Login to MyKarger

New to MyKarger? Click here to sign up.



Login with Facebook

Forgot your password?

Authors, Editors, Reviewers

For Manuscript Submission, Check or Review Login please go to Submission Websites List.

Submission Websites List

Institutional Login
(Shibboleth or Open Athens)

For the academic login, please select your country in the dropdown list. You will be redirected to verify your credentials.

Original Paper

Free Access

Regional and Temporal Profiles of Calpain and Caspase-3 Activities in Postnatal Rat Brain following Repeated Propofol Administration

Milanovic D.a · Popic J.a · Pesic V.a · Loncarevic-Vasiljkovic N.a · Kanazir S.a · Jevtovic-Todorovic V.b · Ruzdijic S.a

Author affiliations

aDepartment of Neurobiology, Institute for Biological Research, University of Belgrade, Belgrade, Republic of Serbia; bDepartment of Anesthesiology, University of Virginia Health System, Charlottesville, Va., USA

Corresponding Author

Sabera Ruzdijic, PhD

Department of Neurobiology, Institute for Biological Research

University of Belgrade, Bulevar Despota Stefana 142

RS–11060 Belgrade (Republic of Serbia)

Tel. +381 11 2078 336, Fax +381 11 2761 433, E-Mail sabir@ibiss.bg.ac.rs

Related Articles for ""

Dev Neurosci 2010;32:288–301

Do you have an account?

Login Information





Contact Information











I have read the Karger Terms and Conditions and agree.



Abstract

Exposure of newborn rats to a variety of anesthetics has been shown to induce apoptotic neurodegeneration in the developing brain. We investigated the effect of the general anesthetic propofol on the brain of 7-day-old (P7) Wistar rats during the peak of synaptic growth. Caspase and calpain protease families most likely participate in neuronal cell death. Our objective was to examine regional and temporal patterns of caspase-3 and calpain activity following repeated propofol administration (20 mg/kg). P7 rats were exposed for 2, 4 or 6 h to propofol and killed 0, 4, 16 and 24 h after exposure. Relative caspase-3 and calpain activities were estimated by Western blot analysis of the proteolytic cleavage products of α-II-spectrin, protein kinase C and poly(ADP-ribose) polymerase 1. Caspase-3 activity and expression displayed a biphasic pattern of activation. Calpain activity changed in a region- and time-specific manner that was distinct from that observed for caspase-3. The time profile of calpain activity exhibited substrate specificity. Fluoro-Jade B staining revealed an immediate neurodegenerative response that was in direct relationship to the duration of anesthesia in the cortex and inversely related to the duration of anesthesia in the thalamus. At later post-treatment intervals, dead neurons were detected only in the thalamus 24 h following the 6-hour propofol exposure. Strong caspase-3 expression that was detected at 24 h was not followed by cell death after 2- and 4-hour exposures to propofol. These results revealed complex patterns of caspase-3 and calpain activities following prolonged propofol anesthesia and suggest that both are a manifestation of propofol neurotoxicity at a critical developmental stage.

