Affiliations: Department of Psychology, Emory University, Atlanta,
GA 30322, USA | Department of Emergency Medicine, Emory University,
Atlanta, GA 30322, USA | Department of Neurology, Emory University, Atlanta, GA
30322, USA
Note: [] Corresponding author. Current address Dr. Stein: Brain Research
Lab, 1648 Pierce Dr. / Evans Bldg. Room 261, Emory University, Atlanta, GA
30322, USA. Tel.: +1 404 712 9704; Fax: +1 404 727 2388; E-mail:
dstei04@emory.edu
Abstract: Purpose: In the current study we investigated whether
allopregnanolone, a metabolite of progesterone, could replicate progesterone's
beneficial effects in promoting spatial learning ability after bilateral medial
prefrontal cortex contusions in rats. Allopregnanolone has been shown to
enhance GABA neurotransmission, whereas its isomer epiallopregnanolone does not
have this property. Thus, epiallopregnanolone was chosen as a control substance
to examine further the role of GABA transmission in post-trauma
neuroprotection. Methods: After the contusion, rats were given 4 mg/kg treatment of
either allopregnanolone or epiallopregnanolone for five consecutive days
beginning 1hr post-injury. Control groups only received vehicle treatment at
the same time points. A spatial learning task (Morris Water Maze, MWM) was
performed at 7 days post-injury for 10 days. Subsequent histological analyses
of brain tissue were conducted to determine quantitatively the neuronal losses
in both the mediodorsal nucleus of the thalamus (MDN) and the nucleus basalis
magnocellularis (NBM). Results: Allopregnanolone-treated rats showed better performance in
the MWM compared to the vehicle-treated injury group. The histological analyses
also revealed that the allopregnanolone-treated injury group had less neuronal
loss in both the MDN and the NBM compared to the vehicle-treated injury group.
In contrast, epiallopregnanolone did not facilitate MWM performance or reduce
neuronal loss in the MDN and the NBM after TBI. Conclusion: Based on our findings, we suggest that allopregnanolone
may mediate the effects of progesterone in promoting cognitive and
morphological recovery from TBI through, among others, its direct or indirect
effects on GABA-modulated neurons in the MDN and the NBM.
