The Neurosteroids Progesterone and Allopregnanolone Reduce Cell Death, Gliosis, and Functional Deficits after Traumatic Brain Injury in Rats

Abstract

This report compares the effects of progesterone and its metabolite, allopregnanolone, on the early injury cascade (apoptosis) and long-term functional deficits after TBI. Progesterone (16 mg/kg) or allopregnanolone (4, 8, or 16 mg/kg) were injected at 1 h, 6 h, and then for 5 consecutive days after bilateral contusions of the frontal cortex in adult male rats. Within one day after injury, progesterone and allopregnanolone reduced both the expression of pro-apoptotic proteins caspase-3 and Bax, and apoptotic DNA fragmentation. Progesterone and allopregnanolone also reduced the size of glial fibrillary acid protein (GFAP)-positive astrocytes at the lesion site 24 h after injury. Compared to sham-operated controls at 19 days after injury, injured rats given either progesterone or any of three doses of allopregnanolone had equivalent numbers of ChAT-positive cells in the nucleus basalis magnocellularis. At 19 days post-injury, rats given progesterone or allopregnanolone (8 mg/kg) showed improved performance in a spatial learning task compared to injured rats given only the vehicle. These results provide evidence of the anti-apoptotic and anti-astrogliotic effects of progesterone and allopregnanolone and help to explain why better cognitive performance is observed after injury when animals are given either neurosteroid.

Sex-dependent effect of a low neurosteroid environment and intrauterine growth restriction on fetal guinea pig brain development.

“…In vitro studies in organotypic brain slice cultures have previously shown that pretreatment with allopregnanolone reduces astrogliosis following a hypoxic insult (Kruse et al 2009). Studies of traumatic brain injury in adult rats have also shown that both progesterone and allopregnanolone administration reduces the size of GFAP-positive astrocytes (Djebaili et al 2005). Despite the increase in GFAP expression when allopregnanolone synthesis was inhibited, qualitative analysis identified no overt areas of glial scarring or obvious signs of damage related to GFAP staining.…”

“…The suppression of allopregnanolone synthesis increases markers of cell proliferation, an effect that is ameliorated when the synthetic neurosteroid, alfaxalone, is used to replace the loss of the endogenous neurosteroid (Yawno et al 2009). In adult rat models of traumatic brain injury, allopregnanolone administration has also reduced the size of GFAP-positive astrocytes at the site of the experimental lesions (Djebaili et al 2005), and there is increasing evidence for the effectiveness of allopregnanolone in reducing lesion size and enhancing functional recovery in animal models of traumatic brain injury (Djebaili et al 2004, Schumacher et al 2007. In addition to the previously reported neuroprotective actions of allopregnanolone, this study provides evidence of delayed neurodevelopment in the presence of a low neurosteroid environment and suggests an important role of allopregnanolone in the regulation of developmental processes in the late gestation foetal brain.…”

Neurosteroids reduce inflammation after TBI through CD55 induction

“…In rats with bilateral medial frontal cortex (MFC) contusions, post-injury injections of PROG reduced cerebral edema, blood-brain barrier disruption, and the expression of inflammatory cytokines [7,31,32]. We have also shown that PROG's metabolite, allopregnanolone (ALLO; 5α-pregnan-3β-ol-20-one), a GABA-A agonist, can reduce the mediators of inflammation after TBI at a dose that is 50% lower than PROG [14].…”

Endogenous and synthetic neurosteroids in treatment of Niemann–Pick Type C disease

“…These include neuroprotection against ischemia and stroke (Cutler, et al, 2005,Djebaili, et al, 2005,Hoffman, et al, 2003,Lapchak, 2004,Meffre, et al, 2007,Shear, et al, 2002,VanLandingham, et al, 2006, recovery of motor function after spinal cord injury (di Michele, et al, 2000,Fiore, et al, 2004,Labombarda, et al, 2006,Patte-Mensah, et al, 2004,Pomata, et al, 2000, regulation of myelination (Chavez-Delgado, et al, 2005,Gago, et al, 2001,Ghoumari, et al, 2005,Ghoumari, et al, 2003,Le Goascogne, et al, 2000,Schumacher, et al, 2000,Schumacher, et al, 2004, proliferation of neuronal stem cells (Suzuki, et al, 2004,Wang, et al, 2005 , neurogenesis in the hippocampus (Keller, et al, 2004,Suzuki, et al, 2004,Wang, et al, 2005, and induction of analgesia (Pathirathna, et al, 2005,Todorovic, et al, 2004. Many of these actions of neurosteroids are discussed in detail in other papers in this issue.…”