Skip to main content
SpringerLink
Log in

Pharmacological preconditioning by milrinone: Memory preserving and neuroprotective effect in ischemia-reperfusion injury in mice

  • Drug Actions
  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

We tested the neuroprotective effect of milrinone, a phosphodiesterase III inhibitor, in pharmacological preconditioning. Bilateral carotid artery occlusion for 12 min followed by reperfusion for 24 h produced ischemia-reperfusion (I/R) cerebral injury in male Swiss albino mice. Cerebral infarct size was measured using triphenyltetrazolium chloride staining. Memory was assessed using the Morris water maze test, and motor coordination was evaluated using the inclined beam walking test, rota-rod test, and lateral push test. Milrinone (50 μg/kg & 100 μg/kg i.v.) was administered 24 h before surgery in a separate group of animals to induce pharmacological preconditioning. I/R increased cerebral infarct size and impaired memory and motor coordination. Milrinone treatment significantly decreased cerebral infarct size and reversed I/R-induced impairments in memory and motor coordination. This neuroprotective effect was blocked by ruthenium red (3 mg/kg, s.c.), an intracellular ryanodine receptor blocker. These findings indicate that milrinone preconditioning exerts a marked neuroprotective effect on the ischemic brain, putatively due to increased intracellular calcium levels activating calcium-sensitive signal transduction cascades.

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

Similar content being viewed by others

References

  • Baim, D. S., McDowell, A. V., Cherniles, J., Monrad, E. S., Parker, J. A., Edelson J., Braunwald, E., and Grossman, W., Evaluation of a new bipyridine inotropic agentmilrinone in patients with severe congestive heart failure. N. Engl. J. Med., 309, 748–756 (1983).

    CAS  PubMed  Google Scholar 

  • Bederson, J. B., Pitts, L. H., Tsuji, M., Nishimur, M. C., Davis, R. L., and Bartowski, H., Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination. Stroke, 17, 472–476 (1986).

    CAS  PubMed  Google Scholar 

  • Bochelen, D., Rudin, M., and Sauter, A., Calcineurin inhibitors FK506 and SDZ ASM 981 alleviate the outcome of focal cerebral ischemic/reperfusion injury. J. Pharmacol. Exp. Ther., 288, 653–659 (1999).

    CAS  PubMed  Google Scholar 

  • Budde, T., Munsch, T., and Pape, H. C., Distribution of Ltype calcium channels in rat thalamic neurons. Eur. J. Neurosci., 10, 586–597 (1998).

    Article  CAS  PubMed  Google Scholar 

  • Carafoli, E., Santalla, L., Branca, D., and Brini, M., Generation, control and processing of cellular calcium signals. Crit. Rev. Biochem. Mol. Biol., 36, 107–260 (2001).

    Article  CAS  PubMed  Google Scholar 

  • Conti, M., Phosphodiesterases and cyclic nucleotide signalling in endocrine cells. Mol. Endocrinol., 14, 1317–1327 (2000).

    Article  CAS  PubMed  Google Scholar 

  • Davis, D. P. and Patel, P. M., Ischemic preconditioning in the brain. Curr. Opin. Anaesthesiol., 16, 447–452 (2003).

    Article  PubMed  Google Scholar 

  • Dobkin, B. H., The rehabilitation of elderly stroke patients. Clin. Geriatr. Med., 7, 507–523 (1991).

    CAS  PubMed  Google Scholar 

  • Dunham, N. W. and Miya, T. S., A note on a simple apparatus for detecting neurological deficit in rats and mice. J. Am. Pharm. Assoc. Am. Pharm. Assoc. (Baltim), 46, 208–209 (1957).

    CAS  Google Scholar 

  • Edwards, R. J., Saurin, A. T., Rakhit, R. D., and Marber, M. S., Therapeutic potential of ischaemic preconditioning. Br. J. Clin. Pharmacol., 50, 87–97 (2000).

    Article  CAS  PubMed  Google Scholar 

  • Evans, D. B., Overview of cardiovascular physiologic and pharmacologic aspects of selective phosphodiesterase peak III inhibitors. Am. J. Cardiol., 63, 9A–11A (1989).

    Article  CAS  PubMed  Google Scholar 

  • Fabiato, A., Time and calcium dependence of activation and inactivation of calcium-induced release of calcium from the sarcoplasmic reticulum of a skinned canine cardiac Purkinjee cell. J. Gen. Physiol., 85, 247–289 (1985).

    Article  CAS  PubMed  Google Scholar 

  • Feeney, D. M., Boyeson, M. G., Linn, R. T., Murray, H. M., and Dail, W. G., Responses to cortical injury: I. Methodology and local effects of contusions in the rat. Brain Res., 211, 67–77 (1981).

