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

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 CCKA and CCKB 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 CCKA receptor antagonist blocked the CCK-induced NGF increase in the hypothalamus and pituitary. In the hippocampus the same effect was obtained with a CCKB 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.