Orally administered FPRL1 receptor agonist peptide MMK-1 inhibits etoposide-induced alopecia by a mechanism different from intraperitoneally administered MMK-1

Oral administration for 6 days of 100 mg/kg MMK-1, an agonist peptide selective for the FPRL1 receptor, suppressed alopecia induced by the anticancer drug etoposide in neonatal rats. The anti-alopecia effect of orally administered MMK-1 was not inhibited by pyrilamine or cimetidine, antagonists for histamine H1 and H2 receptors, respectively, which blocked the anti-alopecia effect of intraperitoneally administered MMK-1 at a dose of 10 mg/kg for 4 days. However, the anti-alopecia effect of orally administered MMK-1 was inhibited by indomethacin, an inhibitor of cyclooxygenase (COX), or AH-23848B, an antagonist of the EP4 receptor for prostaglandin (PG) E2, suggesting involvement of PGE2 release and the EP4 receptor in the oral MMK-1 anti-alopecia mechanism. The anti-alopecia effect of orally administered MMK-1 was also blocked by an inhibitor of nuclear factor-kappaB (NF-kappaB), pyrrolidine dithiocarbamate, suggesting that the oral anti-alopecia effect of MMK-1 may be mediated by activation of NF-kappaB. These results suggest that MMK-1 bound to FPRL1 receptor might suppress etoposide-induced apoptosis of hair follicle cells and alopecia by way of PGE2 release and NF-kappaB activation.     

Effects of fermentation products of Ganoderma lucidum on growth performance and immunocompetence in weanling pigs

The purpose of this study was to test fermentation, for its products of a Chinese medicinal mushroom, Ganoderma lucidum, cultured by submerged fermentation for its effect on growth performance and immunocompetence in weanling piglets. In Experiment 1, 72 weanling piglets were allotted to one of four treatments receiving these fermentation products (GLF, expressed as amount of beta-glucans) at 0 (control), 50, 100, and 150 mg/kg feed for 4 weeks. The results showed that at a supplementation level of 50 mg/kg feed, GLF caused the best growth performance, the highest pseudorabies antibody titre, and a decrease of blood glucose level. It was also demonstrated that GLF up-regulated the cell-mediated immune response related cytokines (IL-2, IFN-gamma, and TNF-alpha) expression in different lymphoid tissues. After challenging with porcine circovirus (PCV) type 2 (Experiment 2), a supplementation with 50 mg GLF per kg feed also inhibited PCV-2 virus amplification, and ameliorated lymphocyte depletion in different lymphoid tissues. Conclusively, feed supplemented with GLF at 50 mg/kg could be beneficial to counteract the physiological stress in weanling piglets.     

Effects of fermentation products of Ganoderma lucidum on growth performance and immunocompetence in weanling pigs

The purpose of this study was to test fermentation, for its products of a Chinese medicinal mushroom, Ganoderma lucidum, cultured by submerged fermentation for its effect on growth performance and immunocompetence in weanling piglets. In Experiment 1, 72 weanling piglets were allotted to one of four treatments receiving these fermentation products (GLF, expressed as amount of β-glucans) at 0 (control), 50, 100, and 150 mg/kg feed for 4 weeks. The results showed that at a supplementation level of 50 mg/kg feed, GLF caused the best growth performance, the highest pseudorabies antibody titre, and a decrease of blood glucose level. It was also demonstrated that GLF up-regulated the cell-mediated immune response related cytokines (IL-2, IFN-γ, and TNF-α) expression in different lymphoid tissues. After challenging with porcine circovirus (PCV) type 2 (Experiment 2), a supplementation with 50 mg GLF per kg feed also inhibited PCV-2 virus amplification, and ameliorated lymphocyte depletion in different lymphoid tissues. Conclusively, feed supplemented with GLF at 50 mg/kg could be beneficial to counteract the physiological stress in weanling piglets.     

Dose- and duration-dependent alterations by tellurium on lipid levels: differential effects in cerebrum,cerebellum, and brain stem of mice

