It has been hypothesized [Colpaert, F.C., 1994. In: Briley, M., Marien, M. (Eds.), Noradrenergic Mechanisms in
Parkinson's Disease. CRC Press, Boca Raton, FL, pp. 225-254] that a deficiency in the noradrenergic system originating from the locus coeruleus is a decisive factor in the progression of central
neurodegenerative disorders including
Alzheimer's disease, and that treatments which boost noradrenergic transmission (e.g. via blockade of alpha(2)-
adrenoceptors) could provide both symptomatic and trophic benefits against the disease. Studies in the rat in vivo demonstrating that the selective alpha(2)-adrenoceptor antagonist
dexefaroxan increases
acetylcholine release in the cortex, improves measures of cognitive performance and protects against
excitotoxin lesions, support this concept. As a further test of the hypothesis, we investigated the effect of
dexefaroxan in a rat model of unilateral cortical devascularization that induces a loss of the cortical
cholinergic terminal network and a
retrograde degeneration of the
cholinergic projections that originate in the nucleus basalis magnocellularis. Lesioned and
sham-operated rats received a 28-day
subcutaneous infusion of
dexefaroxan (0.63 mg/rat/day) or vehicle, delivered by osmotic minipumps implanted on the day of the cortical devascularization procedure. In lesioned rats, the
dexefaroxan treatment was associated with a significantly higher number and size of
vesicular acetylcholine transporter-immunoreactive boutons in comparison to the vehicle treatment; this effect was most marked within cortical layer V.
Dexefaroxan also significantly reduced the
atrophy of cholinergic neurons within the nucleus basalis magnocellularis.
Dexefaroxan had no observable effect on any of these parameters in
sham-operated cohorts. These results show that systemically administered
dexefaroxan mitigates
cholinergic neuronal degeneration in vivo, and provide further evidence for a therapeutic potential of the
drug in
neurodegenerative diseases such as
Alzheimer's disease, where central
cholinergic function is progressively compromised.