No abstract

The tryptophan metabolite, kynurenic acid (KYNA), is a preferential antagonist of the α7 nicotinic acetylcholine receptor and N-methyl-D-aspartic acid receptor at endogenous brain concentrations. Recent studies have suggested that increases of brain KYNA levels are involved in psychiatric disorders such as schizophrenia and depression, and regulation of KYNA production has become a new target for treatment of these diseases. Kynurenine (KYN), the immediate precursor of KYNA, is transported into astrocytes via large neutral amino acid transporters (LATs). In the present study, the effect of LATs regulation on KYN uptake and KYNA production was investigated in vitro and in vivo using an LATs inhibitor, 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH). In the in vitro study, cortical slices of rat brain were incubated with a physiological concentration of KYN and 3 µmol/L-3 mmol/L BCH. BCH inhibited KYNA production and KYN uptake in a dose-dependent manner, and their IC50 values were 90.7 and 97.4 µmol/L, respectively. In the in vivo study, mice were administered KYN (50 mg/kg BW) orally and BCH (200 mg/kg BW) intravenously. Administration of KYN increased brain KYN and KYNA levels compared with the mice treated with vehicle, whereas additional administration of BCH suppressed KYN-induced elevations in KYN and KYNA levels to 50 and 70 % in the brain. These results suggest that inhibition of LATs prevented the increase of KYNA production via blockade of KYN uptake in the brain in vitro and in vivo. LATs can be a target to modulate brain function by regulation of KYNA production in the brain.

BackgroundThe peritoneum begins to undergo morphologic changes before the start of peritoneal dialysis (PD), particularly in diabetic patients. The present study was conducted to investigate the effects of diabetes on the peritoneum.MethodsThis study involved 17 patients who began receiving PD and had diabetes as an underlying disease (DM group), and 30 patients without diabetes who served as a control group (nonDM group). At the start of PD, the parietal peritoneum was sampled to assess submesothelial connective tissue thickness, number of capillaries and postcapillary venules, and indications of vasculopathy (grades 0 – 3).ResultsSubmesothelial connective tissue thickness was significantly greater in the DM group than in the nonDM group ( p < 0.01). The number of capillaries was significantly greater in the DM group ( p < 0.01). Based on multivariate linear regression analysis, diabetes was identified as a significant independent variable of both submesothelial connective tissue thickness and number of capillaries ( p < 0.01).ConclusionsIn diabetic patients, morphologic changes of the peritoneum are marked at the start of PD.

Background: Deposition of advanced glycation end products (AGEs) is frequently found in the peritoneum of patients on peritoneal dialysis (PD). Angiogenesis is also observed in the peritoneum. However, the clinical significance of AGEs and angiogenesis in the peritoneum is not fully understood. We evaluated the maturation of capillary vessels and investigated whether AGEs are associated with angiogenesis and peritoneal function in the peritoneal membrane. Methods: Peritoneum obtained when PD catheters were removed from 61 patients with PD was analyzed. The peritoneum was immunohistochemically stained with anti-CD34 (for endothelial cells), anti-alpha smooth muscle actin (αSMA) (for pericytes), and anti-AGE antibodies. We defined CD34-positive and αSMA-negative vessels as immature capillary vessels in peritoneal membranes using serial sections. We evaluated the associations between vessel density, peritoneal function (dialysate-to-plasma ratio for creatinine (D/P creatinine)), and the degree of AGE deposition. Results: AGE accumulation in the interstitium was positively associated with the duration of PD ( p < 0.01). AGE accumulation in the interstitium and vascular wall was positively correlated with the use of acidic solution ( p < 0.05) and the maximum value of D/P creatinine ( p < 0.05). AGE accumulation in the vascular wall was significantly associated with immature capillary density (CD34+/αSMA−) in the peritoneum ( p < 0.01). Vessel density was not significantly correlated with the last measurement of D/P creatinine ( p = 0.126, r = 0.202), However, immature capillary density was positively correlated with the last measurement of D/P creatinine ( p < 0.05, r = 0.278). Conclusions: AGE accumulation is significantly associated with immature angiogenesis and peritoneal dysfunction in patients undergoing PD.