We have previously reported that the alpha2-adrenoceptor antagonist
dexefaroxan protects against the degeneration of nucleus basalis magnocellularis (NbM) cholinergic neurons following cortical devascularization in the adult rat. Since
nerve growth factor (
NGF) is critical to the survival of NbM cholinergic neurons in the adult brain and its synthesis is known to be regulated by noradrenergic mechanisms, we examined whether the protective effect of
dexefaroxan in the devascularization model was associated with regional induction of
NGF biosynthesis.
Dexefaroxan or vehicle was administered to rats via subcutaneous minipumps for 28 days following devascularization or
sham operation procedures. In vehicle-treated devascularized rats,
NGF protein levels in the cortex were increased at 5 days but had normalized by 2 weeks postoperation;
NGF levels in NbM remained unchanged during this time. In
dexefaroxan-treated devascularized rats, increases in
NGF protein levels (2-fold) and immunoreactivity were maintained in both the cortex and NbM over the entire 28-day postoperation period; these increases were coincident with changes in functional markers characteristic of
NGF's actions, including increases in
choline acetyltransferase (ChAT), p75 and TrkA immunoreactivities, and a preservation of NbM
cholinergic cell numbers.
Dexefaroxan also increased
NGF protein levels in
sham-operated rats, but without any significant consequence to the otherwise normal NbM
cholinergic phenotype in these animals. Results indicate that activation of endogenous
NGF systems could contribute to the
cholinergic protective effect of
dexefaroxan in the cortical devascularization model, and provide further support for a potential therapeutic utility of
dexefaroxan in
neurodegenerative diseases where central
cholinergic function is progressively compromised.