Skip to main content
SpringerLink
Log in

Intranasal Delivery of a Caspase-1 Inhibitor in the Treatment of Global Cerebral Ischemia

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Caspase-1 is an enzyme implicated in neuroinflammation, a critical component of many diseases that affect neuronal degeneration. However, it is unknown whether a caspase-1 inhibitor can modify apoptotic neuronal damage incurred during transient global cerebral ischemia (GCI) and whether intranasal administration of a caspase-1 inhibitor is an effective treatment following GCI. The present study was conducted to examine the potential efficiency of post-ischemic intranasal administration of the caspase-1 inhibitor Boc-D-CMK in a 4-vessel occlusion model of GCI in the rat. Herein, we show that intranasal Boc-D-CMK readily penetrated the central nervous system, subsequently inhibiting caspase-1 activity, decreasing mitochondrial dysfunction, and attenuating caspase-3-dependent apoptotic pathway in ischemia-vulnerable hippocampal CA1 region. Further investigation regarding the mechanisms underlying Boc-D-CMK’s neuroprotective effects revealed marked inhibition of reactive gliosis, as well as reduction of the neuroinflammatory response via inhibition of the downstream pro-inflammatory cytokine production. Intranasal Boc-D-CMK post-treatment also significantly enhanced the numbers of NeuN-positive cells while simultaneously decreasing the numbers of TUNEL-positive and PARP1-positive cells in hippocampal CA1. Correspondingly, behavioral tests showed that deteriorations in spatial learning and memory performance, and long-term recognition memory following GCI were significantly improved in the Boc-D-CMK post-treated animals. In summary, the current study demonstrates that the caspase-1 inhibitor Boc-D-CMK coordinates anti-inflammatory and anti-apoptotic actions to attenuate neuronal death in the hippocampal CA1 region following GCI. Furthermore, our data suggest that pharmacological inhibition of caspase-1 is a promising neuroprotective strategy to target ischemic neuronal injury and functional deficits following transient GCI.

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
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  1. Mozaffarian D, Benjamin EJ, AS G, Arnett DK, Blaha MJ, Cushman M, de Ferranti S, Despres JP, et al. (2015) Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation 131(4):e29–322. doi:10.1161/CIR.0000000000000152

    Article  PubMed  Google Scholar 

  2. Vereczki V, Martin E, Rosenthal RE, Hof PR, Hoffman GE, Fiskum G (2006) Normoxic resuscitation after cardiac arrest protects against hippocampal oxidative stress, metabolic dysfunction, and neuronal death. J Cereb Blood Flow Metab: Off J Int Soc Cereb Blood Flow Metab 26(6):821–835. doi:10.1038/sj.jcbfm.9600234

    Article  CAS  Google Scholar 

  3. Safar P (1993) Cerebral resuscitation after cardiac arrest: research initiatives and future directions. Ann Emerg Med 22(2 Pt 2):324–349

    Article  CAS  PubMed  Google Scholar 

  4. Zhang QG, Han D, Wang RM, Dong Y, Yang F, Vadlamudi RK, Brann DW (2011) C terminus of Hsc70-interacting protein (CHIP)-mediated degradation of hippocampal estrogen receptor-alpha and the critical period hypothesis of estrogen neuroprotection. Proc Natl Acad Sci U S A 108(35):E617–E624. doi:10.1073/pnas.1104391108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Safar P (1986) Cerebral resuscitation after cardiac arrest: a review. Circulation 74(6 Pt 2):IV138–IV153

    CAS  PubMed  Google Scholar 

  6. Harukuni I, Bhardwaj A (2006) Mechanisms of brain injury after global cerebral ischemia. Neurol Clin 24(1):1–21. doi:10.1016/j.ncl.2005.10.004

    Article  PubMed  Google Scholar 

  7. Lipton P (1999) Ischemic cell death in brain neurons. Physiol Rev 79(4):1431–1568

    CAS  PubMed  Google Scholar 

  8. Abe K, Aoki M, Kawagoe J, Yoshida T, Hattori A, Kogure K, Itoyama Y (1995) Ischemic delayed neuronal death. A mitochondrial hypothesis. Stroke J Cereb Circ 26(8):1478–1489

