molecule. Amino Acids 45(1):87–94

    Article  CAS  PubMed  Google Scholar 

  • Kamat PK, Kalani A, Metreveli N, Tyagi SC, Tyagi N (2015) A possible molecular mechanism of hearing loss during cerebral ischemia in mice. Can J Physiol Pharmacol 93(7):505–516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Karimipour M, Zarghani SS, Milani MM, Soraya H (2018) Pre-treatment with metformin in comparison with post-treatment reduces cerebral ischemia reperfusion induced injuries in rats. Bull Emerg Trauma 6(2):115

    Article  PubMed  PubMed Central  Google Scholar 

  • Kimber I, Stone S, Dearman RJ (2003) Assessment of the inherent allergenic potential of proteins in mice. Environ Health Perspect 111(2):227–231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu Y, Fang S, Sun Q, Liu B (2016) Anthelmintic drug ivermectin inhibits angiogenesis, growth and survival of glioblastoma through inducing mitochondrial dysfunction and oxidative stress. Biochem Biophys Res Commun 480(3):415–421

    Article  CAS  PubMed  Google Scholar 

  • Ma C, Wang X, Xu T, Yu X, Zhang S, Liu S, Gao Y, Fan S, Li C, Zhai C, Cheng F, Wang Q (2019) Qingkailing injection ameliorates cerebral ischemia-reperfusion injury and modulates the AMPK/NLRP3 inflammasome signalling pathway. BMC Complement Altern Med 19(1):320

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mehta SL, Manhas N, Raghubir R (2007) Molecular targets in cerebral ischemia for developing novel therapeutics. Brain Res Rev 54(1):34–66

    Article  CAS  PubMed  Google Scholar 

  • Ornellas FM, Ornellas DS, Martini SV, Castiglione RC, Ventura GM, Rocco PR, Gutfilen B, de Souza SA, Takiya CM, Morales MM (2017) Bone marrow-derived mononuclear cell therapy accelerates renal ischemia-reperfusion injury recovery by modulating inflammatory, antioxidant and apoptotic related molecules. Cell Physiol Biochem 41(5):1736–1752

    Article  CAS  PubMed  Google Scholar 

  • Pan J, Konstas AA, Bateman B, Ortolano GA, Pile-Spellman J (2007) Reperfusion injury following cerebral ischemia: pathophysiology, MR imaging, and potential therapies. Neuroradiology 49(2):93–102

    Article  PubMed  Google Scholar 

  • Rameshrad M, Maleki-Dizaji N, Vaez H, Soraya H, Nakhlband A, Garjani A (2015) Lipopolysaccharide Induced activation of toll like receptor 4 in isolated rat heart suggests a local immune response in myocardium. Iran J Immunol 12(2):104–116

    PubMed  Google Scholar 

  • Salehi C, Seiiedy M, Soraya H, Fazli F, Ghasemnejad-Berenji M (2021) Pretreatment with bisoprolol and vitamin E alone or in combination provides neuroprotection against cerebral ischemia/reperfusion injury in rats. Naunyn Schmiedebergs Arch Pharmacol 394(4):685–695

    Article  CAS  PubMed  Google Scholar 

  • Satoh K (1978) Serum lipid peroxide in cerebrovascular disorders determined by a new colorimetric method. Clin Chim Actan 90(1):37–43

    Article  CAS  Google Scholar 

  • Shen P, Hou S, Zhu M, Zhao M, Ouyang Y, Feng J (2017) Cortical spreading depression preconditioning mediates neuroprotection against ischemic stroke by inducing AMP-activated protein kinase‐dependent autophagy in a rat cerebral ischemic/reperfusion injury model. J Neurochem 140(5):799–813

    Article  CAS  PubMed  Google Scholar 

  • Sia DK, Mensah KB, Opoku-Agyemang T, Folitse RD, Darko DO (2020) Mechanisms of ivermectin-induced wound healing. BMC Vet Res 16(1):397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Suter M, Riek U, Tuerk R, Schlattner U, Wallimann T, Neumann D (2006) Dissecting the role of 5’-AMP for allosteric stimulation, activation, and deactivation of AMP-activated protein kinase. J Biol Chem 281(43):32207–32216

    Article  CAS  PubMed  Google Scholar 

  • Tabary M, Aryannejad A, Noroozi N, Tavangar SM, Mohammad Jafari R, Araghi F, Dadkhahfar S, Dehpour AR (2021) Ivermectin increases Random-Pattern skin flap survival in rats: the Novel role of GABAergic System. J Surg Res 259:431–441

