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Maternal immunoglobulin (Ig)G is present in breast milk and has been shown to contribute to the development of the immune system in infants. In contrast, maternal IgG has no known effect on early childhood brain development. We found maternal IgG immunoreactivity in microglia, which are resident macrophages of the central nervous system of the pup brain, peaking at postnatal one week. Strong IgG immunoreactivity was observed in microglia in the corpus callosum and cerebellar white matter. IgG stimulation of primary cultured microglia activated the type I interferon feedback loop by Syk. Analysis of neonatal Fc receptor knockout (FcRn KO) mice that could not take up IgG from their mothers revealed abnormalities in the proliferation and/or survival of microglia, oligodendrocytes, and some types of interneurons. Moreover, FcRn KO mice also exhibited abnormalities in social behavior and lower locomotor activity in their home cages. Thus, changes in the mother-derived IgG levels affect brain development in offsprings., (© 2024. The Author(s).)

The recent guidelines of the Japanese Society of Hospital Pharmacists on the antitumor drug preparation have recommended the use of closed systems such as the PhaSeal® system for preventing cytotoxicity in health care workers involved in the preparation of these drugs. The PhaSeal® system and Clave® Oncology system were evaluated using a practical training kit for the preparation of antitumor drugs. The two systems were compared in terms of handling time, satisfaction as to availability, leakage of drugs from the connections in the system and area of drug spillage because improvements in convenience or lower cost system were available. With the closed systems, the average handling time increased by 10∼20%. The area of drug spillage did not significantly decrease. Leakage of drugs from the system was detected for all samples prepared with the Clave® Oncology system, and for some samples prepared with the PhaSeal® system. In terms of availability, the PhaSeal® system was better than the Clave® Oncology system. In conclusion, to decrease the exposure of health care workers to antitumor drugs during their preparation in a closed system, it is important to evaluate the handling time, operability, robustness with regard to drug leakage and spillage, and proficiency in handling of the closed system.

We studied the effect of TJN-101, a lignan component of Schisandra fruits (Schisandrae fructus), on liver regeneration after partial hepatectomy. TJN-101 was given orally to male Wistar rats 30 min before partial hepatectomy. The mitotic index and the level of DNA synthesis increased after partial hepatectomy and their increase was significantly enhanced by TJN-101. Ornithine decarboxylase (ODC) activity increased in the early stages of liver regeneration and it was also significantly enhanced by TJN-101. Besides, TJN-101 enhanced the increase in hepatic putrescine. These results suggest that TJN-101 stimulates liver regeneration after partial hepatectomy by enhancing ODC activity, which is an important biochemical event in the early stages of liver regeneration.

The Kampo (Japanese herbal) medicine "Juzen-Taiho-To" (TJ-48), which was prepared by decocting a concoction (formula), contains ten kinds of herbs and has several immunostimulating activities. In order to determine the contribution of each herbal component, the complement-activating and mitogenic activities of the hot water extract as well as the polysaccharide fraction from each herb were tested. Hot water extracts of Glycyrrhizae radix, Astragali radix, and Atractylodes lanceae rhizoma showed significant mitogenic activity whereas that of Cinnamomi cortex showed potent complement-activating activity. However, the exclusion of any single component herb whether active or not on its own did not result in a loss or an increase of the overall activity of TJ-48. The polysaccharide fraction from Glycyrrhizae radix showed the most potent of both activities among the same fractions from the other nine herbs, and reduced both activities after periodate oxidation, thus indicating that the carbohydrate moiety may contribute to both activities.

