Abstract
Clinically, neonatal hypoxic encephalopathy is commonly associated with seizure activity. Here we describe a rodent model of cerebral hypoxia in which there is are age dependent effects of hypoxia, with hypoxia inducing seizure activity in the immature rat, but not in the adult. Global hypoxia (3–4% O2) induced acute seizure activity during a window of development between postnatal day (P5–17), peaking at P10–12. Animals which had been rendered hypoxic between P10–12 had long term decreases in seizure threshold, while animals exposed at younger (P5) or older (P60) ages did not. Antagonists of excitatory amino acid (EAA) transmission appear to be superior to benzodiazepines in suppressing the acute and long term effects of perinatal hypoxia, suggesting involvement of the EAA system in these phenomena. No significant histologic damage occurs in this model, suggesting that functional alterations take place in neurons when exposed to an hypoxic insult at a critical developmental stage. Future work is directed at evaluating molecular and cellular events underlying the permanent increase in seizure susceptibility produced by this model.
Sommario
Nell'uomo l'encefalopatia ipossica del neonato è generalmente associata a crisi epilettiche. Qui descriviamo un modello di ipossia cerebrale nel roditore in cui gli effetti dell'ipossia sono età-dipendenti in quanto inducono crisi nel ratto immaturo ma non nell'adulto. L'ipossia globale (3–4% O2) è risultata indurre crisi in un periodo limitato dello sviluppo postnatale (P5–P17) con un picco di efficacia P10 e P12. Gli animali resi ipossici tra P10 e P12 manifestavano un abbassamento persistente della soglia convulsiva che era invece assente in quelli esposti all'ipossia in età precedente (P5) o successiva (P60). Gli antagonisti della trasmissione mediata dagli aminoacidi eccitatori (EAA) sono risultati più potenti delle benzodiazepine nel sopprimere sia gli effetti convulsivanti acuti che quelli persistenti da ipossia perinatale, cosa che porta a riferirli all'azione del sistema degli EAA. L'esame istologico non evidenzia significative alterazioni in accordo con l'idea che l'attività epilettogena dipenda da una alterazione funzionale indotta dall'ipossia in neuroni che si trovano in una fase critica di sviluppo. Gli ulteriori sviluppi di questo lavoro saranno indicizzati alla valutazione degli eventi molecolari e cellulari responsabili dell'aumento persistente di suscettibilità alle crisi che si verifica in questo modello.
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References
Aicardi J., Chevrie J.J.:Convulsive status epilepticus in infants and children. A study of 239 cases. Epilepsia, 11: 187–197, 1970.
Aruffo C., Ferszt R., Hildebrandt A.G., Cervox-Navarroii J.: In vitroneuronal plasticity triggered by subtoxic doses of monosodium glutamate. Clin. Biol. Res. 253: 229–237, 1987.
Baudry M., Davis J.L.:Long term potentiation: a debate of current issues. MIT Press: Cambridge, 1991.
Bergamasco B., Penna P., Ferrero P., Gavinelli R.:Neonatal hypoxia and epileptic risk: A clinical prospective study. Epilepsia, 25: 131–146, 1984.
Bowe M.A., Nadler J.V.:Developmental increase in the sensitivity to magnesium of NMDA receptors on CA1 hippocampal pyramidal cells. Developmental Brain Research, 56: 55–61, 1990.
Choi D.W.:Glutamate neurotoxicity and diseases of the nervous system. Neuron 1 (8): 623–634, 1988.
Choi D.W.:Excitatory cell death. J. Neurobiol., 23: 1261–1276, 1992.
Choi D.W., Rothman S.N.:The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death. Ann. Rev. Neurosci., 12: 171–182, 1990.
Cline H.T., Constantine-Paton M.:NMDA receptor antagonists disrupt the retionotectal topographic map. Neuron., 3: 413–326, 1989.
Collingridge G.L., Singer W.:Excitatory amino acid receptors and synaptic plasticity. Trends in Pharmacol. Sci., 11: 290–296, 1990.
Dubinsky J.M., Rothman S.M.:Intracellular calcium concentrations during “chemical hypoxia” and excitotoxic neuronal injury. J. Neurosci., 11: 2545–2551, 1991.
Facchinetti F., Ciani E., Dall'olio R., Virgili M., Contestable A., Fonnum F.:Structural, neurochemical and behavioural consequences of neonatal blockade of NMDA receptor through chronic treatment with CGP 39551 or MK-801. Brain. Res. Dev. Brain Res., 74: 219–224, 1993.