    Article  CAS  PubMed  Google Scholar 

  • Finkbeiner, S. and Greenberg, M. E., Calcium channel regulated neuronal gene expression. J. Neurobiol., 37, 171–189 (1998).

    Article  CAS  PubMed  Google Scholar 

  • Fraticelli, A. T., Cholley, B. P., Losser, M. R., and Payen, D., Milrinone for the treatment of cerebral vasospasm after aneursymal subarachnoid hemorrhage. Stroke, 39, 893–898 (2008).

    Article  PubMed  Google Scholar 

  • Friedman, L. K., Calcium: A role for neuroprotection and sustained adaptation. Mol. Interv., 6, 315–329 (2006).

    Article  PubMed  Google Scholar 

  • Gluckman, P. D., Wyatt, J. S., Azzopardi, D., Ballard, R., Edwards, A. D., Ferriero, D. M., Polin, R. A., Robertson, C. M., Thoresen, M., Whitelaw, A., and Gunn, A. J., Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet, 365, 663–670 (2005).

    PubMed  Google Scholar 

  • Iwasaki, K., Egashira, N., Takagaki, Y., Yoshimitsu, Y., Hatip-Al-Khatib, I., Mishima, K., and Fujiwara, M., Nilvadipine prevents the impairment of spatial memory induced by cerebral ischemia combined with beta-amyloid in rats. Biol. Pharm. Bull., 30, 698–701 (2007).

    Article  CAS  PubMed  Google Scholar 

  • Jenkins, L. W., Povlishock, J. T., Lewelt, W., Miller, J. D., and Becker, D. P., The role of postischemic recirculation in the development of ischemic neuronal injury following complete cerebral ischemia. Acta Neuropathol., 55, 205–220 (1981).

    Article  CAS  PubMed  Google Scholar 

  • Kaur, S., Jaggi, A. S., and Singh, N., Molecular aspects of ischemic postconditioning. Fundam. Clin. Pharmacol., 23, 521–536 (2009a).

    Article  CAS  PubMed  Google Scholar 

  • Kaur, S., Rehni, A. K., Singh, N., and Jaggi, A. S., Studies on cerebral protection of digoxin against ischemia/reperfusion Injury in Mice. Yakugaku Zasshi, 129, 435–443 (2009b).

    Article  CAS  PubMed  Google Scholar 

  • Kitagawa, K., Matsumoto, M., Tagaya, M., Hata, R., Ueda, H., Niinobe, M., Handa, N., Fukunaga, R., Kimura, K., and Mikoshiba, K., ’Ischemic tolerance’ phenomenon found in the brain. Brain Res., 528, 21–24 (1990).

    Article  CAS  PubMed  Google Scholar 

  • Kobayashi, T., Sugawara, Y., Ohkubo, T., Imamura, H., and Makuuchi, M., Effects of amrinone on hepatic ischemiareperfusion injury in rats. J. Hepatol., 37, 31–38 (2002).

    Article  CAS  PubMed  Google Scholar 

  • Kucuk, C., Akcan, A., Akyyldyz, H., Akgun, H., Muhtaroglu, S., and Sozuer, E., Effects of amrinone in an experimental model of hepatic ischemia-reperfusion injury. J. Surg. Res., 151, 74–79 (2009).

    Article  CAS  PubMed  Google Scholar 

  • Kume, M., Banafsche, R., Yamamoto, Y., Yamaoka, Y., Nobling, R., Gebhard, M. M., and Klar, E., Dynamic changes of post-ischemic hepatic microcirculation improved by a pretreatment of phosphodiesterase III inhibitor, milrinone. J. Surg. Res., 136, 209–218 (2006).

    Article  CAS  PubMed  Google Scholar 

  • Lang, S. C., Elsasser, A., Scheler, C., Vetter, S., Tiefenbacher, C. P., Kubler, W., Katus, H. A., and Vogt, A. M., Myocardial preconditioning and remote renal preconditioning—identifying a protective factor using proteomic methods? Basic Res. Cardiol., 101, 149–158 (2006).

    Article  CAS  PubMed  Google Scholar 

  • Lee, J. H., Lee, Y. K., Ishikawa, M., Koga, K., Fukunaga, M., Miyakoda, G., Mori, T., Hosokawa, T., and Hong, K. W., Cilostazol reduces brain lesion induced by focal cerebral ischemia in rats-an MRI study. Brain Res., 994, 91–98 (2003).

    Article  CAS  PubMed  Google Scholar 

  • Lugnier, C., Cyclic nucleotide phosphodiesterase (PDE) superfamily: A new target for the development of specific therapeutic agents. Pharmacol. Ther., 109, 366–398 (2006).