Gomisin A (TJN-101) is one of the lignan components isolated from Schisandra Fruits and expected to have some efficacies in clinical treatment of hepatitis. The serum concentrations of TJN-101 and Met. B, which was identified as a demethylenated substance and one of the major metabolites of TJN-101 in rats, were investigated. After intravenous administration at doses of 1.6, 4.0 and 10 mg/kg of body weight, the serum concentration of TJN-101 decreased biphasically, and the terminal elimination half-life at each dose was about 70 min. Dose-dependency was observed for the area under the concentration-time curve (AUC). On the other hand, the serum concentration of TJN-101 increased rapidly and reached maximum within 15 to 30 min when administered orally. This result was supported by the in situ roop method. The Cmax and the AUC values were not exactly dose-dependent, but the values increased with a dose-up of TJN-101. The biotransformation of TJN-101 to Met. B, was very rapid in both intravenous and oral administrations. The AUC value of Met. B after oral administration of TJN-101 at a dose of 1.6 mg/kg was relatively larger than any other dosages. It suggested that TJN-101 was extensively underwent the first pass effect in rats. More than 80% of TJN-101 was bound with rat serum protein in vitro and in vivo. Therefore, it seems to be necessary to pay attention when it was administered concurrently with high protein binding drugs.

The absorption and excretion of gomisin A (TJN-101) in rats whose livers were injured by carbon tetrachloride (CCl4) were investigated. After intravenous administration of TJN-101 at a dose of 5 mg/kg, the terminal elimination half-life was 1.5 h in the CCl4-treated rats, which was two times that in normal rats. The mean area under the blood concentration-time curve (AUC) value of TJN-101 in the CCl4-treated rats was twice that in normal rats, and this difference was significant (p less than 0.05). Therefore, the total body clearance of TJN-101 in the CCl4-treated rats decreased less than half of that in normal rats. Similar results were observed when it was administered orally. In the CCl4-treated rats, the serum concentration of Met. B, which was identified as a demethylenated substance and one of major metabolites, tended to decrease more than that in normal rats. On the other hand, the cumulative biliary excretion ratio of TJN-101 in 24 h after dosing in the CCl4-treated rats was 2.5 times that in normal rats. The excretion rate of Met. B in the bile in the CCl4-treated rats tended to be delayed. However, the quantitative variance of biliary excretion of Met. B was not found in both groups. The urinary excretion of TJN-101 or Met. B in 72 h after dosing in the CCl4-treated rats was lower than that in normal rats. Similar results were also observed in excretion in the feces.(ABSTRACT TRUNCATED AT 250 WORDS)

The acidic polysaccharide fraction (F-5-2) from "Juzen-Taiho-To" (TJ-48), a Kampo (Japanese herbal) medicine prepared by decocting a prescription of 10 kinds of herbs, has potent mitogenic activity. In order to clarify the mitogenic activity, F-5-2 was fractionated by amon-exchange chromatography, and 14 acidic polysaccharide fractions were obtained. Mitogenic activities of these polysaccharides were increasing with their molecular masses and affinities to the anion-exchange column. Methylation analysis and endo-alpha-(1----4)-polygalacturonase digestion showed these polysaccharide fractions to be pectic polysaccharides, many of which consisted mainly of polygalacturonan regions in addition to small amounts of "ramified" regions. Gel filtration showed that the molecular masses of the "ramified" regions of the polysaccharides were similar. High molecular mass polygalacturonic acid showed a weak mitogenic activity. The mitogenic (M-1 and M-2) and non-mitogenic (M-3) polysaccharides from the most active polysaccharide fraction (F-5-2IIh) were further purified by gel filtration. M-2 and M-3 were also shown to be pectic polysaccharides, and the neutral glycosidic linkages in M-2 and M-3 were different from each other. Endopolygalacturonase digestion markedly decreased the mitogenic activity of M-2, however, the "ramified" region of M-2 still showed a weak activity.

The effect of cycloheximide, a protein synthesis inhibitor, on hippocampal selective neuronal death was morphologically studied in rats subjected to 10 min forebrain ischemia using a 4-vessel occlusion model. Neuronal damage in the hippocampal CA1 subfield 72 h after ischemic insult was dramatically decreased by the lasting inhibition of protein synthesis through consecutive administration of cycloheximide. Cycloheximide, which was administered once within the first 24 h of recirculation, showed protective action on ischemic cell necrosis and its most potent effect was observed when injected at 12 h of post-ischemia. After 36 h of recirculation, however, treatment with cycloheximide could no longer prevent cell death. The possibility is considered that hippocampal delayed neuronal death following transient ischemia is caused by abnormal protein(s).

