Systemic dexamethasone administration increases septal Trk autophosphorylation in adult rats via an induction of nerve growth factor.
Nerve growth factor (NGF) maintains cholinergic neurons in various animals models of neurodegeneration and is thus a potential treatment for certain neurodegenerative disorders such as Alzheimer's disease. Because NGF does not cross the blood-brain barrier, we have proposed elevating endogenous levels of NGF in the central nervous system with small molecules that induce NGF expression, as an alternative strategy. The present studies were conducted to determine whether pharmacologically elevated levels of NGF are sufficient to cause subsequent stimulation of its high affinity receptor, as measured by increased levels of Trk phosphorylation. Dexamethasone (0.5-20 mg/kg, intraperitoneally) caused a time- and dose-dependent increase in NGF mRNA and NGF protein in the hippocampus and septum of adult male Sprague-Dawley rats. Exogenously administered NGF (1 microgram, intracerebroventricularly) led to a rapid (30 min) and transient increase in Trk phosphorylation in the septum, which has high levels of NGF-specific TrkA. Similarly, dexamethasone led to an increase in Trk phosphorylation only within the septum. Dexamethasone-mediated Trk phosphorylation was dose and time dependent, with peak increases being observed 12 hr after injection, concurrently with peak increases in NGF protein. These data demonstrate an increase in activation of the high affinity NGF receptor with a compound that elevates levels of NGF in the central nervous system, and they support the strategy of discovering a pharmacological agent that induces NGF as a method for treating neurodegenerative disorders.
Saporito
M S
MS
Cephalon Inc., West Chester, Pennsylvania 19380.
Brown
E R
ER
Hartpence
K C
KC
Wilcox
H M
HM
Robbins
E
E
Vaught
J L
JL
Carswell
S
S
D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D009414:Nerve Growth Factors / Q000096:biosynthesis* / Q000235:genetics; D015513:Oncogene Proteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D009414:Nerve Growth Factors; D015513:Oncogene Proteins; D012333:RNA, Messenger; C065400:oncogene protein trk; D003907:Dexamethasone