Skip to main content

Cerebral protection by AMPA- and NMDA-receptor antagonists administered after severe insulin-induced hypoglycemia

Experimental Brain Research volume 92, pages 259–266 (1992)Cite this article

Summary

Excitatory amino acids are implicated in the development of neuronal cell damage following periods of reversible cerebral ischemia or insulin-induced hypoglycemic coma. To explore the importance of glutamate receptor activation in the posthypoglycemic phase, we exposed rats to 20 min of insulin-induced severe hypoglycemia. The rats were treated immediately after the hypoglycemic insult with four regimes of glutamate receptor antagonists: (1) the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propriate)-receptor antagonist NBQX [2.3-dihydroxy-6-nitro-7-sulfamoyl-benzo (F) quinoxaline] given as a bolus dose of 30 mg · kg-1 i.p., followed by an i.v. infusion of 225 μg · kg-1 · min-1 for 6 h; (2) the non-competitive NMDA-receptor antagonist, dizocilpine (MK-801) 1 mg · kg-1 given i.v.; (3) a combined NBQX treatment, (a bolus dose of 10 mg · kg-1 i.p., followed by an i.v. infusion of 225 μg · kg-1 · min-1 for 6 h), with dizocilpine 0.33 mg · kg-1 given twice i.p. at 0 and 15 min after recovery and (4) the competitive NMDA-receptor blocker CGP 40116 [D-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid] 10 mg · kg-1 given i.p.. In the striatum, all glutamate receptor blockers significantly decreased neuronal damage by approximately 30%. An approximately 50% decrease in neuronal damage was demonstrated in neocortex and hippocampus following the combined treatment with NBQX and dizocilpine, while protection was variable following the treatment with a single glutamate-receptor antagonist. We conclude that neuronal damage continues to develop in the striatum and in cortical brain regions in the posthypoglycemic period and that both NMDA- and AMPA-receptors contribute to this process, possibly by a change in the cellular response to both AMPA- and NMDA-receptor stimulation.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

References

  • Agardh C-D, Kalimo H, Olsson Y, Siesjö BK (1981) Hypoglycemic brain injury: metabolic and structural findings in rat cerebellar cortex during profound insulin-induced hypoglycemia and in the recovery period following glucose administration. J Cereb Blood Flow Metab 1:71–84

    Google Scholar 

  • Auer RN, Wieloch T, Olsson Y, Siesjö BK (1984a) The distribution of hypoglycemic brain damage. Acta Neuropathol (Berl) 64:177–191

    Google Scholar 

  • Auer RN, Olsson Y, Siesjö BK (1984b) Hypoglycemic brain injury in the rat. Correlation of density of brain damage with the EEG isoelectric time: a quantitative study. Diabetes 33:1090–1098

    Google Scholar 

  • Auer RN, Kalimo H, Olsson Y, Siesjö BK (1985) The temporal evolution of hypoglycemic brain damage: II. Light and electron microscopic findings in hippocampal gyrus and subiculum of the rat. Acta Neuropathol (Berl) 67:25–36

    Google Scholar 

  • Buchan AM, Li H, Cho C, Pulsinelli WA (1991a) Blockade of the AMPA receptor prevents CA1 hippocampal injury following severe but transient forebrain ischemia in the adult rat. Neurosci Lett 132:255–258

    Google Scholar 

  • Buchan AM, Xue D, Huang Z-G, Smith KH, Lesiuk H (1991b) Delayed AMPA receptor blockade reduces cerebral infarction induced by focal ischemia. Neuroreport 2:473–476

    Google Scholar 

  • Buchan AM, Li H, Pulsinelli WA (1991c) The N-methyl-d-aspartate antagonist MK-801, fails to protect against neuronal damage caused by transient, severe forebrain ischemia in adult rats. J Neurosci 11:1049–1056

    Google Scholar 

  • Choi DW (1988) Calcium-mediated neurotoxicity: relationship to specific channel types and role in ischemic damage. Trends Neurosci 11:465–469

