Skip to main content
Log in

A new concept in the pharmacology of neuroprotection

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

Vasoactive intestinal peptide (VIP), originally discovered in the intestine as a peptide of 28 amino acids, was later found to be a major brain peptide having neuroprotective activities. To exert neuroprotective activity, VIP requires glial cells secreting neuroprotective proteins. Activity-dependent neurotrophic factor (ADNF) is a recently isolated factor secreted by glial cells under the action of VIP. This protein, isolated by sequential chromatographic methods, was named activity-dependent neurotrophic factor since it protected neurons from death associated with blockade of electrical activity. A fourteen-amino-acid fragment of ADNF (ADNF-14) and the more potent, nine-amino-acid derivative (ADNF-9), exhibit activity that surpasses that of the parent protein with regard to potency and a broader range of effective concentration. Furthermore, the peptides exhibit protective activity in Alzheimer’s disease-related systems (e.g., β-amyloid toxicity and apolipoprotein E deficiencies, genes that have been associated with Alzheimer’s disease onset and progression). ADNP is another glial mediator of VIP-associated neuroprotection. NAP, an eight-amino-acid peptide derived from ADNP (sharing structural and functional similarities with ADNF-9), was identified as the most potent neuroprotectant described to-date in an animal model of apolipoprotein E-deficiency (knock-out mice). These femtomolar-acting peptides form a basis for a new concept in pharmacology: femtomolar neuroprotection.

This is a preview of subscription content, log in via an institution to check access.

Access this article

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

  • Agoston D. V., Eiden L. E., Brenneman D. E., and Gozes I. (1991) Spontaneous electrical activity regulates vasoactive intestinal peptide expression in dissociated spinal cord cell cultures. Mol. Brain Res. 10, 235–240.

    Article  PubMed  CAS  Google Scholar 

  • Andersson H., Wetmore C., Lindqvist E., Luthman J., and Olson L. (1997) Trimethyltin exposure in the rat induces delayed changes in brain-derived neurotrophic factor, fos and heat shock protein 70. Neurotoxicology 18, 147–159.

    PubMed  CAS  Google Scholar 

  • Arimura A., Somogyvari-Vigh A., Weill C., Fiore R. C., Tatsuno I., Bay V., and Brenneman D. E. (1994) PACAP functions as a neurotrophic factor. Ann. NY Acad. Sci. 739, 228–243

    Article  PubMed  CAS  Google Scholar 

  • Ashur-Fabian O., Giladi E., Brenneman D. E., and Gozes I. (1997) Identification of VIP/PACAP receptors on astrocytes using antisense oligodeoxynucleotides. J. Mol. Neurosci. 9, 211–222.

    PubMed  CAS  Google Scholar 

  • Bassan M., Zamostiano R., Davidson A., Wollman Y., Pitman J., Hauser J., et al. (1998) The identification of secreted heat shock 60 (hsp60)-like protein from rat glial cells and a human neuroblastoma cell line. Neurosci. Lett. 250, 37–40.

    Article  PubMed  CAS  Google Scholar 

  • Bassan M., Zamostiano R., Davidson A., Pinhasov A., Giladi E., Perl O., et al. (1999) Complete sequence of a novel protein containing a femtomolar-activity-dependent neuroprotective peptide. J. Neurochem. 72, 1283–1293.

    Article  PubMed  CAS  Google Scholar 

  • Brenneman D. E. and Gozes I. (1996) A femtomolar-acting neuroprotective peptide. J. Clin. Invest. 97, 2299–2307.

    Google Scholar 

  • Brenneman D. E., Hill J. M., and Gozes I. (1998a) Vasoactive intestinal peptide in the central nervous system, Chapter 57, in Psychopharmacology on CD ROM (Watson, S. J., ed.), Lippincott Williams & Wilkins, Baltimore, MD.

    Google Scholar 

  • Brenneman D. E., Hauser J., Neale E., Rubinraut S., Fridkin M., Davidson A., and Gozes I. (1998b) Activity-dependent neurotrophic factor: structure-activity relationships of femtomolar-acting peptides. J. Pharmacol. Exp. Ther. 285, 619–627.

    PubMed  CAS  Google Scholar 

  • Dibbern D. A., Glazner G. W., Gozes I., Brenneman D. E., and Hill J. M. (1997) Inhibition of murine embryonic growth by human immunodeficiency virus envelope protein and its prevention by vasoactive intestinal peptide and activity-dependent neurotrophic factor. J. Clin. Invest. 99, 2837–2841.