Gunn A.J., Draunow M., Faull R.L.M., Gluckman D.:Effects of hypoxia-ischemia and seizures on neuronal and glial-lik c-fos protein levels in the infant rat. Brain Res., 531: 105–116, 1990.
Harris G.W., Ganong A.H., Cotman C.W.:Long term potentiation in the hippocampus involves activation of the NMDA receptors. Brain Res. 323: 132–137, 1984.
Hattori H., Morin A.M., Schwartz P.H., Fujikawa D.G., Wasterlain C.G.:Posthypoxic treatment with MK-801 reduces hypoxic-ischemic damage in the neonatal rat. Neurology, 39 (5): 713–718, 1989.
Himwich W.:Developmental Neurobiology. Charles Thomas Publishers: Springfield, IL, 1970.
Holmes G.L.:Neonatal Seizures. In: T.A. Pedley and B.S. Meldrum (Eds.) Recent Advances in Epilepsy. New York: Churchill Livingstone, pp. 207–237, 1985.
Holmes G.L., Kull L.L.:Neonatal seizures. Am. J. EEG Technol., 30: 281–308, 1990.
Insel T.R., Miller L., Gelhard R.E.:The ontogeny of excitatory amino acid in the rat forebrain I: N-methyl-d-aspartate and quisqualate receptors. Neuroscience, 35:31–43, 1990.
Jensen F.E., Alvarado S.P., Blume H., Firkusny I.:Effect of pharamcologic seizure suppression during acute perinatal hypoxia on subsequent long term seizure susceptibility. Epilepsia, 34(6): 22, 1993 (Abstract).
Jensen F.E., Applegate C.D., Burchfield J.L., Lombroso C.T.:Differential effects of perinatal hypoxia and anoxia on long term in seizure susceptibility in the rat. Life Sci, 49(5): 399–307, 1991.
Jensen F.E., Applegate C.D., Holtzman D., Belin T., Burchfield J.:Epileptogenic effects of hypoxia on immature rodent brain. Ann. Neurol., 29(6): 629–637, 1991.
Jensen F.E., Firkusny I., Mower G.:Differences in c-fos immunoreactivity due to age and mode of seizure induction. Mol. Br. Res., 17: 185–193, 1993.
Jensen F.E., Firkusny I.R., Blume H.K.:Improved anticonvulsant efficacy of EAA antagonists over conventional AED's in a rat model of perinatal hypoxia-induced seizures. Epilepsia, 33: 20, 1992.
Jensen F.E., Holmes G.H., Lombroso C.T., Blume H., Firkunsny I.:Age dependent long term changes in seizure susceptibility and neurobehavior following hypoxia in the rat. Epilepsia, 33(6): 971–980, 1992.
Jensen F.E., Wang C.D., Stevens M.C.:Enhanced LTP in hippocampal slices following in vivo perinatal hypoxia. Society for Neuroscience Abs., 20:1668, 1994.
Kleinschmidt A., Bear M.F., Winger W.:Blockage of NMDA receptors disrupts experience-dependent plasticity of kitten striate cortex. Science, 238: 355–358, 1987.
Mares P., Maresova D., Schickova R.:Effect of antiepileptic drugs on metrazol convulsions during ontogenesis in the rat. Physiologia Bohemoslovacoa, 30: 113–121, 1981.
Mattson M.:Neurotransmitters in the regulation of neuronal cytoarchitecture. Brain Res. Rev., 13: 179–212, 1988.
McDonald J.W., Johnston M.V.:Psysiological and pathophysiological roles of excitatory amino acids during central nervous system development. Brain Res. Brain Res. Rev., 15(1): 41–70, 1990.
McDonald J.W., Silverstein F.S., Cardona D., Hudson C., Chen R., Johnston M.V.:Systemic administration of MK-801 protects against N-methyl-d-aspartate-neurotoxicity in perinatal rats. Neuroscience, 36: 589–599, 1990.
Meldrum B., Garthwaite J.:Excitatory amino acid neurotoxicity and neurodegenerative disease, Trends Pharmacol. Sci., 11: 379–387, 1990.
Michaels R., Rothman S.:Glutamate toxicity in vitro:antagonist pharmacology and intracellular calciumn concentrations. J. Neuroscience, 10: 283–292, 1990.
Monyer H., Sprengel R., Schoepfer R., Herb A., Higuchi M., Lomeli H., Burnashev N., Sakmann B., Seeberg P.H.:Heteromic NMDA receptors: molecular and functional distinction of subtypes. Science, 256: 1217–1221, 1992.
