A decrease in interaction between brain regions is observed in individuals with autism spectrum disorder (ASD), which is believed to be related to restricted neural network access in ASD. Propranolol, a beta-adrenergic antagonist, has revealed benefit during performance of tasks involving flexibility of access to networks, a benefit also seen in ASD. Our goal was to determine the effect of propranolol on functional connectivity in ASD during a verbal decision making task as compared to nadolol, thereby accounting for the potential spurious fMRI effects due to peripheral hemodynamic effects of propranolol. Ten ASD subjects underwent fMRI scans after administration of placebo, propranolol or nadolol, while performing a phonological decision making task. Comparison of functional connectivity between pre-defined ROI-pairs revealed a significant increase with propranolol compared to nadolol, suggesting a potential imaging marker for the cognitive effects of propranolol in ASD.

The selective apoptotic elimination of autoreactive T cells in the central nervous system (CNS) contributes to the resolution of inflammation and the spontaneous clinical recovery from experimental autoimmune encephalomyelitis (EAE). To assess the molecular mechanisms involved in this process, we used three-colour flow cytometry to examine the expression of apoptosis-regulating proteins by inflammatory cells isolated from the spinal cords of Lewis rats immunized with myelin basic protein (MBP) and complete Freund's adjuvant. Throughout the course of the disease, which peaked 12-14 days after inoculation and was followed by clinical recovery, we analyzed the DNA content of the spinal cord inflammatory cells to assess apoptosis and, simultaneously, we measured the expression of five proteins (Fas, Fas ligand (Fas-L), Bcl-2, Bcl-x and Bax) which modulate the apoptotic process. Cells expressing the death effector molecules Fas and Fas-L were particularly prone to undergo apoptosis, and were over-represented in the apoptotic population. Of the cells expressing the cell death inhibitor Bcl-2, a low proportion were undergoing apoptosis compared to the proportion of the total inflammatory cell population undergoing apoptosis, indicating that expression of Bcl-2 protects against T cell apoptosis in this disease. There was no evidence, however, that the apoptotic regulators Bcl-x and Bax influenced the susceptibility to apoptosis. We also found that V 8.2 + T cells, which constitute the predominant encephalitogenic MBP-reactive T cell population in the Lewis rat, have a high frequency of Fas and Fas-L expression compared to other inflammatory cells. This would account for the previously demonstrated susceptibility of V 8.2 + T cells to apoptosis in the CNS in EAE. These findings support the hypothesis that autoreactive T cells are eliminated from the CNS during spontaneous recovery from EAE by activation-induced apoptosis involving the Fas pathway.

The objectives of this study were twofold: (1) to characterize the toxicokinetics and dose-dependent systemic/tissue distribution of deltamethrin (DLM) over a range of doses in adult Sprague-Dawley (S-D) rats; (2) to provide comprehensive time course blood and tissue data for development of a physiologically based toxicokinetic (PBTK) model for DLM. DLM is one of the more neurotoxic members of a relatively new and commonly used class of insecticides, the pyrethroids. Despite widespread exposure of the general population to pyrethroids, there is little basic toxicokinetic (TK) data to use in health risk assessments or in development of PBTK models. Male S-D rats were dosed orally with 0.4, 2, or 10 mg DLM/kg dissolved in glycerol formal (GF). Another group received 2 mg/kg iv. Serial blood and tissue samples were taken at sacrifice and analyzed by high-performance liquid chromatography for their DLM content, in order to obtain comprehensive time course data sets for estimation of classical TK, as well as PBTK parameters (e.g., tissues:blood partition coefficients). Gastrointestinal (GI) absorption of DLM was rapid but incomplete. Bioavailability was just 18%. Some 83% of DLM in blood was present in the plasma. Just 0.1-0.3% of systemically absorbed doses reached the brain, the target organ of the bioactive parent compound. Fat, skin and surprisingly, skeletal muscle, accumulated large amounts of the highly lipophilic chemical and served as slow-release depots. Tissue distribution was dose dependent, though generally not proportional to dose. Clearance was dose independent in this dosage range. The time-profiles were used by A. Mirfazaelian et al. (2006, Toxicol. Sci. 93, 432-442) to construct and adjust a PBTK model. Much remains to be learned about physiological/biochemical processes and barriers that govern the GI absorption, transport, brain deposition, and elimination of DLM and other pyrethroids in laboratory animals and humans.

Reversed-phase chromatography is the most common means of separation for small drug molecules. However, polar drugs may suffer from poor retention and peak shape in reversed-phase high-performance liquid chromatography (RP-HPLC). Hydrophilic interaction liquid chromatography (HILIC) provides a viable alternative to RP-HPLC and is an excellent way to separate polar compounds. This paper describes a HILIC/ESI-MS/MS assay for the determination of acyclovir from rat plasma, amniotic fluid, placental tissue, and fetal tissue. The isocratic separation utilizes an underivatized silica column with an acetonitrile/formate buffer mobile phase (80:20). The method is validated over a range of 50 ng/mL to 50 micro g/mL with % error and % relative standard deviation of <15% over 3 days. All samples are prepared by acetonitrile protein precipitation, which yields high recovery (>84% for acyclovir). This assay can be applied to the pharmacokinetic study of the placental transfer of acyclovir.