Facilitation of opiate-and enkephalin-induced motor activity in the mouse by phenytoin sodium and carbamazepine

In the first experiment, adult male Swiss-Webster mice were systemically injected with a standard dose of morphine. Compared to the influence of vehicle, the motor activity of morphine-injected mice was increased. Neither phenytoin sodium nor carbamazepine alone facilitated motor activity, but pretreatment with both drugs further facilitated the increased motor activity produced by morphine. In a second experiment, mice were injected centrally with a long-acting analog of leu-enkephalin. It also increased motor activity in comparison with vehicle. Again, both phenytoin sodium and carbamazepine further facilitated this response. Both experiments suggest a facilitatory interaction between some aspects of these anticonvulsants and opiate-induced motor activity.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46410/1/213_2004_Article_BF00491980.pd

L-2-hydroxyglutarate production arises from non-canonical enzyme function at acidic pH

The metabolite 2-hydroxyglutarate (2HG) can be produced as either a D(R)- or L(S)- enantiomer, each of which inhibits alpha-ketoglutarate (αKG)-dependent enzymes involved in diverse biologic processes. Oncogenic mutations in isocitrate dehydrogenase produce D-2HG, which causes a pathologic blockade in cell differentiation. On the other hand, oxygen limitation leads to accumulation of L-2HG, which can facilitate physiologic adaptation to hypoxic stress in both normal and malignant cells. Here we demonstrate that purified lactate dehydrogenase (LDH) and malate dehydrogenase (MDH) catalyze stereospecific production of L-2HG via ‘promiscuous’ reduction of the alternative substrate αKG. Acidic pH enhances production of L-2HG by promoting a protonated form of αKG that binds to a key residue in the substrate-binding pocket of LDHA. Acid-enhanced production of L-2HG leads to stabilization of hypoxia-inducible factor 1 alpha (HIF-1α) in normoxia. These findings offer insights into mechanisms whereby microenvironmental factors influence production of metabolites that alter cell fate and function

From progress to regression: biomedical research funding

Despite great advances in health-related research and health care, major challenges remain regarding the causes and cures of many diseases; these may be overcome with further research. Our society is enthusiastic about fostering such investigations. However, available federal funds limit many such projects. Previously there have been sizable increases in the NIH budget, but because of the escalating cost of scientific investigation and the pressures of financing other much-needed governmental programs, recent growth in biomedical research funding has barely kept up with inflation. This article focuses on select attempts to sustain the record of scientific achievement enabled in the past by continued increasing investment and also suggests some solutions