Allopregnanolone, a progesterone metabolite, enhances behavioral recovery and decreases neuronal loss after traumatic brain injury.
OBJECTIVE
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 1 hr 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.


CONCLUSIONS
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.
He
Jun
J
Department of Psychology, Emory University, Atlanta, GA 30322, USA.
Hoffman
Stuart W
SW
Stein
Donald G
DG
D000704:Analysis of Variance; D000777:Anesthetics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D020532:Basal Nucleus of Meynert / Q000378:metabolism / Q000473:pathology; D001522:Behavior, Animal; D001930:Brain Injuries / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D002452:Cell Count / Q000379:methods; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D020645:Mediodorsal Thalamic Nucleus / Q000378:metabolism / Q000473:pathology; D009043:Motor Activity / Q000187:drug effects; D011280:Pregnanolone / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D012038:Regeneration / Q000187:drug effects*; D013037:Spatial Behavior / Q000187:drug effects*; D013997:Time Factors
D000777:Anesthetics; D011280:Pregnanolone; D002795:Choline O-Acetyltransferase