Skip to main content

Advertisement

SpringerLink
Log in

Intra-arterial Stem Cell Therapy Diminishes Inflammasome Activation After Ischemic Stroke: a Possible Role of Acid Sensing Ion Channel 1a

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

A Correction to this article was published on 01 January 2021

This article has been updated

Abstract

Studies from our lab demonstrated that 1 × 105 intra-arterial mesenchymal stem cells (IA MSCs) at 6 h following ischemic stroke are efficacious owing to its maximum homing due to elevated stromal derived factor 1 (SDF1) in the tissue. Further, IA MSCs could abate the infarct progression, improve functional outcome, and decrease expression of calcineurin by modifying neuronal Ca2+ channels following ischemic stroke. Since stroke pathology also encompasses acidosis that worsens the condition; hence, the role of acid sensing ion channels (ASICs) in this context could not be overlooked. ASIC1a being the major contributor towards acidosis triggers Ca2+ ions overload which progressively contributes towards exacerbation of neuronal injury following ischemic insult. Inflammasome involvement in ischemic stroke is well reported as activated ASIC1a increases the expression of inflammasome in a pH-dependent manner to trigger inflammatory cascade. Hence, the current study aimed to identify if IA MSCs can decrease the production of inflammasome by attenuating ASIC1a expression to render neuroprotection. Ovariectomized Sprague Dawley (SD) rats exposed to middle cerebral artery occlusion (MCAo) for 90 min were treated with phosphate-buffered saline (PBS) or 1 × 105 MSCs IA at 6 h to check for the expression of ASIC1a and inflammasome in different groups. Inhibition studies were carried out to explore the underlying mechanism. Our results demonstrate that IA MSCs improves functional outcome and oxidative stress parameters, and decreases the expression of ASIC1a and inflammasomes in the cortical brain region after ischemic stroke. This study offers a preliminary evidence of the role of IA MSCs in regulating inflammasome by modulating ASIC1a.

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

Change history

  • 01 January 2021

    It has come to our notice that there was an inadvertent misupload of Fig. 2 (c, d) in the loading control (GAPDH) for ASIC1a and NLRP1 blots. We would like to replace the same with the correct image. This change anyhow does not affect the conclusion of the study. However, the use of GAPDH as a loading control for stroke studies sometimes is debatable (Zhai et al. 2014; Kang et al. 2018). Hence, we repeated our experiments to check the expression of ASIC1a and NLRP1 at different time points following stroke, using beta actin as a loading control. We found that at 24 h post stroke, maximal and significant expression of both ASIC1a and NLRP1 was observed (Fig. 2 e, f). The expression at 48 and 72 h post stroke were not significantly different as compared to that of sham. The expression results obtained using beta actin as a loading control were concurrent with the previous results published with GAPDH as a loading control.

References

  • Abulafia DP, de Rivero Vaccari JP, Lozano JD, Lotocki G, Keane RW, Dietrich WD (2009) Inhibition of the inflammasome complex reduces the inflammatory response after thromboembolic stroke in mice. J Cereb Blood Flow Metab 29:534–544

    Article  CAS  Google Scholar 

  • Barrington J, Lemarchand E, Allan SM (2017) A brain in flame; do inflammasomes and pyroptosis influence stroke pathology? Brain Pathol 27:205–212

    Article  Google Scholar 

  • Bhattacharya P, Pandey AK, Paul S, Patnaik R, Yavagal DR (2013) Aquaporin-4 inhibition mediates piroxicam-induced neuroprotection against focal cerebral ischemia/reperfusion injury in rodents. PLoS One 8:e73481

    Article  CAS  Google Scholar 

  • Bhowmick S, Moore JT, Kirschner DL, Curry MC, Westbrook EG, Rasley BT, Drew KL (2017) Acidotoxicity via ASIC1a mediates cell death during oxygen glucose deprivation and abolishes excitotoxicity. ACS Chem Neurosci 8:1204–1212

    Article  CAS  Google Scholar 

  • Denes A, Coutts G, Lénárt N, Cruickshank SM, Pelegrin P, Skinner J, Rothwell N, Allan SM, Brough D (2015) AIM2 and NLRC4 inflammasomes contribute with ASC to acute brain injury independently of NLRP3. Proc Natl Acad Sci 112:4050–4055

    Article  CAS  Google Scholar 

  • Dirnagl U (2004) Inflammation in stroke: the good, the bad, and the unknown. In: Neuroinflammation in stroke, pp 87-99: Springer

  • Gonzales EB, Sumien N (2017) Acidity and acid-sensing ion channels in the normal and Alzheimer’s disease brain. J Alzheimers Dis 57:1137–1144