    PubMed  CAS  Google Scholar 

  • Festoff B. W., Nelson P. G., Brenneman D. E. (1996) Prevention of activity-dependent neuronal death: vasoactive intestinal polypeptide stimulates astrocytes to secrete the thrombin-inhibiting neurotrophic serpin, protease nexin I. J. Neurobiol. 30, 255–266.

    Article  Google Scholar 

  • Ghosh A., Carnahan J., and Greenberg M. E. (1994) Requirement for BDNF in activity-dependent survival of cortical neurons. Science 263, 1618–1623.

    Article  PubMed  CAS  Google Scholar 

  • Gozes I. and Brenneman D. E. (1989) VIP molecular biology and neurobiological function. Mol. Neurobiol. 3, 201–236.

    PubMed  CAS  Google Scholar 

  • Gozes I. and Brenneman D. E. (1996) Activity-dependent neurotrophic factor (ADNF): an extracellular neuroprotective chaperonin? J. Mol. Neurosci. 7, 235–244.

    Google Scholar 

  • Gozes I., Davidson A., Gozes Y., Mascolo R., Barth R., Warren D., et al. (1997a) Antiserum to activity-dependent neurotrophic factor produces neuronal cell death in CNS cultures: immunological and biological specificity. Dev. Brain Res. 99, 167–175.

    Article  CAS  Google Scholar 

  • Gozes I., Bachar M., Bardea A., Davidson A., Rubinraut S., Fridkin M., and Giladi E. (1997b) Protection against developmental retardation in apolipoprotein E-deficient mice by a fatty neuropeptide: implication for early treatment of Alzheimers disease. J. Neurobiol. 33, 329–342.

    Article  PubMed  CAS  Google Scholar 

  • Gozes I., Perl O., Giladi E., Davidson A., Ashur-Fabian O., Rubinraut S., and Fridkin M. (1999) Mapping the active site in vasoactive intestinal peptide to a core of four amino acids: neuroprotective drug design. Proc. Natl. Acad. Sci. USA 96, 4143–4148.

    Article  PubMed  CAS  Google Scholar 

  • Gressens P., Marret S., Hill J. M., Brenneman D. E., Gozes I., Fridkin M., and Evrard P. (1997) Vasoactive intestinal peptide prevents excitotoxic cell death in the murine developing brain. J. Clin. Invest. 100, 390–397.

    PubMed  CAS  Google Scholar 

  • Guo Q., Sebastian L., Sopher B. L., Miller M. W., Glazner G. W., Ware C. B., et al. (1999) Neurotrophic factors [activity-dependent neurotrophic factor (ADNF) and basic fibroblast growth factor (bFGF)] interrupt excitotoxic neurodegenerative cascades promoted by a PS1 mutation. Proc. Natl. Acad. Sci. USA 96, 4125–4130.

    Article  PubMed  CAS  Google Scholar 

  • Harmar A. J., Arimura A., Gozes I., Journot L., Laburthe M., Pisegna J. R., et al. (1998) International Union of Pharmacology XVIII. Nomenclature of receptors for vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating polypeptide (PACAP). Pharmacol. Rev. 50, 265–270.

    PubMed  CAS  Google Scholar 

  • Hashimoto H., Nogi H., Mori K., Ohishi H., Shigemoto R., Yamamoto K., et al. (1996) Distribution of the mRNA for a pituitary adenylate cyclase-activating polypeptide receptor in the rat brain: an in situ hybridization study. J. Comp. Neurol. 371, 567–577.

    Article  Google Scholar 

  • Hashimoto H., Ogawa N., Hagihara N., Yamamoto K., Imanishi K., Nogi H., et al. (1997) Vasoactive intestinal polypeptide and pituitary adenylate cyclase-activating polypeptide receptor chimeras reveal domains that determine specificity of vasoactive intestinal polypeptide binding and activation. Mol. Pharmacol. 52, 128–135.

    PubMed  CAS  Google Scholar 

  • Khan I., Wallin R., Gupta R. S., and Kammer G. M. (1998) Protein kinase A-catalyzed phosphorylation of heat shock protein 60 chaperone regulates its attachment to histone 2B in the T lymphocyte plasma membrane. Proc. Natl. Acad. Sci. USA 95, 10,425–10,430.