    Google Scholar 

  • Churn SB, Taft WC, Billingsley ML, Blair RE, De Lorenzo RJ (1990) Temperature modulation of ischemia-induced neuronal death and ischemia-induced inhibition of calcium/calmodulin dependent protein kinase II in gerbils. Stroke 21:1715–1721

    Google Scholar 

  • Dumuis A, Pin JP, Oomagari K, Sebben M, Bockaert J (1990) Arachidonic acid released from striatal neurons by joint stimulation of ionotropic and metabotropic quisqualate receptors. Nature 347:182–184

    Google Scholar 

  • Fagg GE, Olpe HR, Schmutz M, Pozza MF, van Riesen H, Bittiger H, Angst C, Brundish D, Allgeier H, Heckendorn R, Dingwall JG (1989) CGP 37 849 and CGP 39 551: Novel competitive N-methyl-d-aspartate receptor antagonist with potent oral anticonvulsant activity. In:Williams M (ed) Current and future trends in anticonvulsant, anxiety and stroke therapy. Princeton Drug Research Symposia 1989. Alan Liss, New York, pp 421–427

    Google Scholar 

  • Giffard RG, Monyer H, Christine CW, Choi DW (1990) Acidosis reduces NMDA-receptor activation, glutamate neurotoxicity, and oxygen-glucose deprivation neuronal injury in cortical cultures. Brain Res 506:339–342

    Google Scholar 

  • Hollmann M, Hartley M, Heinemann S (1991) Ca2+ permeability of KA-AMPA-gated glutamate receptor channels depends on subunit composition. Science 252:851–853

    Google Scholar 

  • Honoré T, Davies SN, Drejer J, Fletcher EJ, Jacobsen P, Lodge D, Nielsen FE (1988) Quinoxalinediones: potent competitive nonNMDA glutamate receptor antagonists. Science 241:701–703

    Google Scholar 

  • Kalimo H, Auer RN, Siesjö BK (1985) The temporal evolution of hypoglycemic brain damage. III. Light and electron microscopic findings in the rat caudoputamen. Acta Neuropathol (Berl) 67:35–50

    Google Scholar 

  • Keinänen K, Wisden W, Sommer B, Werner P, Herb A, Verdoorn TA, Sakmann B, Seeburg PH (1990) A family of AMPA-selective glutamate receptors. Science 249:556–560

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Kraig RP, Chesler M (1990) Astrocytic acidosis in hyperglycemic and complete ischemia. J Cereb Blood Flow Metab 10:104–114

    Google Scholar 

  • Le Peillet E, Arvin B, Moncada C, Meldrum BS (1992) The nonNMDA antagonists, NBQX and GYKI 52 466, protect against cortical and striatal cell loss following transient global ischemia in the rat. Brain Res 571:115–120

    Google Scholar 

  • Lindén T, Kalimo H, Wieloch T (1987) Protective effect of lesion to the glutamatergic cortico-striatal projections on the hypoglycemic nerve cell injury in rat striatum. Acta Neuropathol (Berl) 74:335–344

    Google Scholar 

  • Lindvall O, Ernford P, Bengzon J, Kokaia Z, Smith M-L, Siesjö BK, Persson H (1992) Differential regulation of mRNAs for nerve growth factor, brain derived neurotrophic factor and neurotrophin-3 in the adult brain following cerebral ischemia and hypoglycemic coma. Proc Natl Acad Sci (USA) 89:648–652

    Google Scholar 

  • Mayer ML, Miller RJ (1990) Excitatory amino acid receptors, second messengers and regulation of intracellular Ca2+ in mammalian neurons. Trends Pharmacol Sci 11:254–260

    Google Scholar 

  • Mody I, Salter MW, MacDonald JF (1988) Requirement of NMDA-receptor/channels for intracellular high-energy phosphates and the extent of intraneuronal calcium buffering in cultured mouse hippocampal neurons. Neurosci Lett 93:73–78

    Google Scholar 

  • Monyer H, Goldberg MP, Choi DW (1989) Glucose deprivation in neuronal cortical culture. Brain Res 483:347–354

    Google Scholar 

  • Nellgård B, Wieloch T (1992) Postischemic blockade of AMPA but not NMDA-receptors mitigates neuronal damage in the rat brain following transient severe cerebral ischemia. J Cereb Blood Flow Metab 12:2–11

