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I Gozes

Publications and source records attributed to I Gozes.

146 records · Page 9Linked to original sources
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Interleukin-1 alpha and vasoactive intestinal peptide: enigmatic regulation of neuronal survival.

A neurotrophic role for interleukin-1 alpha (IL-1 alpha) was investigated in dissociated spinal cord-dorsal root ganglion cultures. Three observations suggested a survival-promoting action for IL-1 alpha in nine-day-old cultures: (1) neutralizing antiserum to murine IL-1 alpha decreased neuronal survival; (2) treatment with IL-1 alpha in electrically blocked cultures increased neuronal survival; and (3) antiserum to the type I IL-1 receptor decreased neuronal survival. Treatment with VIP prevented neuronal cell death associated with the antiserum to IL-1 alpha. In contrast, treatment of one-month-old cultures with IL-1 alpha produced neuronal cell death and neutralizing antiserum to the IL-1 receptor had no effect on neuronal survival in these cultures. These experiments suggested that an IL-1-like substance was necessary for neuronal survival during a specific stage in development and that a relationship between VIP and IL-1 alpha might account in part for the neurotrophic properties of VIP. To test if VIP might be a secretagogue for IL-1, a neuron-free model system was utilized: astroglial cultures derived from cerebral cortex. VIP treatment produced a concentration-dependent (EC50: 50 pM) increase in the amount of IL-1 alpha in the medium and a decrease in cellular IL-1 alpha. Interleukin-1 beta (IL-1 beta) was also increased (EC 50: 1 nM) in the medium by VIP but without depleting IL-1 beta in the cytosol. Semi-quantitative measurements of the IL-1 alpha mRNA after VIP treatment indicated a significant but transient decrease. These data indicate that VIP produced an increase in the secretion of IL-1 alpha while depleting IL-1 alpha mRNA.

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A new concept in the pharmacology of neuroprotection.

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., beta-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.

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