    CAS  Google Scholar 

  • Krajnak K., Kashon M. L., Rosewell K. L., and Wise P. M. (1998) Aging alters the rhythmic expression of vasoactive intestinal polypeptide mRNA but not arginine vasopressin mRNA in the suprachiasmatic nuclei of female rats. J. Neurosci. 18, 4767–4774.

    PubMed  CAS  Google Scholar 

  • Krieglstein K., Henheik P., Farkas L., Jaszai J., Galter D., Krohn K., and Unsicker K. (1998) Glial cell line-derived neurotrophic factor requires transforming growth factor-beta for exerting its full neurotrophic potential on peripheral and CNS neurons. J. Neurosci. 18, 9822–9834.

    PubMed  CAS  Google Scholar 

  • Levi-Montalcini R., Caramia F., and Angeletti P. U. (1969) Alterations in the fine structure of nucleoli in sympathetic neurons following NGF-antiserum treatment. Brain Res. 12, 54–73.

    Article  PubMed  CAS  Google Scholar 

  • Maimone D., Cioni C., Rosa S., Macchia G., Aloisi F., and Annunziata P. (1993) Norepinephrine and vasoactive intestinal peptide induce IL-6 secretion by astrocytes: synergism with IL-1 beta and TNF alpha. J. Neuroimmunol. 47, 73–82.

    Article  PubMed  CAS  Google Scholar 

  • Mohney R. P. and Zigmond R. E. (1998) Vasoactive intestinal peptide enhances its own expression in sympathetic neurons after injury. J. Neurosci. 18, 5285–5293.

    PubMed  CAS  Google Scholar 

  • Paspalas C. D. and Papadopoulos G. C. (1998) Ultrastructural evidence for combined action of noradrenaline and vasoactive intestinal polypeptide upon neurons, astrocytes, and blood vessels of the rat cerebral cortex. Brain Res. Bull. 45, 247–259.

    Article  PubMed  CAS  Google Scholar 

  • Pellegri G., Magistretti P. J., and Martin J. L. (1998) VIP and PACAP potentiate the action of glutamate on BDNF expression in mouse cortical neurones. Eur. J. Neurosci. 10, 272–280.

    Article  PubMed  CAS  Google Scholar 

  • Said S. I. (1996) Molecules that protect: the defense of neurons and other cells. J. Clin. Invest. 97, 2163–2164.

    Article  Google Scholar 

  • Said S. I. and Mutt V. (1972) Isolation from porcine intestinal wall of a vasoactive octacoaspeptide related to secretin and to glucagon. Eur. J. Biochem. 28, 199–204.

    Article  PubMed  CAS  Google Scholar 

  • Servidei T., Aoki Y., Lewis S. E., Symes A., Fink J. S., and Reeves S. A. (1998) Coordinate regulation of STAT signaling and c-fos expression by the tyrosine phosphatase SHP-2. J. Biol. Chem. 273, 6233–6241.

    Article  PubMed  CAS  Google Scholar 

  • Shen K. F. and Crain S. M. (1992) Chronic selective activation of excitatory opioid receptor functions in sensory neurons results in opioid ‘dependence’ without tolerance. Brain Res. 597, 74–83.

    Article  PubMed  CAS  Google Scholar 

  • Zafra F., Hengerer B., Leibrock J., Thoenen H., and 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.

    PubMed  CAS  Google Scholar 

  • Zamostiano R., Pinhasov A., Bassan M., Perl O., Steingart R. A., Atlas R., et al. (1999) A femtomolaracting neuroprotective peptide induces increased levels of heat shock protein 60 in rat cortical neurons: a potential neuroprotective mechanism. Neurosci. Lett. 264, 9–12.

    Article  PubMed  CAS  Google Scholar 

  • Zupan V., Hill J. M., Brenneman D. E., Gozes I., Fridkin M., Robberecht P., et al. (1998) Involvement of pituitary adenylate cyclase-activating polypeptide II vasoactive intestinal peptide 2 receptor in mouse neocortical astrocytogenesis. J. Neurochem. 70, 2165–2173.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Illana Gozes.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gozes, I., Brenneman, D.E. A new concept in the pharmacology of neuroprotection. J Mol Neurosci 14, 61–68 (2000). https://doi.org/10.1385/JMN:14:1-2:061

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1385/JMN:14:1-2:061

Index Entries

Navigation