    Article  CAS  PubMed  Google Scholar 

  • Tadi P, Lui F (2023) Acute Stroke. In: StatPearls [Internet]. StatPearls Publishing, Treasure Island (FL)

  • Wardlaw JM, Murray V, Berge E, del Zoppo GJ (2014) Thrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev 2014(7):CD000213

    PubMed  PubMed Central  Google Scholar 

  • Wu L, Xiong X, Wu X, Ye Y, Jian Z, Zhi Z, Gu L (2020) Targeting oxidative stress and inflammation to prevent Ischemia-Reperfusion Injury. Front Mol Neurosci 13:28

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu MY, Yiang GT, Liao WT, Tsai AP, Cheng YL, Cheng PW, Li CY, Li CJ (2018) Current mechanistic concepts in Ischemia and Reperfusion Injury. Cell Physiol Biochem 46(4):1650–1667

    Article  CAS  PubMed  Google Scholar 

  • Zamani M, Soleimani M, Golab F, Mohamadzadeh F, Mehdizadeh M, Katebi M (2013) NeuroProtective effects of adenosine receptor agonist coadministration with ascorbic acid on CA1 hippocampus in a mouse model of ischemia reperfusion injury. Metab Brain Dis 28(3):367–374

    Article  CAS  PubMed  Google Scholar 

  • Zhang X, Song Y, Ci X, An N, Ju Y, Li H, Wang X, Han C, Cui J, Deng X (2008) Ivermectin inhibits LPS-induced production of inflammatory cytokines and improves LPS-induced survival in mice. Inflamm Res 57(11):524–529

    Article  CAS  PubMed  Google Scholar 

  • Zhang PNH, Zhang Y, Xu W, Gao J, Cheng J, Tao L (2020) Ivermectin confers its cytotoxic effects by inducing AMPK/mTOR-mediated autophagy and DNA damage. Chemosphere 259:127448

    Article  CAS  PubMed  Google Scholar 

  • Zhang C, Zhang Z, Zhao Q, Wang X, Ji H, Zhang Y (2014) (S)-ZJM-289 Preconditioning induces a late phase Protection Against Nervous Injury Induced by transient cerebral ischemia and oxygen-glucose deprivation. Neurotox Res 26(1):16–31

    Article  PubMed  Google Scholar 

  • Zhu M, Li Y, Zhou Z (2017) Antibiotic ivermectin preferentially targets renal cancer through inducing mitochondrial dysfunction and oxidative damage. Biochem Biophys Res Commun 492(3):373–378

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by the Urmia University of Medical Sciences (Grant no: 675).

Author information

Authors and Affiliations

  1. Experimental and Applied Pharmaceutical Sciences Research Center, Urmia University of Medical Sciences, Urmia, Iran

    Behdad Seyyedabadi, Shabnam Babataheri & Hamid Soraya

  2. Department of Pharmacology and Toxicology, School of Pharmacy, Urmia University of Medical Sciences, Urmia, Iran

    Behdad Seyyedabadi, Shabnam Babataheri & Hamid Soraya

  3. Department of Anesthesiology, Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada

    Ismail Laher

Authors
  1. Behdad Seyyedabadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shabnam Babataheri
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ismail Laher
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hamid Soraya
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

BS Project implementation and preparing original draft; ShB: Carried out western blot analysis, contributed in the manuscript preparation. IL: Contributed in the manuscript preparation, review, and editing; HS: Designed and conceptualized the study, carried out the data analysis and interpretations and prepared the manuscript.

Corresponding author

Correspondence to Hamid Soraya.

Ethics declarations

Ethics approval

This study was approved by the ethics committee of Urmia University of Medical Sciences (Code: IR.UMSU.REC.1400.126).

Consent to participate

Not applicable.

Consent for publication

The corresponding author has the permission from the authors to publish the details of this research.

Competing interests

The authors have no relevant financial or non-financial interests to disclose.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Seyyedabadi, B., Babataheri, S., Laher, I. et al. Neuroprotective effects of ivermectin against transient cerebral ischemia-reperfusion in rats. Metab Brain Dis 38, 2807–2815 (2023). https://doi.org/10.1007/s11011-023-01290-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11011-023-01290-8

Keywords

Search

Navigation