Advertisement

Journal of Molecular Neuroscience

, Volume 25, Issue 3, pp 275–284 | Cite as

Endogenous neuropeptide Y prevents recurrence of experimental febrile seizures by increasing seizure threshold

  • Céline Dubé
  • Kristen L. Brunson
  • Mariam Eghbal-Ahmadi
  • Rebeca Gonzalez-Vega
  • Tallie Z. Baram
Original Article

Abstract

Febrile seizures (FSs) typically occur at the onset of fever and do not recur within the same febrile episode despite enduring or increased hyperthermia. Recurrent seizures during the same febrile episode are considered “complex,” with potentially altered prognosis. A characterized immature rat model of FS was used to test the hypotheses that (1) a first FS influences the threshold temperature for subsequent ones, and (2) the underlying mechanisms involve the release and actions of the endogenous inhibitory hippocampal neuropeptide Y (NPY). Experimental FSs were induced two or three times, at 3- to 4-h intervals, and threshold temperatures measured. To determine the potential effects of seizure-induced endogenous NPY on thresholds for subsequent seizures, an antagonist of the major hippocampal NPY receptor (type 2) was infused prior to induction of the second seizure. As an indicator of NPY release, NPY expression was determined 4 and 24 h later. Threshold core and brain temperatures for hyperthermic seizures were consistent with those observed during human fever. Threshold temperatures for a second and third seizure were significantly and progressively higher than those required for the first. This “protective” effect involved induction of endogenous NPY because it was abolished by the NPY antagonist. In addition, NPY mRNA expression was increased in dentate gyrus, CA3 and CA1, after an experimental FS, consistent with peptide release. Collectively these data indicate that the absence of repetitive seizures during a febrile episode involves the inhibitory actions of endogenous NPY, suggesting that the signaling cascade triggered by this peptide might provide targets for therapeutic intervention.

