Ms. Saporito et al., SYSTEMIC DEXAMETHASONE ADMINISTRATION INCREASES SEPTAL TRK AUTOPHOSPHORYLATION IN ADULT-RATS VIA AN INDUCTION OF NERVE GROWTH-FACTOR, Molecular pharmacology, 45(3), 1994, pp. 395-401
Nerve growth factor (NGF) maintains cholinergic neurons in various ani
mal models of neurodegeneration and is thus a potential treatment for
certain neurodegenerative disorders such as Alzheimer's disease. Becau
se NGF does not cross the bloodbrain barrier, we have proposed elevati
ng endogenous levels of NGF in the central nervous system with small m
olecules that induce NGF expression, as an alternative strategy. The p
resent studies were conducted to determine whether pharmacologically e
levated levels of NGF are sufficient to cause subsequent stimulation o
f its high affinity receptor, as measured by increased levels of Trk p
hosphorylation. Dexamethasone (0.5-20 mg/kg, intraperitoneally) caused
a time- and dose-dependent increase in NGF mRNA and NGF protein in th
e hippocampus and septum of adult male Sprague-Dawley rats. Exogenousl
y administered NGF (1 mug, intracerebroventricularly) led to a rapid (
30 min) and transient increase in Trk phosphorylation in the septum, w
hich has high levels of NGF-specific TrkA. Similarly, dexamethasone le
d to an increase in Trk phosphorylation only within the septum. Dexame
thasone-mediated Trk phosphorylation was dose and time dependent, with
peak increases being observed 12 hr after injection, concurrently wit
h peak increases in NGF protein. These data demonstrate an increase in
activation of the high affinity NGF receptor with a compound that ele
vates levels of NGF in the central nervous system, and they support th
e strategy of discovering a pharmacological agent that induces NGF as
a method for treating neurodegenerative disorders.