Skip to main content

Advertisement

SpringerLink
Log in

Senicapoc: Repurposing a Drug to Target Microglia KCa3.1 in Stroke

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Stroke is the leading cause of serious long-term disability and the fifth leading cause of death in the United States. Treatment options for stroke are few in number and limited in efficacy. Neuroinflammation mediated by microglia and infiltrating peripheral immune cells is a major component of stroke pathophysiology. Interfering with the inflammation cascade after stroke holds the promise to modulate stroke outcome. The calcium activated potassium channel KCa3.1 is expressed selectively in the injured CNS by microglia. KCa3.1 function has been implicated in pro-inflammatory activation of microglia and there is recent literature suggesting that this channel is important in the pathophysiology of ischemia/reperfusion (stroke) related brain injury. Here we describe the potential of repurposing Senicapoc, a KCa3.1 inhibitor, to intervene in the inflammation cascade that follows ischemia/reperfusion.

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

Similar content being viewed by others

References

  1. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, de Ferranti S, Despres JP, Fullerton HJ, Howard VJ, Huffman MD, Judd SE, Kissela BM, Lackland DT, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Matchar DB, McGuire DK, Mohler ER 3rd, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Willey JZ, Woo D, Yeh RW, Turner MB, American Heart Association Statistics C, Stroke Statistics S (2015) Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation 131:e29–322

    Article  PubMed  Google Scholar 

  2. Prabhakaran S, Ruff I, Bernstein RA (2015) Acute stroke intervention: a systematic review. JAMA 313:1451–1462

    Article  CAS  PubMed  Google Scholar 

  3. Iadecola C, Anrather J (2011) The immunology of stroke: from mechanisms to translation. Nat Med 17:796–808

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Macrez R, Ali C, Toutirais O, Le Mauff B, Defer G, Dirnagl U, Vivien D (2011) Stroke and the immune system: from pathophysiology to new therapeutic strategies. Lancet Neurol 10:471–480

    Article  CAS  PubMed  Google Scholar 

  5. McDonough A, Weinstein JR (2016) Neuroimmune response in ischemic preconditioning. Neurother 13:748–761

    Article  CAS  Google Scholar 

  6. Hayakawa K, Nakano T, Irie K, Higuchi S, Fujioka M, Orito K, Iwasaki K, Jin G, Lo EH, Mishima K, Fujiwara M (2010) Inhibition of reactive astrocytes with fluorocitrate retards neurovascular remodeling and recovery after focal cerebral ischemia in mice. J Cereb Blood Flow Metab 30:871–882

    Article  CAS  PubMed  Google Scholar 

  7. Lo EH (2008) A new penumbra: transitioning from injury into repair after stroke. Nat Med 14:497–500

    Article  CAS  PubMed  Google Scholar 

  8. Maki T, Hayakawa K, Pham LD, Xing C, Lo EH, Arai K (2013) Biphasic mechanisms of neurovascular unit injury and protection in CNS diseases. CNS Neurol Disord Drug Targets 12:302–315

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Dirnagl U (2012) Pathobiology of injury after stroke: the neurovascular unit and beyond. Ann N Y Acad Sci 1268:21–25

    Article  PubMed  Google Scholar 

  10. Benarroch EE (2013) Microglia: multiple roles in surveillance, circuit shaping, and response to injury. Neurology 81:1079–1088

    Article  PubMed  Google Scholar 

  11. Michell-Robinson MA, Touil H, Healy LM, Owen DR, Durafourt BA, Bar-Or A, Antel JP, Moore CS (2015) Roles of microglia in brain development, tissue maintenance and repair. Brain 138:1138–1159

    Article  PubMed  Google Scholar 

  12. Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, Mehler MF, Conway SJ, Ng LG, Stanley ER, Samokhvalov IM, Merad M (2010) Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330:841–845

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zuchero JB, Barres BA (2015) Glia in mammalian development and disease. Development 142:3805–3809