Index Entries

Seizures fever febrile neuropeptide NPY hippocampus animal model rat immature 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Aldenhoff J. B., Gruol D. L., Rivier J., Vale W., and Siggins G. R. (1983) Corticotropin releasing factor decreases postburst hyperpolarizations and excites hippocampal neurons. Science 221, 875–877.PubMedCrossRefGoogle Scholar
  2. American Academy of Pediatrics: Committee on Quality Improvement, Subcommittee on Febrile Seizures. (1999) Practice parameter: long-term treatment of the child with simple febrile seizures. Pediatrics 103, 1307–1309.CrossRefGoogle Scholar
  3. Annegers J. F., Hauser W. A., Shirts S. B., and Kurland L. T. (1987) Factors prognostic of unprovoked seizures after febrile convulsions. N. Engl. J. Med. 316, 493–498.PubMedCrossRefGoogle Scholar
  4. Baram T. Z. (2002) Animal models for febrile seizures, in Febrile Seizures, Baram, T. Z., and Shinnar, S., eds., Academic Press, San Diego, CA, pp. 189–203.Google Scholar
  5. Baram T. Z. and Hatalski C. G. (1998) Neuropeptide-mediated excitability: a key triggering mechanism for seizure generation in the developing brain. Trends Neurosci. 21, 471–476.PubMedCrossRefGoogle Scholar
  6. Baram T. Z., Hirsch E., Snead O. C. III, and Schultz L. (1992) Corticotropin-releasing hormone-induced seizures in infant rats originate in the amygdala. Ann. Neurol. 31, 488–494.PubMedCrossRefGoogle Scholar
  7. Bender R. A., Dubé C., Gonzalez-Vega R., Mina E. W., and Baram T. Z. (2003) Mossy fiber plasticity and enhanced hippocampal excitability, without hippocampal cell loss or altered neurogenesis, in an animal model of prolonged febrile seizures. Hippocampus 13, 399–412.PubMedCrossRefGoogle Scholar
  8. Berg A. T. (2002) Recurrent febrile seizures, in Febrile Seizures, Baram, T. Z., and Shinnar, S., eds., Academic Press, San Diego, CA, pp. 37–52.Google Scholar
  9. Berg A. and Shinnar S. (1996a) Unprovoked seizures in children with febrile seizures: short-term outcome. Neurology 47, 562–568.PubMedGoogle Scholar
  10. Berg A. T. and Shinnar S. (1996b) Complex febrile seizures. Epilepsia 37, 126–133.PubMedCrossRefGoogle Scholar
  11. Berg A. T., Shinnar S., Hauser W. A., Alemany M., Shapiro E. D., Salomon M. E., and Crain E. F. (1992) A prospective study of recurrent febrile seizures. N. Engl. J. Med. 327, 1122–1127.PubMedCrossRefGoogle Scholar
  12. Brunson K. L., Eghbal-Ahmadi M., Bender R., Chen Y., and Baram T. Z. (2001) Long-term, progressive hippocampal cell loss and dysfunction induced by early-life administration of corticotropin-releasing hormone reproduce the effects of early-life stress. Proc. Natl. Acad. Sci. U. S. A. 98, 8856–8861.PubMedCrossRefGoogle Scholar
  13. Chen Y., Bender R., Frotscher M., and Baram T. Z. (2001) Novel and transient populations of corticotropin-releasing hormone-expressing neurons in developing hippocampus suggest unique functional roles: a quantitative spatiotemporal analysis. J. Neurosci. 21, 7171–7181.PubMedGoogle Scholar
  14. Colbourne F., Nurse S. M., and Corbett D. (1993) Spontaneous postischemic hyperthermia is not required for severe CA1 ischemic damage in gerbils. Brain Res. 623, 1–5.PubMedCrossRefGoogle Scholar
  15. Deller T. and Leranth C. (1990) Synaptic connections of neuropeptide Y (NPY) immunoreactive neurons in the hilar area of the rat hippocampus. J. Comp. Neurol. 300, 433–447.PubMedCrossRefGoogle Scholar
  16. Dubé C., Chen K., Eghbal-Ahmadi M., Brunson K., Soltesz I., and Baram T. Z. (2000) Prolonged febrile seizures in immature rat model enhance hippocampal excitability long-term. Ann. Neurol. 47, 336–344.PubMedCrossRefGoogle Scholar
  17. Eghbal-Ahmadi M., Avishai-Eliner S., Hatalski C. G., and Baram T. Z. (1999) Differential regulation of the expression of corticotropin-releasing factor receptor type 2 (CRF2) in hypothalamus and amygdala of the immature rat by sensory input and food intake. J. Neurosci. 19, 3982–3991.PubMedGoogle Scholar
  18. El Bahh B., Cao J. Q., Beck-Sickinger A. G., and Colmers W. F. (2002) Blockade of neuropeptide Y(2) receptors and suppression of NPY’s anti-epileptic actions in the rat hippocampal slice by BIIE0246. Br. J. Pharmacol. 136, 502–509.PubMedCrossRefGoogle Scholar
  19. Gruber B., Greber S., Rupp E., and Sperk G. (1994) Differential NPY mRNA expression in granule cells and interneurons of the rat dentate gyrus after kainic acid injection. Hippocampus 4, 474–482.PubMedCrossRefGoogle Scholar
  20. Hatalski C. G., Brunson K.L., Tantayanubutr B., Chen Y., and Baram T. Z. (2000) Neuronal activity and stress differentially regulate hippocampal and hypothalamic corticotropin-releasing hormone expression in the immature rat. Neuroscience 101, 571–580.PubMedCrossRefGoogle Scholar
