Pituitary adenylate cyclase activating polypeptide : Expression and neurotrophic activity in the rat brain

University dissertation from Uppsala : Acta Universitatis Upsaliensis

Abstract: Neurotrophic factors play an important role in regulating naturally occurring cell death during neurogenesis. In addition to classical neurotrophic factors, some neurotransmitters and neuropeptides have been shown to exhibit neurotrophic activities. PACAP is a neuropeptide, structurally belonging to the secretin/glucagon/VIP family and one of the most potent activators of adenylate cyclase.This thesis establishes the occurrence and neurotrophic potential of pituitary adenylate cyclaseactivating polypeptide (PACAP) during early CNS and PNS development and after certain injuries to adultrat brain.Employing radioactive in situ hybridisation techniques, PACAP and its high-affinity receptorPRI were shown to be expressed differentially in distinct parts of the embryonic rat brain from E13,suggesting an important function for this peptide during brain development.The functional role of PACAP during neuronal development was investigated, employingembryonic rat cultures. PACAP promoted the survival of mesencephalic dopaminergic neurons to thesame extent as GDNF and increased the number of tyrosine hydroxylase (TH)-immunoreactive neurons,elevated TH protein and enhanced tritiated dopamine uptake in these cultures. Likewise, PACAP protectedthe dopaminergic neurons against 6-OH dopamine toxicity. On embryonic GABAergic neurons, PACAPacted neuromodulatory but had no effect on overall survival. In dissociated cultures of DRG neurons,PACAP's effect on survival was comparable to that of NGF. PACAP furthermore induced calcitoningene-related peptide (CGRP) in DRG explants. These results indicate that PACAP acts as a neurotrophicfactor for developing neurons.Finally, in the adult rat, steady state mRNA levels of PACAP and PRI were altered after injuryin conjunction with neuronal cell death. Intraventricular kainic acid treatment showed the neuropeptide tobe rapidly regulated by exitotoxic mechanisms, whereas traumatic brain injury (TBI) induction wasslower. Pretreatement of the rats with a free radical spin trap, showed the involvement of free radicals inthe regulation of PACAP and PRI mRNA after TBI.

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