Rapid non-classical estradiol (E2) signaling has critical role in E2-induced neurorotective mechanisms. Estren (4-estren-3α, 17β-diol) is a selective non-classical estrogen like signaling activator with neuroprotective effects in vitro. Alzheimer`s disease (AD) is characterized by accumulation of neurotoxic beta-amyloid (Aβ) and impaired cognitive function linked to early loss of cholinergic neurons.In this study, we have examined the effects and mechanism of action of estren treatment on Aβ1-42-induced cholinergic neurotoxicity and behavioural deficit in vivo.
Evaluation of adult female wild-type mice that received unilateral Ab1-42 injection into the nucleus basalis magnocellularis complex (NBM) of the basal forebrain showed 30 % decrease in cholin-acetyltransferase (ChAT)-immunoreactive cell bodies in the NBM and acetylcholinesyterase (AChE)-stained fibers in the somatosensory cortex of the lesioned hemisphere. A single injection of 0.33 ng/g estren 1 h after Aβ1-42 administration did not have an effect on cholinergic cell loss in the NBM, but it restored the ipsilateral cholinergic fiber density in the somatosensory cortex. Mice that received bilateral injection of Aβ1-42 into the NBM demonstrated impaired learning skills compared to control groups. However, a single 33 ng/g estren treatment was able to restore the deficits of learning behaviours.
We have previously reported that E2 rapidly induces extracellular-signal-regulated kinase 1 and 2 (ERK1/2) and cAMP response element binding protein (CREB) phosphorylation in cholinergic neurons in vivo. In the present study, we found that administration of estren to adult female mice resulted in significantly increased phosphorylation of ERK1/2 and CREB in cholinergic neurons of the NBM within 30 min. Interestingly, phosphorylation of ERK1/2 was significantly increased at the Aβ1-42 treated brain side compared to non-treated side after estren administration.
In summary, these findings indicate that estren might hold potential as a molecular target for AD prevention and treatment.