Nicotine increases the expression of neurotrophin receptor tyrosine kinase receptor A in basal forebrain cholinergic neurons.
In this study, we investigated whether the potential positive effects of nicotine in Alzheimer's disease (AD) may involve neurotrophic factors, such as nerve growth factor (NGF), closely associated with basal forebrain (BF) cholinergic function and survival. To this aim, we studied the effects of prolonged nicotine treatment on neurotrophin receptors expression and on NGF protein levels in the rat BF cholinergic circuitry. Both in vivo and in vitro experiments were conducted. We found that s.c. nicotine infusion (1.2 mg free base/kg/d delivered by mini-pumps for 7 days) induced in vivo an increase in tyrosine kinase receptor A (TrkA)-but not TrkB, TrkC or low affinity neurotrophin receptor p75 (p75)-expression in BF cholinergic neurons targeting the cerebral cortex. Nicotine did not produce statistically significant long-lasting effects on NGF levels in the cerebral cortex, or in the BF. In vitro experiments performed on primary BF neuronal cultures, showed that 72 h exposure to nicotine increased both TrkA expression, and NGF release in culture medium. Neutralization experiments with an anti-NGF antibody showed that NGF presence was not necessary for nicotine-induced increase of TrkA levels in cultured cholinergic neurons, suggesting that nicotine may act through NGF-independent mechanisms. This study shows that nicotine, independently of its action on NGF levels, may contribute to the restoration of the trophic support to BF cholinergic neurons by increasing TrkA levels.
Formaggio
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E
Department of Medicine and Public Health, Section of Pharmacology, University of Verona, Policlinico GB Rossi, 37134 Verona, Italy. elena.formaggio@gmail.com
Fazzini
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F
Dalfini
A C
AC
Di Chio
M
M
Cantù
C
C
Decimo
I
I
Fiorini
Z
Z
Fumagalli
G
G
Chiamulera
C
C
D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002452:Cell Count; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D007091:Image Processing, Computer-Assisted; D008297:Male; D018613:Microscopy, Confocal; D009415:Nerve Net / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology*; D016548:Prosencephalon / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020917:Receptor, trkA / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D009538:Nicotine; D020917:Receptor, trkA; D000109:Acetylcholine