    Article  CAS  PubMed  Google Scholar 

  • Lukyanenko, V., Gyorke, I., Subramanian, S., Smirnov, A., Weisner, T. F., and Gyorke, S., Inhibition of Ca2+ sparks by Ruthenium red in permeabilized rat ventricular myocytes. Biophys. J., 79, 1273–1284 (2000).

    Article  CAS  PubMed  Google Scholar 

  • McCormick, P. H., Chen, G., Tlerney, S., Kelly, C. J., and Bouchier-Hayes, D. J., Clinically relevant thermal preconditioning attenuates ischemia-reperfusion injury. J. Surg. Res., 109, 24–30 (2003).

    Article  CAS  PubMed  Google Scholar 

  • Mcgarry, S. J. and Williams, A. J., Digoxin activates sarcoplasmic reticulum calcium release channels: possible role in cardiac inotropy. Br. J. Pharmacol., 108, 1043–1050 (1993).

    CAS  PubMed  Google Scholar 

  • Miyawaki, H. and Ashraf, M., Calcium as a mediator of ischemic preconditioning. Circ. Res., 80, 790–799 (1997).

    CAS  PubMed  Google Scholar 

  • Miyawaki, H., Zhou, X., and Ashraf, M., Calcium preconditioning elicits strong protection against ischemic injury via protein kinase C signaling pathway. Circ. Res., 79, 137–146 (1996).

    CAS  PubMed  Google Scholar 

  • Morris, R., Developments of a water-maze procedure for studying spatial learning in the rat. J. Neurosci. Methods, 11, 47–60 (1984).

    Article  CAS  PubMed  Google Scholar 

  • Murray, C. E., Jennings, R. B., and Reimer, K. A., Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation, 74, 1124–1136 (1986).

    Google Scholar 

  • Neumar, R. W., Molecular mechanisms of ischemic neuronal injury. Ann. Emerg. Med., 36, 483–506 (2000).

    CAS  PubMed  Google Scholar 

  • Parle, M. and Singh, N., Animal models for testing memory. Asia Pacific. J. Pharmacol., 16, 101–120 (2004).

    Google Scholar 

  • Pateliya, B. B., Singh, N., and Jaggi, A. S., Possible role of opioids and KATP channels in neuroprotective effect of postconditioning in mice. Biol. Pharm. Bull., 31, 1755–1760 (2008).

    Article  CAS  PubMed  Google Scholar 

  • Peralta, C., Serafin, A., Fernandez-Zabalegui, L., Wu, Z. Y., and Rosello-Catafau, J., Liver ischemic preconditioning: a new strategy for the prevention of ischemia-reperfusion injury. Transplant. Proc., 35, 1800–1802 (2003).

    Article  CAS  PubMed  Google Scholar 

  • Rehni, A. K. and Singh, N., Role of phosphoinositide 3- kinase in ischemic postconditioning-induced attenuation of cerebral ischemia-evoked behavioral deficits in mice. Pharmacol. Rep., 59, 197–198 (2007).

    Google Scholar 

  • Rehni, A. K., Singh, N., and Singh, A. S., Possible role of insulin, endogenous opioids and calcitonin gene related peptide in remote ischemic preconditioning of brain. Yakugaku Zasshi, 127, 1013–1020 (2007).

    Article  PubMed  Google Scholar 

  • Rehni, A. K., Bhateja, P., Singh, N., and Jaggi, A.S., Implication of mast cell degranulation in ischemic precondition ing induced prevention of cerebral injury. Fundam. Clin. Pharmacol., 22, 179–188 (2008a).

    Article  CAS  PubMed  Google Scholar 

  • Rehni, A. K., Singh, T. G., Singh, N., and Jaggi, A. S., Pharmacological preconditioning of the brain: a possible interplay between opioid and calcitonin gene related peptide transduction systems. Pharmacol. Rep., 60, 904–913 (2008b).

    CAS  PubMed  Google Scholar 

  • Rump, A. F., Acar, D., and Klaus, W., A quantitative comparison of functional and anti-ischemic effects of the phosphodiesterase-inhibitors, amrinone, milrinone and levosimendan in rabbit isolated hearts. Br. J. Pharmacol., 112, 757–762 (1994).

    CAS  PubMed  Google Scholar 

  • Saltman, A. E., Gaudette, G. R., Levitsky, S., and Krukenkamp, I. B., Amrinone preconditioning in the isolated perfused rabbit heart. Ann. Thorac. Surg., 70, 609–613 (2000).

    Article  CAS  PubMed  Google Scholar 

  • Schulz, R., Post, H., Vahlhaus, C., and Heusch, G., Ischemic preconditioning in pigs: a graded phenomenon; its relation to adenosine and bradykinin. Circulation, 98, 1022–1029 (1998).