© 2010 S. Karger AG, Basel


References

  1. Loepke AW, Soriano SG: An assessment of the effects of general anesthetics on developing brain structure and neurocognitive function. Anesth Analg 2008;106:1681–1707.
  2. Fredriksson A, Ponten E, Gordh T, Eriksson P: Neonatal exposure to a combination of N-methyl-D-aspartate and γ-aminobutyric acid type A receptor anesthetic agents potentiates apoptotic neurodegeneration and persistent behavioral deficits. Anesthesiology 2007;107:427–435.
  3. Henschel O, Gipson KE, Bordey A: GABAA receptors, anesthetics and anticonvulsants in brain development. CNS Neurol Disord Drug Targets 2008;7:211–224.
  4. Bercker S, Bert B, Bittigau P, Felderhoff-Muser U, Buhrer C, Ikonomidou C, Weise M, Kaisers UX, Kerner T: Neurodegeneration in newborn rats following propofol and sevoflurane anesthesia. Neurotox Res 2009;16:140–147.
  5. Vutskits L, Gascon E, Tassonyi E, Kiss JZ: Clinically relevant concentrations of propofol but not midazolam alter in vitro denditic development of isolated γ-aminobutiric acid-positive interneurons. Anesthesiology 2005;102:970–976.
  6. Cattano D, Young C, Straiko MMW, Olney JW: Subanesthetic doses of propofol induce neuroapoptosis in the infant mouse brain. Anesth Analg 2008;106:1712–1714.
  7. Yon JH, Daniel-Johnson J, Carter LB, Jevtovic-Todorovic V: Anesthesia induces neuronal cell death in the developing rat brain via the intrinsic and extrinsic apoptotic pathways. Neuroscience 2005;135:815–827.
  8. Pesic V, Milanovic D, Tanic N, Popic J, Kanazir S, Jevtovic-Todorovic V, Ruzdijic S: Potential mechanism of cell death in the developing rat brain induced by propofol anesthesia. Int J Dev Neurosci 2009;27:279–287.
  9. Wang KK: Calpain and caspase: can you tell the difference? Trends Neurosci 2000;23:20–26.
  10. Czogalla A, Sikorski AF: Spectrin and calpain: a ‘target’ and a ‘sniper’ in the pathology of neuronal cells. Cell Mol Life Sci 2005;62:1913–1924.
  11. McCollum AT, Nasr P, Estus S: Calpain activates caspase-3 during UV-induced neuronal death but only calpain is necessary for death. J Neurochem 2002;82:1208–1220.
  12. De Roo M, Klauser P, Briner A, Nikonenko I, Mendez P, Dayer A, Kiss JZ, Muller D, Vutskits L: Anesthetics rapidly promote synaptogenesis during a critical period of brain development. PLoS One 2009;4:e7043.
  13. Bjornstrom K, Turina D, Loverock A, Lundgren S, Wijkman M, Lindroth M, Eintrei CH: Characterization of the signal transduction cascade caused by propofol in rat neurons: from the GABAA receptor to the cytoskeleton. J Physiol Pharmacol 2008;59:617–632.
  14. Turina D, Loitto VM, Bjornstrom K, Sundqvist T, Eintrei C: Propofol causes neurite retraction in neurons. Br J Anesth 2008;101:374–379.
  15. Nakao S, Nagata A, Miyamoto E, Masuzawa M, Murayama T, Shingu K: Inhibitory effect of propofol on ketamine-induced c-Fos expression in the rat posterior cingulated and retrosplenial cortices is mediated by GABAA receptor activation. Acta Anesthesiol Scand 2003;47:284–290.
  16. Oscarsson A, Massoumi R, Sjolander A, Eintrei C: Reorganization of actin in neurons after propofol exposure. Acta Anesthesiol Scand 2001;45:1215–1220.
  17. Northington FJ, Zelaya ME, O’Riordan DP, Blomgren K, Flock DL, Hagberg H, Ferriero DM, Martin LJ: Failure to complete apoptosis following neonatal hypoxia-ischemia manifests as ‘continuum’ phenotype of cell death and occurs with multiple manifestations of mitochondrial dysfunction in rodent forebrain. Neuroscience 2007;149:822–833.
  18. Carloni S, Carnevali A, Cimino M, Balduini W: Extended role of necrotic cell death after hypoxia-ischemia-induced neurodegeneration in the neonatal rat. Neurobiol Dis 2007;27:354–361.
  19. Jensen AG, Lindroth M, Sjolander A, Eintrei C: Propofol induces changes in the cytosolyc free calcium concentrations and the cytoskeletal organization of cultured human glial cells and primary embryonic rat brain cells. Anesthesiology 1994;81:1220–1229.
  20. Rao A, Craig AM: Signaling between the actin cytoskeleton and the postsynaptic density of dendritic spines. Hippocampus 2000;10:527–541.