    Google Scholar 

  • Nellgård B, Gustafson I, Wieloch T (1991) Lack of protection by the N-methyl-d-aspartate receptor blocker dizocilpine (MK-801) transient severe cerebral ischemia in the rat. Anesthesiol 75:279–287

    Google Scholar 

  • Papagapiou MP, Auer RN (1990) Regional neuroprotective effects of the NMDA-receptor antagonist MK-801 (Dizocilpine) in hypoglycemic brain damage. J Cereb Blood Flow Metab 10:270–276

    Google Scholar 

  • Park CK, Nehls DG, Graham DI, Teasdale GM, McCulloch J (1988) The glutamate antagonist MK-801 reduces focal ischemic brain damage in the rat. Ann Neurol 24:543–551

    Google Scholar 

  • Paxinos G, Watson C (1982) The rat brain in stereotaxic coordinates. Academic Press, Sydney

    Google Scholar 

  • Pelligrino D, Siesjö BK (1981) Regulation of extra- and intracellular pH in the brain in severe hypoglycemia. J Cereb Blood Flow Metab 1:85–96

    Google Scholar 

  • Sandberg M, Butcher SP, Hagberg H (1986) Extracellular overflow of neuroactive amino acids during severe insulin-induced hypoglycemia: in vivo dialysis of the rat hippocampus. J Neurochem 47:178–184

    Google Scholar 

  • Schoepp D, Bockert J, Sladeczek F (1990) Pharmacological and functional characteristics of the metabotropic excitatory amino acid receptors. Trends Pharmacol Sci 11:508–515

    Google Scholar 

  • Sheardown MJ, Nielsen EØ, Hansen AJ, Jacobsen P, Honoré T (1990) 2.3-Dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline: a neuroprotectant for cerebral ischemia. Science 247:571–574

    Google Scholar 

  • Siesjö BK (1988) Mechanisms of ischemic brain damage. Crit Care Med 16:954–963

    Google Scholar 

  • Westerberg E, Kehr J, Ungerstedt U, Wieloch T (1988) The NMDA-antagonist MK-801 reduces extracellular amino acid levels during hypoglycemia and prevents striatal damage. Neurosci Res Com 3:151–158

    Google Scholar 

  • Wieloch T (1985) Hypoglycemia-induced neuronal damage prevented by an N-methyl-d-aspartate antagonist. Science 230:681–68

    Google Scholar 

  • Wieloch (1990) Neuronal injury and cerebrovascular disorders. Current Opinion Neurol Neurosurg 3:944–950

    Google Scholar 

  • Wieloch T, Engelsen B, Westerberg E, Auer RN (1985) Lesions of the glutamatergic cortico-striatal projections in the rat ameliorate hypoglycemic brain damage in the striatum. Neurosci Lett 58:25–30

    Google Scholar 

  • Wieloch T, Cardell M, Bingren H, Zivin J, Saitoh T (1991) Changes in the activity of protein kinase C and the differential subcellular redistribution of its isozymes in the rat striatum during and following transient forebrain ischemia. J Neurochem 56(4):1227–1235

    Google Scholar 

  • Zafra F, Hengerer B, Leibrock J, Thoenen H, Lindholm D (1990) Activity dependent regulation of BDNF and NGF mRNAs in the rat hippocampus is mediated by non-NMDA glutamate receptors. EMBO J 9:3545–3550

    CAS  PubMed  Google Scholar 

Download references

Author information

Affiliations

  1. Laboratory for Experimental Brain Research, Lund University Hospital, S-221 85, Lund, Sweden

    Bengt Nellgård & Tadeusz Wieloch

Authors
  1. Bengt Nellgård
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tadeusz Wieloch
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Nellgård, B., Wieloch, T. Cerebral protection by AMPA- and NMDA-receptor antagonists administered after severe insulin-induced hypoglycemia. Exp Brain Res 92, 259–266 (1992). https://doi.org/10.1007/BF00227969

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00227969

Key words

  • Hypoglycemia
  • Neuronal death
  • N-methyl-D-aspartate
  • AMPA
  • Rat