    CAS  PubMed  Google Scholar 

  • Schulz, R., Gres, P., and Heusch, G., Role of endogenous opioids in ischemic preconditioning but not in short-term hibernation in pigs. Am. J. Physiol. Heart Circ. Physiol., 280, H2175–H2181 (2001).

    CAS  PubMed  Google Scholar 

  • Setoyama, K., Kamimura, R., Fujiki, M., Misumi, K., Miyahara, K., and Sakamoto, H., Effects of olprinone on myocardial ischemia reperfusion injury in dogs. J. Vet. Med. Sci., 68, 865–868 (2006).

    Article  CAS  PubMed  Google Scholar 

  • Somers, S., Lacerda, L., Suleman, N., Opie, L., and Lecour, S., Critical role of age, strain and number of cycles in ischemic postconditioniong. J. Mol. Cell. Cardiol., 42, S186–S187 (2007).

    Article  Google Scholar 

  • Ueda, T., Mizushige, K., Yukiiri, K., Takahashi, T., and Kondoh, M., Improvement of cerebral blood flow by olprinone, a phosphodiesterase-3 inhibitor, in mild heart failure. Cerebrovasc. Dis., 16, 396–401 (2003).

    Article  CAS  PubMed  Google Scholar 

  • Wang, S. Q., Song, L. S., Lakatta, E. G., and Cheng, H., Ca2+ signaling between single L-type Ca2+ channels and ryanodine receptors in heart cells. Nature, 410, 592–596 (2001).

    Article  CAS  PubMed  Google Scholar 

  • Warner, D. S., McFarlane, C., Todd, M. M., Ludwig, P., and McAllister, A. M., Sevoflurane and halothane reduce focal ischemic brain damage in the rat: Possible influence on thermoregulation. Anesthesiology, 79, 985–992 (1993).

    Article  CAS  PubMed  Google Scholar 

  • Yang, X. M., Proctor, J. B., Cui, L., Krieg, T., Downey, J. M., and Cohen, M. V., Multiple, brief coronary occlusions during early reperfusion protect rabbit hearts by targeting cell signaling pathways. J. Am. Coll. Cardiol., 44, 1103–1110 (2004).

    Article  PubMed  Google Scholar 

  • Yanpallewar, S. U., Hota, D., Rai, S., Kumar, M., and Acharya, S. B., Nimodipine attenuates biochemical, behavioral and histopathological alterations induced by acute transient and long-term bilateral common carotid occlusion in rats. Pharmacol. Res., 49, 143–150 (2004).

    Article  CAS  PubMed  Google Scholar 

  • Yellon, D. M. and Dana, A., The preconditioning phenomenon: a tool for the scientist or a clinical reality? Circ. Res., 87, 543–550 (2000).

    CAS  PubMed  Google Scholar 

  • Ye, Y. L., Shi, W. Z., Zhang, W. P., Wang, M. L., Zhou, Y., Fang, S. H., Liu, L. Y., Zhang, Q., Yu, Y. P., and Wei, E. Q., Cilostazol, a phosphodiesterase 3 inhibitor, protects mice against acute and late ischemic brain injuries. Eur. J. Pharmacol., 557, 23–31 (2007).

    Article  CAS  PubMed  Google Scholar 

  • Zhai, P., Eurell, T. E., Cotthaus, R., Jeffery, E. H., Bahr, J. M., and Gross, D. R., Effect of estrogen on global myocardial ischemia-reperfusion injury in female rats. Am. J. Physiol. Heart Circ. Physiol., 279, H2766–H2775 (2000).

    CAS  PubMed  Google Scholar 

  • Zhao, P., Peng, L., Li, L., Xu, X., and Zuo, Z., Isoflurane preconditioning improves long-term neurologic outcome after hypoxic-ischemic brain injury in neonatal rats. Anesthesiology, 107, 963–970 (2007).

    Article  CAS  PubMed  Google Scholar 

  • Zheng, S. and Zuo, Z., Isoflurane preconditioning induces neuroprotection against ischemia via activation of P38 mitogen-activated protein kinases. Mol. Pharmacol., 65, 1172–1180 (2004).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, 147002, India

    Reetu Saklani, Amteshwar Jaggi & Nirmal Singh

  2. Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, 147002, Punjab, India

    Nirmal Singh

Authors
  1. Reetu Saklani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Amteshwar Jaggi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nirmal Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nirmal Singh.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Saklani, R., Jaggi, A. & Singh, N. Pharmacological preconditioning by milrinone: Memory preserving and neuroprotective effect in ischemia-reperfusion injury in mice. Arch. Pharm. Res. 33, 1049–1057 (2010). https://doi.org/10.1007/s12272-010-0711-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12272-010-0711-6

Key words

Search

Navigation