    Article  CAS  Google Scholar 

  • Kesharwani R, Sarmah D, Kaur H, Mounika L, Verma G, Pabbala V, Kotian V, Kalia K, Borah A, Dave KR, Yavagal DR, Bhattacharya P (2019) Interplay between Mitophagy and inflammasome in neurological disorders. ACS Chem Neurosci

  • Komnig D, Imgrund S, Reich A, Gründer S, Falkenburger BH (2016) ASIC1a deficient mice show unaltered neurodegeneration in the subacute MPTP model of Parkinson disease. PLoS One 11:e0165235

    Article  Google Scholar 

  • Lemarchand E, Barrington J, Chenery A, Haley M, Coutts G, Allen JE, Allan SM, Brough D (2019) Extent of ischemic brain injury after thrombotic stroke is independent of the NLRP3 (NACHT, LRR and PYD domains-containing protein 3) Inflammasome. Stroke 50:1232–1239

    Article  CAS  Google Scholar 

  • Ley JJ, Vigdorchik A, Belayev L, Zhao W, Busto R, Khoutorova L, Becker DA, Ginsberg MD (2005) Stilbazulenyl nitrone, a second-generation azulenyl nitrone antioxidant, confers enduring neuroprotection in experimental focal cerebral ischemia in the rat: neurobehavior, histopathology, and pharmacokinetics. J Pharmacol Exp Ther 313:1090–1100

    Article  CAS  Google Scholar 

  • Li X, Michaeloudes C, Zhang Y, Wiegman CH, Adcock IM, Lian Q, Mak JC, Bhavsar PK, Chung KF (2018) Mesenchymal stem cells alleviate oxidative stress–induced mitochondrial dysfunction in the airways. J Allergy Clin Immunol 141:1634–1645 e1635

    Article  CAS  Google Scholar 

  • Liu Y, Lou G, Li A, Zhang T, Qi J, Ye D, Zheng M, Chen Z (2018) AMSC-derived exosomes alleviate lipopolysaccharide/d-galactosamine-induced acute liver failure by miR-17-mediated reduction of TXNIP/NLRP3 inflammasome activation in macrophages. EBioMedicine 36:140–150

    Article  Google Scholar 

  • Miteva K, Pappritz K, Sosnowski M, El-Shafeey M, Müller I, Dong F, Savvatis K, Ringe J, Tschöpe C, Van Linthout S (2018) Mesenchymal stromal cells inhibit NLRP3 inflammasome activation in a model of Coxsackievirus B3-induced inflammatory cardiomyopathy. Sci Rep 8:2820

    Article  Google Scholar 

  • Percie du Sert N, Alfieri A, Allan SM, Carswell HV, Deuchar GA, Farr TD, Flecknell P, Gallagher L, Gibson CL, Haley MJ (2017) The IMPROVE guidelines (ischaemia models: procedural refinements of in vivo experiments). J Cereb Blood Flow Metab 37:3488–3517

    Article  Google Scholar 

  • Pignataro G, Simon RP, Xiong Z-G (2006) Prolonged activation of ASIC1a and the time window for neuroprotection in cerebral ischaemia. Brain 130:151–158

    Article  Google Scholar 

  • Pravalika K, Sarmah D, Kaur H, Vats K, Saraf J, Wanve M, Kalia K, Borah A, Yavagal DR, Dave KR (2019) Trigonelline therapy confers neuroprotection by reduced glutathione mediated myeloperoxidase expression in animal model of ischemic stroke. Life Sci 216:49–58

    Article  CAS  Google Scholar 

  • Raghava N, Das BC, Ray SK (2017) Neuroprotective effects of estrogen in CNS injuries: insights from animal models. Neurosci Neuroecon 6:15

    Article  Google Scholar 

  • Raval A, Schatz M, Bhattacharya P, d’Adesky N, Rundek T, Dietrich W, Bramlett H (2018) Whole body vibration therapy after ischemia reduces brain damage in reproductively senescent female rats. Int J Mol Sci 19:2749

    Article  Google Scholar 

  • Saraf J, Bhattacharya P, Kalia K, Borah A, Sarmah D, Kaur H, Dave KR, Yavagal DR (2018) A friend or foe: calcineurin across the gamut of neurological disorders. ACS Central Science 4:805–819

    Article  CAS  Google Scholar 

  • Saraf J, Sarmah D, Vats K, Kaur H, Pravalika K, Wanve M, Kalia K, Borah A, Dave KR, Yavagal DR, Bhattacharya P (2019) Intra-arterial stem cell therapy modulates neuronal calcineurin and confers neuroprotection after ischemic stroke. International Journal of Neuroscience:1–10