Morgan J.I., Cohen D.R., Hempstead J.L., Curran T.:Mapping patterns of c-fos expression in the central nervous system after seizure. Science, 237: 192–201, 1987.
Morgan J.I., Curran T.:Stimulus-transcription coupling in neurons: role of cellular immediateearly genes. Trends Neurosci., 12(11): 459–462, 1989.
Morgan J.I., Curran T.:Proto-oncogene transcription factors and epilepsy. Trends in Pharmacology, 12: 343–349, 1991.
Morgan J.I., Curran T.:Stimulus-transcription coupling in the nervous system: involvement of the inducible proto-oncogenes fos and jun. Ann. Rev. Neurosci., 14: 421–451, 1991.
Olney J.W., Labnuyere J., Wang G., Wozniak D.F., Price M.T., Sesma M.A.:NMDA antagonist neurotoxicity: mechanism and prevention. Science, 254: 1515–1518, 1991.
Olney J.W., Labruyere J., Price M.T.:Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs. Science, 244: 1360–1362, 1989.
Pearce I.A., Cambray-Deakin M.A., Burgoyne R.D.:Glutamate acting on NMDA receptors stimulates neurite outgrowth from cerebellar granule cells. FEBS. Lett., 223: 143–147, 1987.
Pellegrini-Giampietro D.E.:Are Ca 2+ permeable kainate/AMPA receptors more abundant in immature brain. Neurosci. Lett., 144: 65–69, 1992.
Pollard H.:Transient expression of the NR2C subunit of the NMDA receptor in developing rat brain. Neuro Report., 4: 411–414, 1993.
Rauschecker J., Hahn S.:Ketamine-xylazine anaesthesia blocks consolidation of ocular dominance changes in kitten visual cortex. Nature (Lond.), 326: 183–185, 1987.
Rogawski M.:The NMDA receptor, NMDA antagonists and epilepsy therapy: A status report. Drugs., 44: 279–292, 1992.
Romijn H.J.:At what age is the developing cerebral cortex of the rat comparable to that of the full-term newborn human baby? Early Human Development, 26 61–67, 1991.
Ruppert C., Willie W.:Proto-oncogene c-fos is highly induced by distruption of netonatal but not mature brain tissue. Mol. Br. Res., 2: 51–56, 1987.
Scherwin A.L., Val Gelder N.M.:Amino acid and catecholamine markers of metabolic abnormalities in human focal epilepsy. In: A. V. Delgado-Escueta, A.A. Ward, Jr. D.M. Woodbury and R.J. Porter (Eds.) Advances in Neurology, Raven Press: New York, 1994, pp. 1011–1032.
Sheng M., Greenberg M.:The regulation and function of c-fos and other immediate early genes in the nervous system. Neuron, 4: 477–485, 1990.
Sherwood N.M., Timiras P.S.:A Stereotaxic Atlas of the Developing Rat Brain. Univ. of Calif. Press: Berkeley., 1970.
Sonnenberg J.L., Macgregor-Leon P.F., Curran T., Morgan J.I.:Dynamic alterations occur in the levels and composition of factor AP-1 complexes after seizures. Neuron, 3: 359–365, 1989.
Thompson A.M., West D.C.:N-methyl-d aspartate receptors mediate epileptiform activity evoked in some, but not all, conditions in rat neocortical slices. Neuroscience, 19: 1161–1177, 1986.
Vanier M.T., Holm M., Ohman R., Svennerholm L.:Developmental profiles of gangliosides in human and rat brain. J. Neurochem., 18: 581–592, 1971.
Volpe J.J.:Neurology of the Newborn. W.B. Saunders: Philadelphia, 1987.
Volpe J.J.:Neonatal seizures. Pediatrics, 84: 422–428, 1989.
Wang C., Jensen F.E.:Increased seizure susceptibility to low magnesium and hypoxia in immature hippocampal slices in suppressed by APV, a NMDA receptor antagonist. Soviety for Neuroscience Abstracts, 20: 396, 1994 (Abs.).
Wasterlain C.G., Hattori H., Yang C., Schwartz P.H., Rujikawa D.G., Morin A.M., Dwyer B.E.:Selective vulnerability of neuronal subpopulations during ontogeny reflects discrete molecular events associated with normal brain development. In: C.G. Wasterlain and P. Vert. (Eds.) Neonatal Seizures, Raven Press: New York, 1991.