"Juzen-Taiho-To" (TJ-48), which is a kampo (Japanese herbal) medicine prepared by decocting a prescription of ten kinds of herbs, has several immunostimulating activities. In order to characterize the active substances for anti-complementary and mitogenic activities, TJ-48 was fractionated. Anti-complementary activity was observed in the water- and methanol-insoluble fraction (F-2) and the crude polysaccharide fraction (F-5), whereas mitogenic activity was only found in F-5. However, other low molecular mass fractions did not show both activities. Methylation analysis indicated that F-2 mainly contained amylopectin-like polysaccharides. Both Pronase digestion and periodate oxidation decreased the anti-complementary activity of F-2, and the beta-amylase-resistant fraction of F-2 still retained the potent anti-complementary activity. When F-5, which has the most potent of both activities, was further fractionated, only the major acidic polysaccharide fraction, F-5-2, showed potent mitogenic activity. Endo-alpha-(1----4)-polygalacturonase digestion showed that F-5-2 mainly contained pectic polysaccharides, and the endo-polygalacturonase treatment of F-5-2 reduced the mitogenic activity but not the anti-complementary activity. F-2 and F-5 each activated the complement system by a different mode of action.

It has been reported that leukotrienes (LTs) may play a role in inflammatory liver diseases, and several inhibitors of LTs show an inhibitory effect on experimental liver injuries. In this study, the effect of Gomisin A (TJN-101), which is a lignan component of schisandra fruits, on the arachidonic acid cascade in macrophages was examined to explain the mechanisms of the inhibitory effect of TJN-101 on liver injuries. The production of leukotriene B4 was suppressed by treatment with TJN-101, while the activity of 5-lipoxygenase was not affected. The release of arachidonic acid from macrophages stimulated with fMet-Leu-Phe or the Ca++ ionophore A23187 was suppressed by treatment with TJN-101. The activity of phospholipase A2 was not affected by treatment with TJN-101. These results suggested that TJN-101 produces an inhibitory effect on the biosynthesis of LTs by preventing the release of arachidonic acid, and it was thought that the preventive effect on the arachidonic acid cascade may be partially associated with the inhibitory effect of TJN-101 on liver injuries.

Effects of Juzen-taiho-toh (TJ-48) on the recovery of hemopoietic systems from radiation injury are analyzed. Female C57BL/6N mice (6-8 weeks old) were irradiated at doses of 1, 2, 3, 5, or 7 Gy from a 60Co source. After irradiation, the mice were given TJ-48 (1.25 g in 100 ml drinking water). Seven days after irradiation, the mice were sacrificed, and bone marrow (both femurs), thymus, spleen, and peripheral blood counts were made. The bone marrow cells were used for fibroblast colony-forming unit (CFU-f), spleen colony-forming unit (CFU-S), granulocyte-macrophage colony-forming unit (CFU-GM), erythroid colony-forming unit (CFU-E), and erythroid burst-forming unit (BFU-E) assays. No difference was observed between the experimental and control groups except for CFU-S counts. In the assay for day-14 CFU-S, the mice injected with TJ-48-treated bone marrow cells showed better general condition (including increased body weight) and heavier spleens with larger and more numerous colonies. The effect of TJ-48 does not seem to be elicited via the hemopoietic microenvironment, because mice that had been given TJ-48 before irradiation at 8 Gy and then injected with syngeneic bone marrow cells did not show enhanced day-14 CFU-S counts. These results suggest that TJ-48 manifests a radioprotective effect by increasing the number and size of day-14 CFU-S.

After oral administration of gomisin A (1) to rats, the bile and urine were collected and treated with beta-glucuronidase and arylsulfatase. Seven metabolites, met B (2), met A-III (3), met E (4), met D (5), met F (6), met G (7), and met H (8) were isolated from the bile treated with the enzymes. Eight metabolites 2-8, and met A-II (9) were isolated from the urine treated with the enzymes. A major metabolite 2, and two minor metabolites 3 and 9 were identified as met B, met A-III, and met A-II, respectively, which are oxidative products of 1 formed by rat liver S9 mix. The structures of five new metabolites 4-7, and 8 were determined on the basis of chemical and spectral studies.