    Article  CAS  Google Scholar 

  9. Burke DT, Shah MK, Dorvlo AS, Al-Adawi S (2005) Rehabilitation outcomes of cardiac and non-cardiac anoxic brain injury: a single institution experience. Brain Inj 19(9):675–680. doi:10.1080/02699050400024953

    Article  CAS  PubMed  Google Scholar 

  10. Silva BC, de Miranda AS, Rodrigues FG, Silveira AL, Resende GH, Moraes MF, de Oliveira AC, Parreiras PM, et al. (2015) The 5-lipoxygenase (5-LOX) inhibitor zileuton reduces inflammation and infarct size with improvement in neurological outcome following cerebral ischemia. Curr Neurovasc Res 12(4):398–403

    Article  CAS  PubMed  Google Scholar 

  11. Onetti Y, Dantas AP, Perez B, Cugota R, Chamorro A, Planas AM, Vila E, Jimenez-Altayo F (2015) Middle cerebral artery remodeling following transient brain ischemia is linked to early postischemic hyperemia: a target of uric acid treatment. Am J Phys Heart Circ Phys 308(8):H862–H874. doi:10.1152/ajpheart.00001.2015

    CAS  Google Scholar 

  12. Shao ZQ, Liu ZJ (2015) Neuroinflammation and neuronal autophagic death were suppressed via rosiglitazone treatment: new evidence on neuroprotection in a rat model of global cerebral ischemia. J Neurol Sci 349(1-2):65–71. doi:10.1016/j.jns.2014.12.027

    Article  CAS  PubMed  Google Scholar 

  13. Alnemri ES, Livingston DJ, Nicholson DW, Salvesen G, Thornberry NA, Wong WW, Yuan J (1996) Human ICE/CED-3 protease nomenclature. Cell 87(2):171

    Article  CAS  PubMed  Google Scholar 

  14. Thornberry NA, Bull HG, Calaycay JR, Chapman KT, Howard AD, Kostura MJ, Miller DK, Molineaux SM, et al. (1992) A novel heterodimeric cysteine protease is required for interleukin-1 beta processing in monocytes. Nature 356(6372):768–774. doi:10.1038/356768a0

    Article  CAS  PubMed  Google Scholar 

  15. Howard AD, Kostura MJ, Thornberry N, Ding GJ, Limjuco G, Weidner J, Salley JP, Hogquist KA, et al. (1991) IL-1-converting enzyme requires aspartic acid residues for processing of the IL-1 beta precursor at two distinct sites and does not cleave 31-kDa IL-1 alpha. J Immunol 147(9):2964–2969

    CAS  PubMed  Google Scholar 

  16. Zhang WH, Wang X, Narayanan M, Zhang Y, Huo C, Reed JC, Friedlander RM (2003) Fundamental role of the Rip2/caspase-1 pathway in hypoxia and ischemia-induced neuronal cell death. Proc Natl Acad Sci U S A 100(26):16012–16017. doi:10.1073/pnas.2534856100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Guegan C, Vila M, Teismann P, Chen C, Onteniente B, Li M, Friedlander RM, Przedborski S (2002) Instrumental activation of bid by caspase-1 in a transgenic mouse model of ALS. Mol Cell Neurosci 20(4):553–562

    Article  CAS  PubMed  Google Scholar 

  18. Li M, Ona VO, Guegan C, Chen M, Jackson-Lewis V, Andrews LJ, Olszewski AJ, Stieg PE, et al. (2000) Functional role of caspase-1 and caspase-3 in an ALS transgenic mouse model. Science 288(5464):335–339

    Article  CAS  PubMed  Google Scholar 

  19. Willingham SB, Bergstralh DT, O’Connor W, Morrison AC, Taxman DJ, Duncan JA, Barnoy S, Venkatesan MM, et al. (2007) Microbial pathogen-induced necrotic cell death mediated by the inflammasome components CIAS1/cryopyrin/NLRP3 and ASC. Cell Host Microbe 2(3):147–159. doi:10.1016/j.chom.2007.07.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Pasinelli P, Borchelt DR, Houseweart MK, Cleveland DW, Brown RH Jr (1998) Caspase-1 is activated in neural cells and tissue with amyotrophic lateral sclerosis-associated mutations in copper-zinc superoxide dismutase. Proc Natl Acad Sci U S A 95(26):15763–15768