  21. Henker R. A., Brown S. D., and Marion D. W. (1998) Comparison of brain temperature with bladder and rectal temperatures in adults with severe head injury. Neurosurgery 42, 1071–1075.PubMedCrossRefGoogle Scholar
  22. Hokfelt T., Broberger C., Xu Z. Q., Sergeyev V., Ubink R., and Diez M. (2000) Neuropeptides—an overview. Neuropharmacology 39, 1337–1356.PubMedCrossRefGoogle Scholar
  23. Hollrigel G. S., Chen K., Baram T. Z., and Soltesz I. (1998) The pro-convulsant actions of corticotropin-releasing hormone in the hippocampus of infant rats. Neuroscience 84, 71–79.PubMedCrossRefGoogle Scholar
  24. International League Against Epilepsy: Commission on Classification and Terminology. (1981) Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 33, 661–666.Google Scholar
  25. Klapstein G. J. and Colmers W. F. (1993) On the sites of presynaptic inhibition by neuropeptide Y in rat hippocampus in vitro. Hippocampus 3, 103–111.PubMedCrossRefGoogle Scholar
  26. Kohler C., Eriksson L., Davies S., and Chan-Palay V. (1986) Neuropeptide Y innervation of the hippocampal region in the rat and monkey brain. J. Comp. Neurol. 244, 384–400.PubMedCrossRefGoogle Scholar
  27. Malmstrom R. E. (2001) Vascular pharmacology of BIIE0246, the first selective non-peptide neuropeptide YY(2) receptor antagonist, in vivo. Br. J. Pharmacol. 133, 1073–1080.PubMedCrossRefGoogle Scholar
  28. Merali Z., McIntosh J., Kent P., Michaud D., and Anisman H. (1998) Aversive and appetitive events evoke the release of corticotropin-releasing hormone and bombesin-like peptides at the central nucleus of the amygdala. J. Neurosci. 18, 4758–4766.PubMedGoogle Scholar
  29. Nelson K. B. and Ellenberg J. H. (1981) Febrile seizures, Raven Press, New York.Google Scholar
  30. Offringa M., Bossuyt P. M., Lubsen J., Ellenberg J. H., Nelson K. B., Knudsen F. U., et al. (1994) Risk factors for seizure recurrence in children with febrile seizures: a pooled analysis of individual patient data from five studies. J. Pediatr. 124, 574–584.PubMedCrossRefGoogle Scholar
  31. Richichi C., Lin E. J., Stefanin D., Colella D., Ravizza T., Grignaschi G., et al. (2004) Anticonvulsant and antiepileptogenic effects mediated by adeno-associated virus vector neuropeptide Y expression in the rat hippocampus. J. Neurosci. 24, 3051–3059.PubMedCrossRefGoogle Scholar
  32. Schwab S., Spranger M., Aschof A., Steiner T., and Hacke W. (1997) Brain temperature monitoring and modulation in patients with severe MCA infarction. Neurology 48, 762–767.PubMedGoogle Scholar
  33. Schwarzer C., Kofler N., and Sperk G. (1998) Up-regulation of neuropeptide Y-Y2 receptors in an animal model of temporal lobe epilepsy. Mol. Pharmacol. 53, 6–13.PubMedGoogle Scholar
  34. Sherwood N. M. and Timiras P.S. (1970) A Stereotaxic Atlas of the Developing Rat Brain, University of California Press Berkeley, CA.Google Scholar
  35. Stafstrom C. E. (2002) The incidence and prevalence of febrile seizures, in Febrile Seizures, Baram, T.Z., and Shinnar, S., eds., Academic Press, San Diego, CA, pp. 1–21.Google Scholar
  36. Toth Z., Yan X. X., Haftoglou S., Ribak C. E., and Baram T. Z. (1998) Seizure-induced neuronal injury: vulnerability to febrile seizures in an immature rat model. J. Neurosci. 18, 4285–4294.PubMedGoogle Scholar
  37. Verity C. M. and Golding J. (1991) Risk of epilepsy after febrile convulsions: a national cohort study. Br. Med. J. 303, 1373–1376.CrossRefGoogle Scholar
  38. Vezzani A. and Sperk G. (2004) Overexpression of NPY and Y2 receptors in epileptic brain tissue: an endogenous neuroprotective mechanism in temporal lobe epilepsy? Neuropeptides 38, 245–252.PubMedCrossRefGoogle Scholar
  39. Vezzani A., Schwarzer C., Lothman E. W., Williamson J., and Sperk G. (1996) Functional changes in somatostatin and neuropeptide Y containing neurons in the rat hippocampus in chronic models of limbic seizures. Epilepsy Res. 26, 267–279.PubMedCrossRefGoogle Scholar
  40. Woldbye D. P., Larsen P. J., Mikkelsen J. D., Klemp K., Madsen T. M., and Boldwig T. G. (1997) Inhibition of kainic acid seizures by neuropeptide Y via Y5-like receptors. Nat. Med. 3, 761–764.PubMedCrossRefGoogle Scholar
  41. Woldbye D. P., Madsen T. M., Larsen P. J., Mikkelsen J. D., and Bolwig T. G. (1996) Neuropeptide Y inhibits hippocampal seizures and wet dog shakes. Brain Res. 737, 162–168.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2005

Authors and Affiliations

  • Céline Dubé
    • 1
  • Kristen L. Brunson
    • 1
  • Mariam Eghbal-Ahmadi
    • 2
  • Rebeca Gonzalez-Vega
    • 1
  • Tallie Z. Baram
    • 1
    • 2
  1. 1.Department of Anatomy and NeurobiologyUniversity of California at IrvineIrvine
  2. 2.Department of PediatricsUniversity of California at IrvineIrvine

Personalised recommendations