Adult male rats were administered morphine twice a day for 45 days and the effects of morphine on the copulation rate, the weight of various organs, and on the hypothalamic-pituitary-gonadal axis were examined. Morphine administered rats showed a loss of weight, hypertrophy of the adrenals, decreased weight of accessory sex organs, low sperm count, and decreased copulation rate. The contents of the luteinizing hormone releasing hormone in the hypothalamus and the luteinizing hormone in the pituitary remained unchanged. Serum luteinizing hormone and testosterone levels decreased, but serum follicle-stimulating hormone levels increased. These results suggest that morphine inhibits the hypothalamic-pituitary-gonadal axis and causes a diminution in the number of fertilizations of the partner females.

To elucidate the differences between neurons of epileptogenic animals and those of normal animals, cellular characteristics of neurons of mutant strain El mice which are highly susceptible to seizures were investigated using immunocytochemical techniques. In neurons of 3-day primary cultures, the control ddY mouse neurons showed dividing stages in about 0.2% of neurofilament (NF)-positive neurons, whereas no dividing neurons were observed among the NF-positive El mouse neurons. In 7-day cultures, localization of GD3 ganglioside in the proliferating control ddY mouse neurons was observed, but there was no GD3 ganglioside in the mutant El mouse neuron. The content of GD3 ganglioside detected by high-performance thin-layer chromatography of El mouse cultured cells was ca. 1/4 of that of ddy mice. These findings suggest that neurons of the El mouse are differentiated earlier than those of the control ddY mouse.

Experiments were performed to investigate the effects of TJ-41 on spermatogenic disorders under current treatment with adriamycin (ADR). Male ICR mice were intraperitoneally injected with ADR at the dose of 0.15 mg/kg, twice a week for 5 weeks. Simultaneously, these mice were orally administered TJ-41 at the dose of 1, 2 or 4 g/kg for 12 weeks. The effects of TJ-41 were evaluated by histological analysis of germ cells in the testis at 7 weeks after the last injection of ADR. TJ-41 at a dose of 4 g/kg significantly inhibited the decrease of testis weight in mice treated with ADR. TJ-41 at doses of 1 and 4 g/kg significantly decreased the proportion of seminiferous tubules without germ cells as compared with the ADR-treated group. On the other hand, TJ-41 at doses of 1 and 4 g/kg significantly increased the proportion of normal seminiferous tubules and the Sertoli cell ratio of spermatocytes as compared with the ADR-treated group. These results indicate that TJ-41 may qualitatively and quantitatively protect against the decrease of germ cells in the testis of mice treated with ADR.

The effect of anticonvulsants on pentylenetetrazol (PTZ)-induced EEG power spectrum changes was examined. When the minimum dose of PTZ (15 mg/kg) was administered intravenously twice, with an interval of 80 min, a clear EEG power spectrum change was observed after the second PTZ administration, irrespective of whether or not the first PTZ administration evoked marked EEG changes. We defined the values F/N, S/N and S/F. The value F/N, obtained by dividing the power spectrum area after the first PTZ administration by the normal power spectrum area, was 1.06 +/- 0.05 (mean +/- S.E.). The value S/N, obtained by dividing the power spectrum area after the second PTZ administration by the normal power spectrum area, was 2.00 +/- 0.21. The value S/F, obtained by dividing S/N by F/N, was 1.86 +/- 0.16. The S/F value was almost constant regardless of whether or not the first PTZ administration could evoke marked EEG changes. The effect of anticonvulsants was examined by S/F value changes, and 100 mg/kg of PHT completely inhibited the double PTZ effect. Phenobarbital, ethosuximide and sodium valproate also inhibited the double PTZ effect. Using the S/F value of the EEG power spectrum with minimum dose double PTZ administration, quantitative evaluation is possible for anticonvulsant drugs.