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kozai TD, Li X, Bodily LM, Caparosa EM, Zenonos GA, Carlisle DL, Friedlander RM, Cui XT (2014) Effects of caspase-1 knockout on chronic neural recording quality and longevity: insight into cellular and molecular mechanisms of the reactive tissue response. Biomaterials 35(36):9620–9634. doi:10.1016/j.biomaterials.2014.08.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ross J, Brough D, Gibson RM, Loddick SA, Rothwell NJ (2007) A selective, non-peptide caspase-1 inhibitor, VRT-018858, markedly reduces brain damage induced by transient ischemia in the rat. Neuropharmacology 53(5):638–642. doi:10.1016/j.neuropharm.2007.07.015

    Article  CAS  PubMed  Google Scholar 

  23. Rabuffetti M, Sciorati C, Tarozzo G, Clementi E, Manfredi AA, Beltramo M (2000) Inhibition of caspase-1-like activity by Ac-Tyr-Val-Ala-Asp-chloromethyl ketone induces long-lasting neuroprotection in cerebral ischemia through apoptosis reduction and decrease of proinflammatory cytokines. J Neurosci: Off J Soc Neurosci 20(12):4398–4404

    CAS  Google Scholar 

  24. Ray AM, Owen DE, Evans ML, Davis JB, Benham CD (2000) Caspase inhibitors are functionally neuroprotective against oxygen glucose deprivation induced CA1 death in rat organotypic hippocampal slices. Brain Res 867(1-2):62–69

    Article  CAS  PubMed  Google Scholar 

  25. Zhang QG, Wang RM, Scott E, Han D, Dong Y, Tu JY, Yang F, Reddy Sareddy G, et al. (2013) Hypersensitivity of the hippocampal CA3 region to stress-induced neurodegeneration and amyloidogenesis in a rat model of surgical menopause. Brain J Neurol 136(Pt 5):1432–1445. doi:10.1093/brain/awt046

    Article  Google Scholar 

  26. Migliore MM, Vyas TK, Campbell RB, Amiji MM, Waszczak BL (2010) Brain delivery of proteins by the intranasal route of administration: a comparison of cationic liposomes versus aqueous solution formulations. J Pharm Sci 99(4):1745–1761. doi:10.1002/jps.21939

    Article  CAS  PubMed  Google Scholar 

  27. Thorne RG, Pronk GJ, Padmanabhan V, Frey WH 2nd (2004) Delivery of insulin-like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration. Neuroscience 127(2):481–496. doi:10.1016/j.neuroscience.2004.05.029

    Article  CAS  PubMed  Google Scholar 

  28. Zhang QG, Raz L, Wang R, Han D, De Sevilla L, Yang F, Vadlamudi RK, Brann DW (2009) Estrogen attenuates ischemic oxidative damage via an estrogen receptor alpha-mediated inhibition of NADPH oxidase activation. J Neurosci: Off J Soc Neurosci 29(44):13823–13836. doi:10.1523/JNEUROSCI.3574-09.2009

    Article  CAS  Google Scholar 

  29. Han D, Scott EL, Dong Y, Raz L, Wang R, Zhang Q (2015) Attenuation of mitochondrial and nuclear p38alpha signaling: a novel mechanism of estrogen neuroprotection in cerebral ischemia. Mol Cell Endocrinol 400:21–31. doi:10.1016/j.mce.2014.11.010

    Article  CAS  PubMed  Google Scholar 

  30. Lu Q, Tucker D, Dong Y, Zhao N, Zhang Q (2015) Neuroprotective and functional improvement effects of methylene blue in global cerebral ischemia. Mol Neurobiol. doi:10.1007/s12035-015-9455-0

    Google Scholar 

  31. Gan SD, Patel KR (2013) Enzyme immunoassay and enzyme-linked immunosorbent assay. J Investig Dermatol 133(9):e12. doi:10.1038/jid.2013.287

    Article  CAS  PubMed  Google Scholar 

  32. Ferguson SA, Law CD, Abshire JS (2012) Developmental treatment with bisphenol A causes few alterations on measures of postweaning activity and learning. Neurotoxicol Teratol 34(6):598–606. doi:10.1016/j.ntt.2012.09.006