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Jha MK, Lee WH, Suk K (2015) Functional polarization of neuroglia: implications in neuroinflammation and neurological disorders. Biochem Pharmacol 103:1–16

    Article  PubMed  Google Scholar 

  15. Weinstein JR, Koerner IP, Möller T (2010) Microglia in ischemic brain injury. Future Neurol 5:227–246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. van Rossum D, Hanisch UK (2004) Microglia. Metab Brain Dis 19:393–411

    Article  PubMed  Google Scholar 

  17. Dave KR, Saul I, Prado R, Busto R, Perez-Pinzon MA (2006) Remote organ ischemic preconditioning protect brain from ischemic damage following asphyxial cardiac arrest. Neurosci Lett 404:170–175

    Article  CAS  PubMed  Google Scholar 

  18. Lalancette-Hebert M, Gowing G, Simard A, Weng YC, Kriz J (2007) Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain. J Neurosci 27:2596–2605

    Article  CAS  PubMed  Google Scholar 

  19. Nedergaard M, Dirnagl U (2005) Role of glial cells in cerebral ischemia. Glia 50:281–286

    Article  PubMed  Google Scholar 

  20. Cunningham LA, Wetzel M, Rosenberg GA (2005) Multiple roles for MMPs and TIMPs in cerebral ischemia. Glia 50:329–339

    Article  PubMed  Google Scholar 

  21. Umekawa T, Osman AM, Han W, Ikeda T, Blomgren K (2015) Resident microglia, rather than blood-derived macrophages, contribute to the earlier and more pronounced inflammatory reaction in the immature compared with the adult hippocampus after hypoxia-ischemia. Glia 63:2220–2230

    Article  PubMed  PubMed Central  Google Scholar 

  22. Denes A, Vidyasagar R, Feng J, Narvainen J, McColl BW, Kauppinen RA, Allan SM (2007) Proliferating resident microglia after focal cerebral ischaemia in mice. J Cereb Blood Flow Metab 27:1941–1953

    Article  CAS  PubMed  Google Scholar 

  23. Szalay G, Martinecz B, Lenart N, Kornyei Z, Orsolits B, Judak L, Csaszar E, Fekete R, West BL, Katona G, Rozsa B, Denes A (2016) Microglia protect against brain injury and their selective elimination dysregulates neuronal network activity after stroke. Nat Commun 7:11499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Chen YJ, Wallace BK, Yuen N, Jenkins DP, Wulff H, O’Donnell ME (2015) Blood-brain barrier KCa3.1 channels: evidence for a role in brain Na uptake and edema in ischemic stroke. Stroke 46:237–244

    Article  CAS  PubMed  Google Scholar 

  25. Dale E, Staal RG, Eder C, Möller T (2016) KCa 3.1-a microglial target ready for drug repurposing? Glia 64:1733–1741

    Article  PubMed  Google Scholar 

  26. Nguyen HM, Grossinger EM, Horiuchi M, Davis KW, Jin LW, Maezawa I, Wulff H (2016) Differential Kv1.3, KCa3.1, and Kir2.1 expression in “classically” and “alternatively” activated microglia. Glia 65:106–121

    Article  PubMed  PubMed Central  Google Scholar 

  27. Wulff H, Castle NA (2010) Therapeutic potential of KCa3.1 blockers: recent advances and promising trends. Expert Rev Clin Pharmacol 3:385–396

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wulff H, Kolski-Andreaco A, Sankaranarayanan A, Sabatier JM, Shakkottai V (2007) Modulators of small- and intermediate-conductance calcium-activated potassium channels and their therapeutic indications. Curr Med Chem 14:1437–1457

    Article  CAS  PubMed  Google Scholar 

  29. Suzuki S, Kurata N, Nishimura Y, Yasuhara H, Satoh T (2000) Effects of imidazole antimycotics on the liver microsomal cytochrome P450 isoforms in rats: comparison of in vitro and ex vivo studies. Eur J Drug Metab Pharmacokinet 25:121–126

