Although the administration of progesterone has been shown to be neuroprotective in experimental models of traumatic brain injury (TBI), the mechanisms for this beneficial effect are still poorly understood. The present study examined the effects of progesterone on mRNA and protein levels of the Bcl-2 apoptosis regulatory genes, bax, bad, bcl-2, and bcl-x(L), in cerebral cortex after TBI. Male Sprague-Dawley rats were subjected to either sham surgery or lateral fluid percussion brain injury of moderate severity (2.4-2.6 atm). Within 1 h post-surgery, progesterone (4 mg/kg) or vehicle (corn oil) administration was initiated for 1-7 days postoperatively. Our results indicate that bax and bad mRNA levels and Bax and Bad protein expression in the ipsilateral, injured cerebral cortex were significantly elevated post-TBI, while mRNA levels of bcl-2 and bcl-x(L) or Bcl-2 and Bcl-x(L) protein expression were not changed. Under the sham-treated condition, progesterone significantly increased mRNA levels of the anti-apoptotic gene, bcl-2, but down-regulated pro-apoptotic gene expression (bax and bad) in cerebral cortex. After TBI, progesterone treatment reduced bax and bad mRNA levels in the ipsilateral cerebral cortex of TBI rats, and decreased Bax and Bad protein levels. In addition, bcl-2 and bcl-x(L) mRNA levels, as well as Bcl-2 and Bcl-x(L) protein expression, were increased by progesterone in TBI injured cortex. These data indicate that one of the neuroprotective mechanisms of progesterone may be related to its differential regulation of apoptotic signals.

Combined hemorrhagic shock (Shock) and unilateral common carotid artery occlusion (Stroke) results in a decrease of oxygen availability to peripheral tissues and organs and the central nervous system (CNS). A variety of biochemical processes ensue, including organ failure, cellular apoptosis, and necrosis. The present study used male, Sprague-Dawley rats to assess the impact of cerebral insult. Using heat-shock protein 25 and 70 (HSP25, HSP70) as biomarkers, measured 24 h after injury, we tested the hypothesis that pharmacological induction of preconditioning can offer cytoprotection from combined Stroke and Shock. The compound, diazoxide (DZ), is known to induce preconditioning through its effect as a mitochondrial potassium ATP (mK(ATP)) channel opener and succinate dehydrogenase inhibitor. When administered 24 h prior to Stroke and Shock (delayed preconditioning), DZ increased cerebral cortical and hippocampal levels of HSP25 and HSP70. A more clinically relevant treatment paradigm was tested, where DZ was administered after the induction of Stroke and Shock (postconditioning). When administered 60 min (but not 10 min) after the induction of Stroke and Shock, DZ significantly increased HSP25 and HSP70 expression in the ipsilateral cerebral cortex and hippocampus. Taken together, these results suggest that DZ treatment may be efficacious for CNS injury resulting from blood loss and anoxia from combined cerebral ischemia and hemorrhagic shock. "Postconditioning" triggered by DZ, immediately before resuscitation, is a potentially effective treatment for ischemia-reperfusion injury from combined Stroke and Shock.

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Hemorrhagic shock is a clinical syndrome that manifests as hypoperfusion, hypoxia, and ischemia initiating various cellular stress responses involved in the synthesis and release of an assortment of pro-inflammatory molecules, cytokines, chemokines, and reactive oxidant species (ROS). The ROS have been shown to oxidize and damage proteins making them targets for ubiquitination and proteasomal degradation. Cullin-5 (cul-5), an E3 ligase that binds ubiquitin to proteins targeted for degradation via the proteasome, was investigated for its gene expression during hemorrhagic shock. Male Long-Evans rats were subjected to volume controlled (27 ml kg-1) hemorrhage over 10 min and kept in shock for 60 min. Quantitative realtime polymerase chain reaction showed cul-5 mRNA levels were significantly increased in the brainstem and cerebellum, and decreased in the hypothalamus of rats as a result of hemorrhagic shock (n = 6) compared to sham-treated rats (n = 6). Cul-5 mRNA levels in the cerebral cortex, small intestine, kidney, liver, lung, or pituitary gland did not significantly change after hemorrhagic shock. This is the first report of cul-5 mRNA regulation by hemorrhagic shock. Evidence indicates this protein may have a regulatory role in ubiquitin-proteasomal protein degradation in response to hemorrhagic shock.

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