Protease activated receptors (PARs) populate neurons and astrocytes in the brain. The serine protease thrombin, which activates PAR-1 during the first hours after stroke, appears to be associated with the cytotoxicity. Thrombin antagonists and PAR-1 inhibitors have been correlated with reduced cell death and behavioral protection after stroke, but no data yet supports a mechanistic link between PAR-1 action and benefit. We sought to establish the essential role of PAR-1 in mediating ischemic damage. Using a short hairpin mRNA packaged with green fluorescent protein in a lentivirus vector, we knocked downPAR-1 in the medial caudate nucleus prior to rat middle cerebral artery occlusion (MCAo) and in rat neurons prior to oxygen-glucose deprivation. We also compared aged PAR-1 knockout mice with aged PAR-3, PAR-4 mice and young wild-type mice in a standard MCAo model. Silencing PAR-1 significantly reduced neurological deficits, reduced endothelial barrier leakage, and decreased neuronal degeneration in vivo during MCAo. PAR-1 knock-down in the ischemic medial caudate allowed cells to survive the ischemic injury; infected cells were negative for TUNEL and c-Fos injury markers. Primary cultured neurons infected with PAR-1 shRNA showed increased neuroprotection during hypoxic/aglycemic conditions with or without added thrombin. The aged PAR-1 knockout mice showed decreased infarction and vascular disruption compared to aged controls or young wild types. We demonstrated an essential role for PAR-1 during ischemia. Silencing or removing PAR-1 significantly protected neurons and astrocytes. Further development of agents that act at PAR-1or its downstream pathways could yield powerful stroke therapy.

Splenectomy increases the risk for post-operative infectious complications. Further studies identifying strategies to decrease the associated morbidity are necessary.

Traumatic brain injury (TBI) is an enormous public health problem, with 1.7 million new cases of TBI recorded annually by the Centers for Disease Control. However, TBI has proven to be an extremely challenging condition to treat. Here, we apply a nanoprodrug strategy in a mouse model of TBI. The novel nanoprodrug contains a derivative of the nonsteroidal anti-inflammatory drug (NSAID) ibuprofen in an emulsion with the antioxidant α-tocopherol. The ibuprofen derivative, Ibu2TEG, contains a tetra ethylene glycol (TEG) spacer consisting of biodegradable ester bonds. The biodegradable ester bonds ensure that the prodrug molecules break down hydrolytically or enzymatically. The drug is labeled with the fluorescent reporter Cy5.5 using nonbiodegradable bonds to 1-octadecanethiol, allowing us to reliably track its accumulation in the brain after TBI. We delivered a moderate injury using a highly reproducible mouse model of closed-skull controlled cortical impact to the parietal region of the cortex, followed by an injection of the nanoprodrug at a dose of 0.2 mg per mouse. The blood brain barrier is known to exhibit increased permeability at the site of injury. We tested for accumulation of the fluorescent drug particles at the site of injury using confocal and bioluminescence imaging of whole brains and brain slices 36 hours after administration. We demonstrated that the drug does accumulate preferentially in the region of injured tissue, likely due to an enhanced permeability and retention (EPR) phenomenon. The use of a nanoprodrug approach to deliver therapeutics in TBI represents a promising potential therapeutic modality.

BACKGROUND:The purpose of the current study was to investigate the effect of early adrenergic hyperactivity as manifested by prehospital (emergency medical service [EMS]) hypertension on outcomes of traumatic brain injury (TBI) patients and to develop a prognostic model of the presence of TBI based on EMS and admission (emergency department [ED]) hypertension. METHODS:This study is a retrospective review of the 2007 to 2008 National Trauma Data Bank including blunt trauma patients 15 years or older with available EMS and ED vital signs. Patients with head Abbreviated Injury Scale (AIS) score of 3 or greater were selected, and mortality was examined within EMS systolic blood pressure (SBP) groups: lower than 100 mm Hg, 110 mm Hg to 150 mm Hg, 160 mm Hg to 180 mm Hg, and 190 mm Hg to 230 mm Hg. A forward logistic regression model including the EMS heart rate, EMS SBP, EMS Glasgow Coma Scale (GCS) score, ED heart rate, and ED SBP was used to identify predictors of a TBI in patients with ED GCS score of less than or equal to 8, 9 to 13, and 14 to 15. RESULTS:For the 5-year study period, 315,242 patients met inclusion criteria. Adjusted odds for mortality increased in a stepwise fashion with increasing EMS SBP compared with patients with normal EMS SBP (adjusted odds ratio [95% confidence interval], 1.33 [1.22Y1.44], p G 0.001, for EMS SBP of 160Y180 mm Hg and 1.97 [1.76Y2.21], p G 0.001, for EMS SBP of 190Y230 mm Hg).A 7-point scoring system was developed for each ED GCS score group to predict the presence of a TBI. EMS SBP of greater than 150 mm Hg and ED SBP of greater than 150 mm Hg were both predictive of the presence of a TBI in patients with ED GCS score of 8 or less and in patients with ED GCS score of 9 to 13 or 14 to 15, respectively. CONCLUSION:Prehospital hypertension in TBI is associated with a higher mortality risk. Early hypertension in the prehospital setting and at admission can be used to predict the presence of such injuries. These findings may have important early triage and treatment implications. (J Trauma Acute Care Surg. 2014;77: 592Y598.