Cholecystokinin-8 regulation of NGF concentrations in adult mouse brain through a mechanism involving CCK_A and CCK_B receptors

Abstract

1. Nerve growth factor (NGF), a powerful agent for the growth, differentiation and regeneration of lesioned cells of the central and peripheral nervous systems, has in recent years been indicated as a potential therapeutic agent capable of reversing the processes of cell damage in neurodegenerative events in man. Since NGF does not cross the blood-brain barrier and central NGF administration requires invasive surgical procedures, the discovery of substances modulating in vivo NGF synthesis in the brain will be extremely useful for a possible clinical use of NGF.

2. The aim of the present study to analyse if the content of NGF in the brain of adult mice can be affected by peripheral administration of cholecystokinin-8 (CCK-8), a well known neuropeptide which has stimulant actions on neurons in the brain and promotes a variety of neurobehavioural effects both in man and rodents.

3. The dose-response and time course effects of an i.p. injection of CCK-8 on the NGF concentrations in the hippocampus, cortex, hypothalamus and pituitary of adult male mice were analysed by use of a sensitive immunoenzymatic assay for NGF. The effects of pretreatment with selective CCK_A and CCK_B receptor antagonists and atropine on the NGF response to CCK injection were also studied.

4. The effects of CCK-8 were dose- and time-dependent and the injection of 8 nmol kg⁻¹ resulted in a 3 fold increase of NGF levels in the hypothalamus and pituitary, and about a 60% increase in the hippocampus. No effects were observed in the cortex. Pretreatment with a selective CCK_A receptor antagonist blocked the CCK-induced NGF increase in the hypothalamus and pituitary. In the hippocampus the same effect was obtained with a CCK_B receptor antagonist. Pretreatment with atropine suppressed the CCK-induced effects on NGF levels in all the brain regions examined.

5. Our results showing that i.p. injection with CCK-8 can modulate NGF levels in the brain through a mechanism which seems, in part, to be mediated via the vagal afferents, indicate that this neuropeptide may represent a useful pharmacological approach to enhance endogenous NGF levels in neuropathologies associated with a neurotrophin deficit.

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