    Article  CAS  PubMed  Google Scholar 

  30. Zhang W, Ramamoorthy Y, Kilicarslan T, Nolte H, Tyndale RF, Sellers EM (2002) Inhibition of cytochromes P450 by antifungal imidazole derivatives. Drug Metab Dispos 30:314–318

    Article  CAS  PubMed  Google Scholar 

  31. Wulff H, Miller MJ, Hansel W, Grissmer S, Cahalan MD, Chandy KG (2000) Design of a potent and selective inhibitor of the intermediate-conductance Ca2+-activated K+ channel, IKCa1: a potential immunosuppressant. Proc Natl Acad Sci USA 97:8151–8156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Reich EP, Cui L, Yang L, Pugliese-Sivo C, Golovko A, Petro M, Vassileva G, Chu I, Nomeir AA, Zhang LK, Liang X, Kozlowski JA, Narula SK, Zavodny PJ, Chou CC (2005) Blocking ion channel KCNN4 alleviates the symptoms of experimental autoimmune encephalomyelitis in mice. Eur J Immunol 35:1027–1036

    Article  CAS  PubMed  Google Scholar 

  33. Kaushal V, Koeberle PD, Wang Y, Schlichter LC (2007) The Ca2+-activated K+ channel KCNN4/KCa3.1 contributes to microglia activation and nitric oxide-dependent neurodegeneration. J Neurosci 27:234–244

    Article  CAS  PubMed  Google Scholar 

  34. Bouhy D, Ghasemlou N, Lively S, Redensek A, Rathore KI, Schlichter LC, David S (2011) Inhibition of the Ca(2)(+)-dependent K(+) channel, KCNN4/KCa3.1, improves tissue protection and locomotor recovery after spinal cord injury. J Neurosci 31:16298–16308

    Article  CAS  PubMed  Google Scholar 

  35. Chen YJ, Raman G, Bodendiek S, O’Donnell ME, Wulff H (2011) The KCa3.1 blocker TRAM-34 reduces infarction and neurological deficit in a rat model of ischemia/reperfusion stroke. J Cereb Blood Flow Metab 31:2363–2374

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. D’Alessandro G, Catalano M, Sciaccaluga M, Chece G, Cipriani R, Rosito M, Grimaldi A, Lauro C, Cantore G, Santoro A, Fioretti B, Franciolini F, Wulff H, Limatola C (2013) KCa3.1 channels are involved in the infiltrative behavior of glioblastoma in vivo. Cell Death Dis 4:e773

    Article  PubMed  PubMed Central  Google Scholar 

  37. Schilling T, Eder C (2007) TRAM-34 inhibits nonselective cation channels. Pflugers Arch 454:559–563

    Article  CAS  PubMed  Google Scholar 

  38. Agarwal JJ, Zhu Y, Zhang QY, Mongin AA, Hough LB (2013) TRAM-34, a putatively selective blocker of intermediate-conductance, calcium-activated potassium channels, inhibits cytochrome P450 activity. PLoS ONE 8:e63028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Maezawa I, Jenkins DP, Jin BE, Wulff H (2012) Microglial KCa3.1 channels as a potential therapeutic target for Alzheimer’s disease. Int J Alzheimers Dis 2012:868972

    PubMed  PubMed Central  Google Scholar 

  40. Ataga KI, Orringer EP, Styles L, Vichinsky EP, Swerdlow P, Davis GA, Desimone PA, Stocker JW (2006) Dose-escalation study of ICA-17043 in patients with sickle cell disease. Pharmacotherapy 26:1557–1564

    Article  CAS  PubMed  Google Scholar 

  41. Ataga KI, Reid M, Ballas SK, Yasin Z, Bigelow C, James LS, Smith WR, Galacteros F, Kutlar A, Hull JH, Stocker JW, Investigators ICAS (2011) Improvements in haemolysis and indicators of erythrocyte survival do not correlate with acute vaso-occlusive crises in patients with sickle cell disease: a phase III randomized, placebo-controlled, double-blind study of the Gardos channel blocker senicapoc (ICA-17043). Br J Haematol 153:92–104

