RESUMO
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.
Assuntos
Apoptose/efeitos dos fármacos , Lesões Encefálicas/metabolismo , Fármacos Neuroprotetores/farmacologia , Pregnanolona/farmacologia , Progesterona/farmacologia , Animais , Astrócitos/efeitos dos fármacos , Lesões Encefálicas/complicações , Lesões Encefálicas/fisiopatologia , Caspase 3 , Caspases/efeitos dos fármacos , Caspases/metabolismo , Fragmentação do DNA/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/efeitos dos fármacos , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-akt , Proteínas Proto-Oncogênicas c-bcl-2/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Fatores de Tempo , Proteína X Associada a bcl-2RESUMO
Apoptotic death is known to be an active process requiring the activation of several apoptotic proteins. Depending on the tissue studied and the stimulus used, these processes are distinct. In this work, we studied if there is a putative implication of the p53 and the caspase-3 proteins in kainic acid (KA) and N-methyl-D-aspartic acid (NMDA)-induced apoptosis in organotypic cultures and if there is any relationship between their respective expressions. We found that KA and NMDA both induce apoptosis but only KA-induced apoptosis is p53- and caspase-3-dependent. This demonstrates that KA and NMDA induce apoptosis following different intracellular pathways.