Enterococcus faecalis EF-2001 protects DNBS-induced inflammatory bowel disease in mice model.

Recent studies have demonstrated the immunomodulatory effects of heat-killed lactic acid bacteria. The aim of this study was to evaluate the protective effect of heat-killed Enterococcus faecalis EF-2001 (EF-2001) on a model of inflammatory bowel disease (IBD). A total of 28 female NC/Nga mice were divided into 4 treatment groups. Controls were fed a normal commercial diet. In the experimental groups, colitis was induced by rectal administration of dinitrobenzene sulfonic acid. Two groups were orally administered 2 and 17 mg/kg EF-2001, respectively. EF-2001 treatment decreased the expression of several cytokines, including cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS), interferon (IFN)-γ, interleukin (IL)-1ß, and IL-6 in inflamed colon compared to the DNBS alone group. In addition, EF-2001 suppressed DNBS-induced colonic tissue destruction. Therefore, this study strongly suggests that EF-2001 could alleviate the inflammation associated with mouse IBD.

Involvement of Proton-Coupled Organic Cation Antiporter in Varenicline Transport at Blood-Brain Barrier of Rats and in Human Brain Capillary Endothelial Cells.

Varenicline is a selective partial α4ß2 nicotinic acetylcholine receptor agonist, which is used to help achieve smoking cessation. Here, we investigated varenicline transport at the blood-brain barrier by means of in vivo microdialysis, in situ brain perfusion, and brain efflux index measurements in rats, and in vitro uptake studies in human brain capillary endothelial cells. Microdialysis demonstrated that varenicline is actively transported from blood to brain in rats. Blood-to-brain uptake transport of varenicline, as measured by the in situ brain perfusion technique, was strongly inhibited by diphenhydramine, a potent inhibitor of proton-coupled organic cation (H+/OC) antiporter. However, brain efflux index study showed that brain-to-blood efflux transport of varenicline was not inhibited by diphenhydramine. In human brain capillary endothelial cells, varenicline was taken up time- and concentration-dependently. The uptake was dependent on an oppositely directed proton gradient, but was independent of extracellular sodium and membrane potential. The uptake was inhibited by a metabolic inhibitor, and by substrates of H+/OC antiporter, but not by substrates or inhibitors of OCTs, OCTNs, PMAT, and MATE1, which are known organic cation transporters. The present results suggest that the H+/OC antiporter contributes predominantly to varenicline uptake at the blood-brain barrier.

Utility of cerebrospinal fluid drug concentration as a surrogate for unbound brain concentration in nonhuman primates.

In central nervous system drug discovery, cerebrospinal fluid (CSF) drug concentration (C(CSF)) has been widely used as a surrogate for unbound brain concentrations (C(u,brain)). However, previous rodent studies demonstrated that when drugs undergo active efflux by transporters, such as P-glycoprotein (P-gp), at the blood-brain barrier, the C(CSF) overestimates the corresponding C(u,brain). To investigate the utility of C(CSF) as a surrogate for interstitial fluid (ISF) concentration (C(ISF)) in nonhuman primates, this study simultaneously determined the C(CSF) and C(ISF) of 12 compounds, including P-gp substrates, under steady-state conditions in cynomolgus monkeys using intracerebral microdialysis coupled with cisternal CSF sampling. Unbound plasma concentrations of non- or weak P-gp substrates were within 2.2-fold of the C(ISF) or C(CSF), whereas typical P-gp substrates (risperidone, verapamil, desloratadine, and quinidine) showed ISF-to-plasma unbound (K(p,uu,ISF)) and CSF-to-plasma unbound concentration ratios (K(p,uu,CSF)) that were appreciably lower than unity. Although the K(p,uu,CSF) of quinidine, verapamil, and desloratadine showed a trend of overestimating the K(p,uu,ISF), K(p,uu,CSF) showed a good agreement with K(p,uu,ISF) within 3-fold variations for all compounds examined. C(u,brain) of some basic compounds, as determined using brain homogenates, overestimated the C(ISF) and C(CSF). Therefore, C(CSF) could be used as a surrogate for C(ISF) in nonhuman primates.

A possible monosynaptic pathway links the pedunculopontine tegmental nucleus to thalamostriatal neurons in the hooded rat.

The thalamic lateral posterior nucleus (LP) of the hooded rat is regarded as a relay nucleus for the transmission of information from visuomotor-related structures such as the superior colliculus, pedunculopontine tegmental nucleus (PPT) and substantia nigra, pars reticulata, to visual cortical areas as well as the striatum. The aim of the present study was to examine the relationships of the thalamo-striatal projection neurons with the LP afferent fibers derived from the PPT, using injections of the anterograde tracer biotinylated dextran amine (BDA) and the retrograde tracer cholera toxin-B (CTB) into the PPT and the striatum, respectively. Findings showed that the location of terminals derived from PPT and LP neurons projecting to the striatum overlapped considerably in the ventral portion of the LP. Ultrastructural observations within this overlapped LP region showed that BDA-labeled terminals make synaptic contacts with dendrites of CTB-labeled neurons. The present results thus provide morphological support for the contention that information from the PPT neurons is relayed to the striatum through by the LP.