  • Sarmah D, Kaur H, Saraf J, Pravalika K, Goswami A, Kalia K, Borah A, Wang X, Dave KR, Yavagal DR (2018a) Getting closer to an effective intervention of ischemic stroke: the big promise of stem cell. Transl Stroke Res 9:356–374

    Article  Google Scholar 

  • Sarmah D, Agrawal V, Rane P, Bhute S, Watanabe M, Kalia K, Ghosh Z, Dave KR, Yavagal DR, Bhattacharya P (2018b) Mesenchymal stem cell therapy in ischemic stroke: a meta-analysis of preclinical studies. Clin Pharmacol Ther 103:990–998

    Article  Google Scholar 

  • Vats K, Sarmah D, Kaur H, Wanve M, Kalia K, Borah A, Dave KR, Yavagal DR, Bhattacharya P (2018) Inflammasomes in stroke: a triggering role for acid-sensing ion channels. Annals of the New York Academy of Sciences

  • Walsh JG, Muruve DA, Power C (2014) Inflammasomes in the CNS. Nat Rev Neurosci 15:84

    Article  CAS  Google Scholar 

  • Wang Y-C, Li W-Z, Wu Y, Yin Y-Y, Dong L-Y, Chen Z-W, Wu W-N (2015) Acid-sensing ion channel 1a contributes to the effect of extracellular acidosis on NLRP1 inflammasome activation in cortical neurons. J Neuroinflammation 12:246

    Article  Google Scholar 

  • Xiong ZG, Xu TL (2012) The role of ASICS in cerebral ischemia. Wiley Interdisciplinary Reviews: Membrane Transport and Signaling 1:655–662

    CAS  PubMed  Google Scholar 

  • Yang F, Wang Z, Wei X, Han H, Meng X, Zhang Y, Shi W, Li F, Xin T, Pang Q (2014) NLRP3 deficiency ameliorates neurovascular damage in experimental ischemic stroke. J Cereb Blood Flow Metab 34:660–667

    Article  CAS  Google Scholar 

  • Yavagal DR, Lin B, Raval AP, Garza PS, Dong C, Zhao W, Rangel EB, McNiece I, Rundek T, Sacco RL (2014) Efficacy and dose-dependent safety of intra-arterial delivery of mesenchymal stem cells in a rodent stroke model. PLoS One 9:e93735

    Article  Google Scholar 

Download references

Funding

Authors acknowledge International Society for Neurochemistry (ISN) Return Home grant, Department of Pharmaceuticals, Ministry of Chemical and Fertilizers, Govt. of India, and National Institute of Pharmaceutical Education and Research (NIPER) Ahmedabad, Gandhinagar, India.

Author information

Author notes

  1. Kanchan Vats and Deepaneeta Sarmah contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gandhinagar, Gujarat, India

    Kanchan Vats, Deepaneeta Sarmah, Aishika Datta, Jackson Saraf, Harpreet Kaur, Kanta Pravalika, Madhuri Wanve, Kiran Kalia & Pallab Bhattacharya

  2. Cellular and Molecular Neurobiology Laboratory, Department of Life Science and Bioinformatics, Assam University, Silchar, Assam, India

    Anupom Borah

  3. Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA

    Kunjan R Dave

  4. Department of Neurology and Neurosurgery, University of Miami Miller School of Medicine, Miami, FL, USA

    Dileep R Yavagal

Authors
  1. Kanchan Vats
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Deepaneeta Sarmah
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Aishika Datta
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jackson Saraf
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Harpreet Kaur
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kanta Pravalika
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Madhuri Wanve
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kiran Kalia
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Anupom Borah
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Kunjan R Dave
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Dileep R Yavagal
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Pallab Bhattacharya
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Pallab Bhattacharya.

Ethics declarations

Animal experimentation was performed as per the stated guidelines in Guide for the Care and Use of Laboratory Animals published by the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA). The Institutional Animal Ethical Committee of NIPER-Ahmedabad approved the experimental protocol (NIPERA/IAEC/2017/005).

Conflict of Interest

The authors declare that they have no conflicts of interest.

Additional information

Publisher’s Note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vats, K., Sarmah, D., Datta, A. et al. Intra-arterial Stem Cell Therapy Diminishes Inflammasome Activation After Ischemic Stroke: a Possible Role of Acid Sensing Ion Channel 1a. J Mol Neurosci 71, 419–426 (2021). https://doi.org/10.1007/s12031-019-01460-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-019-01460-3

Keywords

Search

Navigation