  21. Gomez RS, Guatimosim C, Gomez MV: Mechanism of action of volatile anesthetics: role of protein kinase C. Cell Mol Neurobiol 2003;23:877–885.
  22. Shea TB, Cressman CM, Spencer MJ, Beermann ML, Nixon RA: Enhancement of neurite outgrowth following calpain inhibition is mediated by protein kinase C. J Neurochem 1995;65:517–527.
  23. Buki KG, Bauer PI, Kun E: Isolation and identification of a proteinase from calf thymus that cleaves poly(ADP-ribose) polymerase and histone H1. Biochim Biophys Acta 1997;1338:100–106.
  24. Shah GM, Shah RG, Poirier GG: Different cleavage pattern for poly(ADP-ribose) polymerase during necrosis and apoptosis in HL-60 cells. Biochem Biophys Res Commun 1996;229:838–844.
  25. Chiarugi A: Poly(ADP-ribose) polymerase: killer or conspirator? The ‘suicide hypothesis’ revisited. Trends Pharmacol Sci 2002;23:122–129.
  26. Visochek L, Steingart RA, Vulih-Shultzman I, Klein R, Priel E, Gozes I, Cohen-Armon M: PolyADP-rybosylation is involved in neurotrophic activity. J Neurosci 2005;25:7420–7428.
  27. Tanaka Y, Koide S, Yoshihara K, Kamiya T: Poly (ADP-ribose) synthetase is phosphorylated by protein kinase C in vitro. Biochem Biophys Res Commun 1987;148:709–717.
  28. Nicolas G, Fournier CM, Galand C, Malbert-Colas L, Bournier O, Kroviarski Y, Bourgeois M, Camonis JH, Dhermy D, Grandchamp B, Lecomte MC: Tyrosine phosphorylation regulates alpha II spectrin cleavage by calpain. Molec Cell Biol 2002;22:3527–3536.
  29. Ikonomidou C, Bittigau P, Ishimaru MJ, Wozniak DF, Koch C, Genz K, Tenkova TI, Stefanovska V, Horster F, Tenkova T, Dikranian K, Olney JW: Ethanol-induced apoptotic neurodegeneration and fetal alcohol syndrome. Science 2000;283:1056–1060.
    External Resources
  30. Heaton MB, Paiva M, Madorsky I, Shaw G: Ethanol effects on neonatal rat cortex: comparative analyses of neurotrophic factors, apoptosis-related proteins, and oxidative processes during vulnerable and resistant periods. Dev Brain Res 2003;145:249–262.
  31. Kahraman S, Zup SL, McCarthy MM, Fiskum G: GABAergic mechanisms of propofol toxicity in immature neurons. Neurosurg Anesthesiol 2008;20:233–240.
  32. McLaughlin B: The kinder side of killer proteases: caspase activation contributes to neuroprotection and CNS remodeling. Apoptosis 2004;9:111–121.
  33. Villapol S, Acarin L, Faiz M, Castellano B, Gonzales B: Survivin and heat shock protein 25/75 colocalize with cleaved caspase-3 in surviving reactive astrocytes following excitotoxicity to the immature brain. Neuroscience 2008;153:108–119.
  34. Acarin L, Villapol S, Faiz M, Rohn TT, Castellano B: Caspase-3 activation in astrocytes following postnatal excitotoxic damage correlates with cytoskeletal remodeling but not with cell death or proliferation. Glia 2007;55:954–965.
  35. Bazin JE, Constantin JM, Gindre G: Laboratory animal anesthesia: influence of anesthetic protocols on experimental models. Ann Fr Anesth Reanim 2004;23:811–818.
  36. Anand KJS, Coskun V, Thrivikraman KV, Nemeroff CB, Plotsky PM: Long-term behavioral effects of repetitive pain in neonatal rat pups. Physiol Behav 1999;66:627–637.
  37. Anand KJS, Garg S, Rovnaghi CR, Narsinghani U, Bhutta AT, Hall RW: Ketamine reduces the cell death following inflammatory pain in newborn rat brain. Pediatr Res 2007;62:283–290.
  38. Yang H, Liang G, Hawkins B, Madesh M, Pierwola A, Wei H: Inhalational anesthetics induce cell damage by disruption of intracellular calcium homeostasis with different potencies. Anesthesiology 2008;109:243–250.
  39. Zhang G, Dong Y, Zhang B, Ichinose F, Wu X, Culley D J, Crosby G, Tanzi RE, Xie Z: Isoflurane-induced caspase-3 activation is dependent on cytosolic calcium and can be attenuated by memantine. J Neurosci 2008;28:4551–4560.

Article / Publication Details

First-Page Preview
Abstract of Original Paper

Received: March 30, 2010
Accepted: June 14, 2010
Published online: August 12, 2010
Issue release date: December 2010

Number of Print Pages: 14
Number of Figures: 7
Number of Tables: 0

ISSN: 0378-5866 (Print)
eISSN: 1421-9859 (Online)

For additional information: https://www.karger.com/DNE


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.