Cholecystokinin-8 protects central cholinergic neurons against fimbria-fornix lesion through the up-regulation of nerve growth factor synthesis.
In this study, we demonstrate that cholecystokinin-8 (CCK-8) induces an increase in both nerve growth factor (NGF) protein and NGF mRNA in mouse cortex and hippocampus when i.p. injected at physiological doses. By using fimbria-fornix-lesioned mice, we have also demonstrated that repeated CCK-8 i.p. injections result in recovery of lesion-induced NGF deficit in septum and restore the baseline NGF levels in hippocampus and cortex. Parallel to the effects on NGF, CCK-8 increases choline acetyltransferase (Chat) activity in forebrain when injected in unlesioned mice and counteract the septo-hippocampal Chat alterations in fimbria-fornix-lesioned mice. To assess the NGF involvement in the mechanism by which CCK-8 induces brain Chat, NGF antibody was administrated intracerebrally to saline- and CCK-8-injected mice. We observe that pretreatment with NGF antibody causes a marked reduction of NGF and Chat activity in septum and hippocampus of both saline- and CCK-8-injected mice. This evidence indicates that the CCK-8 effects on cholinergic cells are mediated through the synthesis and release of NGF. Taken together, our results suggest that peripheral administration of CCK-8 may represent a potential experimental model for investigating the effects of endogenous NGF up-regulation on diseases associated with altered brain cholinergic functions.
Tirassa
P
P
Institute of Neurobiology Consiglio Nazionale delle Ricerche, 00137 Rome, Italy.
Aloe
L
L
Stenfors
C
C
Turrini
P
P
Lundeberg
T
T
D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D009414:Nerve Growth Factors / Q000235:genetics*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018696:Neuroprotective Agents; D014176:Protein Biosynthesis / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D012844:Sincalide / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects
D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D002795:Choline O-Acetyltransferase; D012844:Sincalide