    Article  CAS  PubMed  Google Scholar 

  33. Barnes CA (1979) Memory deficits associated with senescence: a neurophysiological and behavioral study in the rat. J Comp Physiol Psychol 93(1):74–104

    Article  CAS  PubMed  Google Scholar 

  34. Ennaceur A, Delacour J (1988) A new one-trial test for neurobiological studies of memory in rats. 1: Behavioral data. Behav Brain Res 31(1):47–59

    Article  CAS  PubMed  Google Scholar 

  35. Steckler T, Drinkenburg WH, Sahgal A, Aggleton JP (1998) Recognition memory in rats—I. Concepts and classification. Prog Neurobiol 54(3):289–311

    Article  CAS  PubMed  Google Scholar 

  36. Ennaceur A, Aggleton JP (1994) Spontaneous recognition of object configurations in rats: effects of fornix lesions. Exp Brain Res 100(1):85–92

    Article  CAS  PubMed  Google Scholar 

  37. de Lima MN, Laranja DC, Bromberg E, Roesler R, Schroder N (2005) Pre- or post-training administration of the NMDA receptor blocker MK-801 impairs object recognition memory in rats. Behav Brain Res 156(1):139–143. doi:10.1016/j.bbr.2004.05.016

    Article  PubMed  Google Scholar 

  38. Botton PH, Costa MS, Ardais AP, Mioranzza S, Souza DO, da Rocha JB, Porciuncula LO (2010) Caffeine prevents disruption of memory consolidation in the inhibitory avoidance and novel object recognition tasks by scopolamine in adult mice. Behav Brain Res 214(2):254–259. doi:10.1016/j.bbr.2010.05.034

    Article  CAS  PubMed  Google Scholar 

  39. Gaskin S, Tardif M, Cole E, Piterkin P, Kayello L, Mumby DG (2010) Object familiarization and novel-object preference in rats. Behav Process 83(1):61–71. doi:10.1016/j.beproc.2009.10.003

    Article  Google Scholar 

  40. Kalogeris T, Bao Y, Korthuis RJ (2014) Mitochondrial reactive oxygen species: a double edged sword in ischemia/reperfusion vs preconditioning. Redox Biol 2:702–714. doi:10.1016/j.redox.2014.05.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Sanderson TH, Reynolds CA, Kumar R, Przyklenk K, Huttemann M (2013) Molecular mechanisms of ischemia-reperfusion injury in brain: pivotal role of the mitochondrial membrane potential in reactive oxygen species generation. Mol Neurobiol 47(1):9–23. doi:10.1007/s12035-012-8344-z

    Article  CAS  PubMed  Google Scholar 

  42. Schroder K, Tschopp J (2010) The inflammasomes. Cell 140(6):821–832. doi:10.1016/j.cell.2010.01.040

    Article  CAS  PubMed  Google Scholar 

  43. Hentze H, Lin XY, Choi MS, Porter AG (2003) Critical role for cathepsin B in mediating caspase-1-dependent interleukin-18 maturation and caspase-1-independent necrosis triggered by the microbial toxin nigericin. Cell Death Differ 10(9):956–968. doi:10.1038/sj.cdd.4401264

    Article  CAS  PubMed  Google Scholar 

  44. Cohen RM, Rezai-Zadeh K, Weitz TM, Rentsendorj A, Gate D, Spivak I, Bholat Y, Vasilevko V, et al. (2013) A transgenic Alzheimer rat with plaques, tau pathology, behavioral impairment, oligomeric abeta, and frank neuronal loss. J Neurosci: Off J Soc Neurosci 33(15):6245–6256. doi:10.1523/JNEUROSCI.3672-12.2013

    Article  CAS  Google Scholar 

  45. Barnes CA, Jung MW, McNaughton BL, Korol DL, Andreasson K, Worley PF (1994) LTP saturation and spatial learning disruption: effects of task variables and saturation levels. J Neurosci: Off J Soc Neurosci 14(10):5793–5806

    CAS  Google Scholar 

  46. Goodrich-Hunsaker NJ, Hunsaker MR, Kesner RP (2008) The interactions and dissociations of the dorsal hippocampus subregions: how the dentate gyrus, CA3, and CA1 process spatial information. Behav Neurosci 122(1):16–26. doi:10.1037/0735-7044.122.1.16

