Progesterone Differentially Regulates Pro- and Anti-Apoptotic Gene Expression in Cerebral Cortex Following Traumatic Brain Injury in Rats

Abstract

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.

The Effect of Progesterone Dose on Gene Expression after Traumatic Brain Injury

“…The caspase family is subdivided into two sub-groups, those that are activated during apoptosis (caspase-2, -3, -7, -8, -9, -10) and those that undergo activation by the inflammatory response (caspase-1, -4, -5, -11) and are implicated in the maturation of cytokines, (Creagh et al, 2003). Previous studies of progesterone initiated 1 hr post-injury resulted in an increased expression of anti-apoptotic molecules, Bcl-2 and Bcl-XL (Yao et al, 2005) and decreased expression of Bax, Bad (Yao et al, 2005) and caspase-3, pro-apoptotic molecules (Djebaili et al, 2004) that were not differentially expressed in the current study.…”

Progesterone sharpens temporal response profiles of sensory cortical neurons in animals exposed to traumatic brain injury.

“…41,42 TBI-induced pathophysiology results in immediate and short-term hypo-excitation in neuronal response rates in upper-to-middle cortical layers, 24,26 possibly due to stress wave phenomena, damage to endothelial cells in the BBB, an increase in intracranial pressure, alterations in the ionic balance, [42][43][44][45] and by a wave of cortical spreading depression which causes widespread hyperpolarization and long-term presynaptic depression. 33 We now show that the short-term changes in firing rate are not accompanied by any systematic changes in the temporal response properties. Thus, the neural mechanisms that control for temporal precision in cortex, such as L4 neurogliaform activation as well as temporally precise thalamocortical Long-term responses are tabulated using the same model as that used for short-term results with "up" arrows indicating a broader response profile and "down" narrower comparisons for the first group mentioned.…”

“…Animals were randomly assigned to receive either P4 in peanut oil (Sigma-Aldrich, St. Louis, MO; 16 mg/kg; *0.6 mL) or vehicle treatment (peanut oil only, *0.6 mL; Sigma-Aldrich) postsurgery. The dosing regimen was based on previous studies, indicating that 16 mg/kg provided cognitive benefits and a reduction in apoptotic markers to brain-injured animals 19,[32][33][34][35] and was consistent with a clinical dosing regimen that had some success. 4 The first drug or vehicle injection (as appropriate) was given intraperitoneally within the first hour postsurgery, followed by subcutaneous injections at 6 and 24 h. In the short-term survival group (details below), no further injections were given and animals were left to recover for 4 d postsurgery until the electrophysiological study.…”

Neurosteroids and their neuroprotective actions

“…Decreasing injury-induced lipid peroxidation and oxidative stress via inhibition of TNF-α production or up-regulation of antioxidant enzymes (Roof, et al 1997;Stein, 2008;Stein & Wright, 2010). It is aso worth mentioning that PROG increased expression of the antiapoptotic genes (Bcl-2, Bcl-x) and decreased expression of pro-apoptotic (bax and bad) genes (Yao, et al, 2005).…”