    Article  CAS  PubMed  Google Scholar 

  42. Ataga KI, Smith WR, De Castro LM, Swerdlow P, Saunthararajah Y, Castro O, Vichinsky E, Kutlar A, Orringer EP, Rigdon GC, Stocker JW, Investigators ICA (2008) Efficacy and safety of the Gardos channel blocker, senicapoc (ICA-17043), in patients with sickle cell anemia. Blood 111:3991–3997

    Article  CAS  PubMed  Google Scholar 

  43. Ataga KI, Stocker J (2009) Senicapoc (ICA-17043): a potential therapy for the prevention and treatment of hemolysis-associated complications in sickle cell anemia. Expert Opin Investig Drugs 18:231–239

    Article  CAS  PubMed  Google Scholar 

  44. McNaughton-Smith GA, Burns JF, Stocker JW, Rigdon GC, Creech C, Arrington S, Shelton T, de Franceschi L (2008) Novel inhibitors of the Gardos channel for the treatment of sickle cell disease. J Med Chem 51:976–982

    Article  CAS  PubMed  Google Scholar 

  45. Staal RG, Khayrullina T, Zhang H, Davis S, Fallon SM, Cajina M, Nattini ME, Hu A, Zhou H, Poda SB, Zorn S, Chandrasena G, Dale E, Cambpell B, Biilmann Ronn LC, Munro G, Möller T (2017) Inhibition of the potassium channel KCa3.1 by senicapoc reverses tactile allodynia in rats with peripheral nerve injury. Eur J Pharmacol 795:1–7

    Article  CAS  PubMed  Google Scholar 

  46. Bennett GJ, Xie YK (1988) A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 33:87–107

    Article  CAS  PubMed  Google Scholar 

  47. Lambertsen KL, Gramsbergen JB, Sivasaravanaparan M, Ditzel N, Sevelsted-Moller LM, Olivan-Viguera A, Rabjerg M, Wulff H, Kohler R (2012) Genetic KCa3.1-deficiency produces locomotor hyperactivity and alterations in cerebral monoamine levels. PLoS ONE 7:e47744

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Strobaek D, Brown DT, Jenkins DP, Chen YJ, Coleman N, Ando Y, Chiu P, Jorgensen S, Demnitz J, Wulff H, Christophersen P (2013) NS6180, a new K(Ca) 3.1 channel inhibitor prevents T-cell activation and inflammation in a rat model of inflammatory bowel disease. Br J Pharmacol 168:432–444

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The study was supported by Lundbeck Research USA.

Author information

Authors and Affiliations

  1. Alentis Pharma LLC, 72 Hillside Avenue, Metuchen, NJ, 08840, USA

    Roland G. W. Staal

  2. Department of Neurology, School of Medicine, University of Washington, Seattle, WA, 98195, USA

    Jonathan R. Weinstein

  3. Neuroinflammation Disease Biology Unit, Lundbeck Research USA Inc., 215 College Rd, Paramus, NJ, 07652, USA

    Megan Nattini, Manuel Cajina & Gamini Chandresana

  4. Abbvie, Foundational Neuroscience Center, Cambridge, MA, 02139, USA

    Thomas Möller

Authors
  1. Roland G. W. Staal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jonathan R. Weinstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Megan Nattini
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Manuel Cajina
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gamini Chandresana
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Thomas Möller
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thomas Möller.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Staal, R.G.W., Weinstein, J.R., Nattini, M. et al. Senicapoc: Repurposing a Drug to Target Microglia KCa3.1 in Stroke. Neurochem Res 42, 2639–2645 (2017). https://doi.org/10.1007/s11064-017-2223-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-017-2223-y

Keywords

Search

Navigation