    Article  PubMed  Google Scholar 

  47. Broadbent NJ, Squire LR, Clark RE (2004) Spatial memory, recognition memory, and the hippocampus. Proc Natl Acad Sci U S A 101(40):14515–14520. doi:10.1073/pnas.0406344101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Liu XF, Fawcett JR, Hanson LR, Frey WH 2nd (2004) The window of opportunity for treatment of focal cerebral ischemic damage with noninvasive intranasal insulin-like growth factor-I in rats. J Stroke Cerebrovasc Dis: Off J Natl Stroke Assoc 13(1):16–23. doi:10.1016/j.jstrokecerebrovasdis.2004.01.005

    Article  Google Scholar 

  49. De Rosa R, Garcia AA, Braschi C, Capsoni S, Maffei L, Berardi N, Cattaneo A (2005) Intranasal administration of nerve growth factor (NGF) rescues recognition memory deficits in AD11 anti-NGF transgenic mice. Proc Natl Acad Sci U S A 102(10):3811–3816. doi:10.1073/pnas.0500195102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Capsoni S, Giannotta S, Cattaneo A (2002) Nerve growth factor and galantamine ameliorate early signs of neurodegeneration in anti-nerve growth factor mice. Proc Natl Acad Sci U S A 99(19):12432–12437. doi:10.1073/pnas.192442999

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Benchoua A, Guegan C, Couriaud C, Hosseini H, Sampaio N, Morin D, Onteniente B (2001) Specific caspase pathways are activated in the two stages of cerebral infarction. J Neurosci: Off J Soc Neurosci 21(18):7127–7134

    CAS  Google Scholar 

  52. Stoll G, Kleinschnitz C, Nieswandt B (2010) Combating innate inflammation: a new paradigm for acute treatment of stroke? Ann N Y Acad Sci 1207:149–154. doi:10.1111/j.1749-6632.2010.05730.x

    Article  CAS  PubMed  Google Scholar 

  53. Danton GH, Dietrich WD (2003) Inflammatory mechanisms after ischemia and stroke. J Neuropathol Exp Neurol 62(2):127–136

    Article  CAS  PubMed  Google Scholar 

  54. Lu P, Kamboj A, Gibson SB, Anderson CM (2014) Poly(ADP-ribose) polymerase-1 causes mitochondrial damage and neuron death mediated by Bnip3. J Neurosci: Off J Soc Neurosci 34(48):15975–15987. doi:10.1523/JNEUROSCI.2499-14.2014

    Article  Google Scholar 

  55. Cohen A, Barankiewicz J (1987) Metabolic consequences of DNA damage: alteration in purine metabolism following poly(ADP ribosyl)ation in human T-lymphoblasts. Arch Biochem Biophys 258(2):498–503

    Article  CAS  PubMed  Google Scholar 

  56. Andrabi SA, Kim NS, Yu SW, Wang H, Koh DW, Sasaki M, Klaus JA, Otsuka T, et al. (2006) Poly(ADP-ribose) (PAR) polymer is a death signal. Proc Natl Acad Sci U S A 103(48):18308–18313. doi:10.1073/pnas.0606526103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Yu SW, Andrabi SA, Wang H, Kim NS, Poirier GG, Dawson TM, Dawson VL (2006) Apoptosis-inducing factor mediates poly(ADP-ribose) (PAR) polymer-induced cell death. Proc Natl Acad Sci U S A 103(48):18314–18319. doi:10.1073/pnas.0606528103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Garcia-Calvo M, Peterson EP, Leiting B, Ruel R, Nicholson DW, Thornberry NA (1998) Inhibition of human caspases by peptide-based and macromolecular inhibitors. J Biol Chem 273(49):32608–32613

    Article  CAS  PubMed  Google Scholar 

  59. Freund-Levi Y, Vedin I, Hjorth E, Basun H, Faxen Irving G, Schultzberg M, Eriksdotter M, Palmblad J, et al. (2014) Effects of supplementation with omega-3 fatty acids on oxidative stress and inflammation in patients with Alzheimer’s disease: the OmegAD study. J Alzheimers Dis: JAD 42(3):823–831. doi:10.3233/JAD-132042

