Progesterone modulates m TOR in the hippocampus of mice after traumatic brain injury

the mechanistic target of rapamycin(m tor) is an intracellular protein kinase that functions as an energy and nutrient sensor in the cellular microenvironment of neurons. modulation of m tor is vital when nutrient and energy sources become limited. hypoxia, traumatic brain injury, cellular energy states, and growth factors all regulate the phosphorylation and total levels of m tor in cells. alterations in the microenvironment induce transduction of signals to downstream proteins by m tor allowing for cells to make the necessary adjustments to counteract stressors and survive. progesterone, a hydrophobic steroid hormone, has been shown in studies of non-neural tissue to be a suppressor of m tor and modulator of m tor phosphorylation. our study tested the effects of progesterone on m tor expression following traumatic brain injury. c57 bl/6 mice were treated with progesterone(8 mg/kg) at 1(intraperitoneal), 6(subcutaneous), 24(subcutaneous), and 48(subcutaneous) hours post closed skull traumatic brain injury. the hippocampus was then harvested 72 hours post injury and prepared for western blot analysis. we found that progesterone significantly decreased total m tor levels in all groups compared to sham treated with vehicle. this was further confirmed by immunostaining showing decreased cytoplasmic m tor levels compared to sham. our study shows progesterone is a significant modulator of m tor levels in the hippocampus of mice following traumatic brain injury.     

Survey of Bicycling Accidents in Boulder,Colorado

In brief: To determine what public and individual efforts might reduce bicycling accidents and injuries, a survey was conducted during the primary cycling months (April through September) in Boulder, Colorado. Of 253 patients (87 women, 166 men, average age 22) treated for injuries in bicycling accidents, almost 30% of the accidents were caused by gravel, and nearly half involved a motor vehicle. The most frequent types of injury were abrasions, contusions, lacerations, and fractures. The survey results confirm the need for adequate head protection, satisfactory lighting, and increased awareness on the bicyclist's part. In addition, improved street maintenance will drastically reduce the number of cycling injuries and accidents.     

Developing Therapeutic Antibodies for Neurodegenerative Disease

The central nervous system has been considered off-limits to antibody therapeutics. However, recent advances in preclinical and clinical drug development suggest that antibodies can cross the blood–brain barrier in limited quantities and act centrally to mediate their effects. In particular, immunotherapy for Alzheimer’s disease has shown that targeting beta amyloid with antibodies can reduce pathology in both mouse models and the human brain, with strong evidence supporting a central mechanism of action. These findings have fueled substantial efforts to raise antibodies against other central nervous system targets, particularly neurodegenerative targets, such as tau, beta-secretase, and alpha-synuclein. Nevertheless, it is also apparent that antibody penetration across the blood–brain barrier is limited, with an estimated 0.1–0.2 % of circulating antibodies found in brain at steady-state concentrations. Thus, technologies designed to improve antibody uptake in brain are receiving increased attention and are likely going to represent the future of antibody therapy for neurologic diseases, if proven safe and effective. Herein we review briefly the progress and limitations of traditional antibody drug development for neurodegenerative diseases, with a focus on passive immunotherapy. We also take a more in-depth look at new technologies for improved delivery of antibodies to the brain.     

Carbamazepine: a 'blind' assessment of CYP-associated metabolism and interactions in human liver-derived in vitro systems

1. The ability of various in vitro systems for CYP enzymes (computer modelling, human liver microsomes, precision-cut liver slices, hepatocytes in culture, recombinant enzymes) to predict various aspects of in vivo metabolism and kinetics of carbamazepine (CBZ) was investigated. 2. The study was part of the EUROCYP project that aimed to evaluate relevant human in vitro systems to study drug metabolism. 3. CBZ was given to the participating laboratories without disclosing its chemical nature. 4. The most important enzyme (CYP3A4) and metabolic route (10,11-epoxidation) were predicted by all the systems studied. 5. Minor enzymes and routes were predicted to a different extent by various systems. 6. Prediction of a clearance class, i.e. slow clearance, was correctly predicted by microsomes, slices, hepatocytes and recombinant enzymes (CYP3A4). 7. The 10,11-epoxidation of CBZ by the recombinant CYP3A4 was enhanced by the addition of exogenous cytochrome-b5, leading to a considerable over-prediction. 8. Induction potency of CBZ was predicted in cultured hepatocytes in which 7- ethoxycoumarin O-deethylase was used as an index activity. 9. It seems that for a principally CYP-metabolized substance such as CBZ, all liverderived systems provide useful information for prediction of metabolic routes, rates and interactions.