Endocannabinoids and synaptic function in the CNS.

Marijuana affects neural functions through the binding of its active component (Delta(9)-THC) to cannabinoid receptors in the CNS. Recent studies have elucidated that endogenous ligands for cannabinoid receptors, endocannabinoids, serve as retrograde messengers at central synapses. Endocannabinoids are produced on demand in activity-dependent manners and released from postsynaptic neurons. The released endocannabinoids travel backward across the synapse, activate presynaptic CB1 cannabinoid receptors, and modulate presynaptic functions. Retrograde endocannabinoid signaling is crucial for certain forms of short-term and long-term synaptic plasticity at excitatory or inhibitory synapses in many brain regions, and thereby contributes to various aspects of brain function including learning and memory. Molecular identities of the CB1 receptor and enzymes involved in production and degradation of endocannabinoids have been elucidated. Anatomical studies have demonstrated unique distributions of these molecules around synapses, which provide morphological bases for the roles of endocannabinoids as retrograde messengers. CB1-knockout mice exhibit various behavioral abnormalities and multiple defects in synaptic plasticity, supporting the notion that endocannabinoid signaling is involved in various aspects of neural function. In this review article, the authors describe molecular mechanisms of the endocannabinoid-mediated synaptic modulation and its possible physiological significance.     

A pH-sensitive microsphere system for the colon delivery of tacrolimus containing nanoparticles.

Nanoparticles (NP) are known to accumulate at the site of inflammation in inflammatory bowel disease. In order to avoid premature uptake or degradation of NP during their passage through the small intestine, it appeared necessary to devise a form of local delivery system for NP. Tacrolimus (FK506) loaded poly(lactic-co-glycolic acid) NP entrapped into pH-sensitive microspheres (NPMS) were designed to achieve greater selectivity to their site of action when administered orally. The therapeutic efficacy of this drug delivery system was tested in an experimental colitis in rats. The in vitro characterization showed a successful incorporation of FK506-NP and strongly pH-sensitive release kinetics of both NP and drug. During the in vivo studies, clinical activity, colon/body weight index, and myeloperoxidase activity were determined to assess the severity of inflammation. Systemic availability of a fluorescent dye entrapped in the microspheres was measured in order to determine possible adverse effects. The NPMS as well as the controls of NP and MS formulations exhibited significant mitigating effects in the clinical activity index after 3 days of treatment with similar levels for the various therapies. When observing colon/body weight index and myeloperoxidase activity, only the NPMS group reached statistically significant differences (P<0.05) compared to the colitis control group while other groups did not (colitis control: 21.94+/-4.97; FK506 solution: 15.81+/-3.42; FK506-NP: 17.03+/-5.52; FK506-MS: 15.17+/-7.81; and FK-NPMS: 10.26+/-7.76 U/mg tissue). Moreover, the NPMS system reduced the systemic absorption of the entrapped dye compared to the dye solution or simple NP formulation (relative biovailability-solution: 100+/-14.9%; NP: 46.8+/-8.6%; and NPMS: 29.4+/-3.3%). The results suggest that the NPMS system can provide selective delivery of NP in the colon and develop a significant mitigating effect, while the control group treatments appeared to be insufficient.     

A case of acute hepatitis E associated with multidrug hypersensitivity and cytomegalovirus reactivation

A 65-year-old Japanese man was hospitalized because of acute hepatitis and severe cholestasis due to hepatitis E virus (HEV) infection combined with a drug reaction to a cold preparation. He died of disseminated intravascular coagulation and severe intestinal bleeding due to systemic cytomegalovirus reactivation following the development of severe eruptions with marked eosinophilia due to drug hypersensitivity to taurine and ursodeoxycholate preparations. The close interaction between viral infection or reactivation and drug hypersensitivity was considered as a pathophysiology in this case, which emphasizes the need for further study of the immunological mechanism of the interaction.     

Effects of subacute toluene exposure on neuronal and glial marker proteins in rat brain

The behavior of marker proteins of neurons (gamma-enolase) and glial cells (alpha-enolase, beta-S100 protein and creatine kinase-B) was investigated quantitatively by using enzyme immunoassay systems in toluene-exposed rat brains. Three groups of animals were exposed to toluene vapor at 300 ppm, 1000 ppm, and 3000 ppm, respectively, 8 h/day, 6 days/week, for 2 weeks. After subacute repeated solvent exposure, both neuron-specific gamma-enolase and glial marker proteins displayed an overall concentration-dependent increase tendency in separate brain regions. In cerebrum, only the 3000 ppm group showed a significant increase in alpha-enolase by 27% and creatine kinase-B (CK-B) by 26%. alpha-Enolase and gamma-enolase exhibited a pronounced elevation in cerebellum relative to other brain regions, while beta-S100 protein appeared to be the most markedly altered marker in brainstem. The development of gliosis, which is a frequent phenomenon following CNS damage, is presumed to be responsible for the elevation of glial marker content. Energy metabolism disruption in brain tissues may also bring about the compensatory oversynthesis of glycolytic enzymes such as gamma-enolase, alpha-enolase and CK-B. The dose-dependent alteration patterns following toluene exposure suggest the feasibility of using these brain specific markers to evaluate solvent-induced CNS effects.     

A new strategy for management of retroperitoneal tumors with supradiaphragmatic vena caval thrombi

A new surgical technique to treat retroperitoneal tumors with supradiaphragmatic vena caval invasion is described. In this technique, hepatic warm ischemia can be avoided with reversed hepatic outflow through the portal vein and neither hypothermic circulatory arrest nor cardiopulmonary bypass is necessary using centrifugal blood pump-driven bypass.     

High human IgG levels in severe combined immunodeficient mouse reconstituted with human splenic tissues from patients with gastric cancer.

We implanted normal peripheral blood lymphocytes (PBL) from healthy donors and splenic tissues from patients with gastric cancers into the severe combined immunodeficient (SCID) mouse, demonstrating that SCID mouse with splenic tissue can produce a high level of human immunoglobulin G (IgG). The normal PBLs at 10(7) and 10(8)/mouse were implanted intraperitoneally, and three splenic tissues with a size of 3 x 3 x 3 mm from gastric cancer patients were inoculated subcutaneously into the bilateral backs of the mice. At 2, 4, 6 and 8 weeks after inoculation, mice were killed, and the human IgG was assessed by an ELISA method. SCID mice with splenic tissue revealed high human IgG levels from 2 weeks after inoculation and approximately 2 mg of IgG per ml was observed at 8 weeks post-implantation, while the IgG levels in mice treated with PBLs were limited. Since the half life of the extrinsic human IgG was 10.2 days, the high level of human IgG in the SCID mice was supposed to be produced by human plasma cells in the splenic tissue from gastric cancer patients. This model was thought to be adequate for evaluating human immunological functions in vivo.