Neuroprotective effects of progesterone in traumatic brain injury: blunted in vivo neutrophil activation at the blood-brain barrier

Abstract

BACKGROUND Progesterone (PRO) may confer a survival advantage in traumatic brain injury (TBI) by reducing cerebral edema. We hypothesized that PRO reduces edema by blocking polymorphonuclear (PMN) interactions with endothelium (EC) in the blood-brain barrier (BBB). METHODS CD1 mice received repeated PRO (16 mg/kg intraperitoneally) or vehicle (cyclodextrin) for 36 hours after TBI. Sham animals underwent craniotomy without TBI. The modified Neurological Severity Score graded neurologic recovery. A second craniotomy allowed in vivo observation of pial EC/PMN interactions and vascular macromolecule leakage. Wet/dry ratios assessed cerebral edema. RESULTS Compared with the vehicle, PRO reduced subjective cerebral swelling (2.9 ± .1 vs 1.2 ± .1, P <.001), PMN rolling (95 ± 1.8 vs 57 ± 2.0 cells/100 μm/min, P <.001), total EC/PMN adhesion (2.0 ± .4 vs .8 ± .1 PMN/100 μm, P <.01), and vascular permeability (51.8% ± 4.9% vs 27.1% ± 4.6%, P <.01). TBI groups had similar a Neurological Severity Score and cerebral wet/dry ratios (P > .05). CONCLUSIONS PRO reduces live pericontusional EC/PMN and BBB macromolecular leakage after TBI. Direct PRO effects on the microcirculation warrant further investigation.

Older patients with traumatic brain injury present with a higher GCS score than younger patients for a given severity of injury

“…It is difficult to envisage the biological mechanism underlying such an observation, particularly given the likely positive effect of progesterone on neuroinflammation during the evolution of TBI 24. In our large study, gender did not independently influence GCS.…”

Does enoxaparin interfere with HMGB1 signaling after TBI? A potential mechanism for reduced cerebral edema and neurologic recovery

“…While LEU rolling is an important step in LEU/EC interactions leading to transmigration into the tissue phase, in the current study, the number of sticking or adherent LEUs was extremely low as we could only safely record 30 seconds of fluorescent exposure at a time to prevent fluorescent light effects on the pial surface. 21,26,47 We can only postulate that differences could not be ascertained with such low frequency of adhesion. It is important to note that other plausible explanations may also exist linking heparinoids to reduced LEU rolling.…”

“…5,12 CCI was used to induce severe TBI as previously described. 25,26 Briefly, after anesthesia with ketamine/xylazine/acepromazine (100/10/1 mg/kg, intraperitoneal) and placement of the animal in a stereotactic device, mice underwent a midline sagittal incision to expose the surface of the skull. A left-sided, 4-mm circular craniotomy was prepared between the bregma and the lambda using a dental drill (Henry Schein, Melville, NY) (Fig.…”

“…26 Briefly, a second 2.5-mm craniotomy was made just anterior to the first craniotomy and covered with a 5-mm coverslip (Fisher Scientific, Waltham, MA) (Fig. 1 B ).…”

Progesterone attenuates Aβ 25–35 -induced neuronal toxicity via JNK inactivation and progesterone receptor membrane component 1-dependent inhibition of mitochondrial apoptotic pathway

“…Based on its safety and effectiveness demonstrated in a variety of TBI models, progesterone has been tested in human clinical trials for traumatic brain injury [16,17]. Evidence suggests it exerts its neuroprotective effects through several pathways, including improving neuronal survival, reducing swelling, and inhibiting apoptosis and inflammatory reaction [18,19].…”