    CAS  PubMed  Google Scholar 

  60. Urrutia PJ, Mena NP, Nunez MT (2014) The interplay between iron accumulation, mitochondrial dysfunction, and inflammation during the execution step of neurodegenerative disorders. Front Pharmacol 5:38. doi:10.3389/fphar.2014.00038

    Article  PubMed  PubMed Central  Google Scholar 

  61. Witte ME, Geurts JJ, de Vries HE, van der Valk P, van Horssen J (2010) Mitochondrial dysfunction: a potential link between neuroinflammation and neurodegeneration? Mitochondrion 10(5):411–418. doi:10.1016/j.mito.2010.05.014

    Article  CAS  PubMed  Google Scholar 

  62. Dutta RK, Kathania M, Raje M, Majumdar S (2012) IL-6 inhibits IFN-gamma induced autophagy in Mycobacterium tuberculosis H37Rv infected macrophages. Int J Biochem Cell Biol 44(6):942–954. doi:10.1016/j.biocel.2012.02.021

    Article  CAS  PubMed  Google Scholar 

  63. Shi CS, Shenderov K, Huang NN, Kabat J, Abu-Asab M, Fitzgerald KA, Sher A, Kehrl JH (2012) Activation of autophagy by inflammatory signals limits IL-1beta production by targeting ubiquitinated inflammasomes for destruction. Nat Immunol 13(3):255–263. doi:10.1038/ni.2215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Jia G, Cheng G, Gangahar DM, Agrawal DK (2006) Insulin-like growth factor-1 and TNF-alpha regulate autophagy through c-jun N-terminal kinase and Akt pathways in human atherosclerotic vascular smooth cells. Immunol Cell Biol 84(5):448–454. doi:10.1111/j.1440-1711.2006.01454.x

    Article  CAS  PubMed  Google Scholar 

  65. Kirino T (1982) Delayed neuronal death in the gerbil hippocampus following ischemia. Brain Res 239(1):57–69

    Article  CAS  PubMed  Google Scholar 

  66. Pulsinelli WA, Brierley JB, Plum F (1982) Temporal profile of neuronal damage in a model of transient forebrain ischemia. Ann Neurol 11(5):491–498. doi:10.1002/ana.410110509

    Article  CAS  PubMed  Google Scholar 

  67. Sulzgruber P, Kliegel A, Wandaller C, Uray T, Losert H, Laggner AN, Sterz F, Kliegel M (2015) Survivors of cardiac arrest with good neurological outcome show considerable impairments of memory functioning. Resuscitation 88:120–125. doi:10.1016/j.resuscitation.2014.11.009

    Article  PubMed  Google Scholar 

Download references

Acknowledgment

This study was supported by Research Grant NS086929 from the National Institute of Neurological Disorders and Stroke, National Institutes of Health, USA; an American Heart Association Grant-in-Aid 15GRNT25240004; and by the Priority Academic Program Development of Jiangsu Higher Education Institutions and Open project of Key Laboratory of Brain Diseases Bioimformation (Xuzhou Medical University, JSBL1406), and the Jiangsu Government Scholarship Fund (JS2013245).

Author information

Authors and Affiliations

  1. Department of Emergency Medicine, Xuzhou Medical University, and Laboratory of Emergency Medicine, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221002, China

    Ningjun Zhao & Xiaoying Zhuo

  2. Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, 1120 15th Street, CA3050, Augusta, GA, 30912, USA

    Ningjun Zhao, Xiaoying Zhuo, Yujiao Lu, Yan Dong, Mohammad Ejaz Ahmed, Donovan Tucker, Erin L. Scott & Quanguang Zhang

Authors
  1. Ningjun Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaoying Zhuo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yujiao Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yan Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mohammad Ejaz Ahmed
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Donovan Tucker
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Erin L. Scott
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Quanguang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Quanguang Zhang.

Ethics declarations

Statement of interest

The authors declare that there is no conflict of interest in the current study.

Additional information

Ningjun Zhao and Xiaoying Zhuo contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhao, N., Zhuo, X., Lu, Y. et al. Intranasal Delivery of a Caspase-1 Inhibitor in the Treatment of Global Cerebral Ischemia. Mol Neurobiol 54, 4936–4952 (2017). https://doi.org/10.1007/s12035-016-0034-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-016-0034-9

Keywords

Search

Navigation