The effect of various doses of sodium tellurite (1/50 LD50=0.4 mg/kg, 1/25 LD50=0.8 mg/kg, and 1/10 LD50=2.0 mg/kg body weight orally) on the lipid levels (cholesterol, triglycerides, phospholipids, esterified fatty acids, gangliosides, and total lipids) in the cerebrum, cerebellum, and brainstem of male albino mice was studied after 7 and 15 d of treatment. Sodium tellurite (2.0 mg/kg body weight) for 7 d has an apparent effect on the depletion of cholesterol, triglycerides, phospholipids, esterified fatty acids, and total lipids. The cholesterol content was decreased significantly in the cerebrum, cerebellum, and brainstem after 7 d of treatment with a 2.0-mg/kg dose compared to the control. On the other hand, treatment for 15 d with doses of 0.4, 0.8, and 2.0 mg/kg body weight resulted in a significant and dose-dependent increment in cholesterol level in the cerebrum, cerebellum, and brainstem. The triglycerides content was decreased significantly in the cerebrum, cerebellum, and brainstem with the 2.0-mg/kg dose after 7 d of treatment. The doses of 0.4, 0.8, and 2.0 mg/kg orally for 15 d resulted in a significant and dose-dependent depletion of triglycerides in the cerebrum, cerebellum, and brainstem. All the doses of tellurium (0.4, 0.8, and 2.0 mg/kg) both for 7 and 15 d have depleted the level of phospholipids in varying degrees of significance in the cerebrum, cerebellum, and brainstem. However, the level of esterified fatty acids was decreased significantly with the 2.0-mg/kg dose of tellurium for 7 d but increased with the 0.4-mg/kg dose for 15 d in the cerebrum and cerebellum. The level of gangliosides was depleted in the cerebrum but elevated in the cerebellum and brainstem after receiving a 2.0-mg/kg dose of sodium tellurite for 7 d. The content of gangliosides was increased with doses of 0.4 and 0.8 mg/kg but decreased with 2.0 mg/kg for 15 d in the cerebrum, cerebellum, and brainstem. The total lipids content was depleted significantly and dose dependently after 7 and 15 d of treatment in the cerebrum, cerebellum, and brainstem. These results suggest that sodium tellurite affects the lipids content differentially in various parts of the mice brain.     

Use of acetylcholinesterase reactivators and central cholinolytics in the treatment of experimental tetanus poisoning]

Experiments were conducted on rabbits with tetanus intoxication induced by the intravenous injection of a lethal dose of the toxin; a study was made of the therapeutic efficacy of the acetylcholinesterase reactivators--dipyroxim and isonitrosine, and also of the central cholinolytics--amizyl and diphacyl. In dose of 25 mg/kg dipyroxim produced no therapeutic effect, and in doses of 30--40 mg/kg caused the animal death. Amizyl and diphacil in a dose of 3--4 mg/kg caused elimination of tonic convulsions for 1 1/2--2 hours. As to isonitrosin--it produced the same effect for 4--5 hours. In case of combined administration of reactivators and cholinolytics convulsions were eliminated for 4--5 hours.     

Toxoplasma encephalitis: influence of the vehicle on the efficacy of different doses of 2',3'-dideoxyinosine in mice

In this study we investigated the effect of the antiretroviral molecule 2',3'-dideoxyinosine (Videx) against cerebral cysts in a murine model of toxoplasmic encephalitis caused by a wild cystic strain of Toxoplasma gondii. The role of the vehicle was also studied. Three doses were used: 50, 100 and 150 mg/kg of body weight/day. The doses of 50 and 150 mg/kg were prepared by dissolving pure 2',3'-dideoxyinosine powder in Maalox suspension before gavaging the mice; the dose of 100 mg/kg was prepared by grinding tablets of Videx that were suspended in water. A decrease in the number of cysts and a morphological modification of them were noted from day 15 with the lowest dose. The most important decrease could be observed with the dose of 100 mg/kg/d. After 30 days of treatment with this dose, 65% of the cysts were destroyed compared to controls. For the doses of 50 and 150 mg/kg/d prepared with Maalox, 36% and 51% of the cysts were destroyed respectively. So ddI has an effect on the cerebral cysts of T. gondii even at a low dose. The galenic formulation influences its action since the doses prepared with Maalox were less efficient than those prepared from ground tablets.     

Potent anti-obese principle from Rosa canina: structural requirements and mode of action of trans-tiliroside

The 80% aqueous acetone extracts from the fruit (50 mg/kg/d) and seeds (12.5 and 25 mg/kg/d) of Rosa canina L., but not from the pericarps, were found to show substantial inhibitory effect on the gain of body weight and/or weight of visceral fat without affecting food intake in mice for 2 weeks after administration of the extracts. With regard to the active constituents, the principal constituent, trans-tiliroside (0.1-10 mg/kg/d), potently inhibited the gain of body weight, especially visceral fat weight, and significantly reduced blood glucose levels after glucose loading (1 g/kg, ip) in mice. On the other hand, kaempferol and p-coumaric acid lacked such effect and kaempferol 3-O-beta-D-glucopyranoside tended to reduce the gain of body weight and visceral fat weight, but not significantly, at a dose of 10 mg/kg/d. These results indicate the importance of both kaempferol 3-O-beta-D-glucopyranoside and p-coumaroyl moieties for anti-obese effects. Furthermore, a single oral administration of trans-tiliroside at a dose of 10 mg/kg increased the expression of PPAR-alpha mRNA of liver tissue in mice.     

Mechanism of the protective effect of intraperitoneally administered agonists for formyl peptide receptors against chemotherapy-induced alopecia

Previously, we found that an intraperitoneally administered chemotactic peptide, N-formyl-Met-Leu-Phe (fMLP), and MMK-1, a selective agonist of formyl peptide receptor-like 1 (FPRL1) receptor, the low affinity subtype of the fMLP receptor, prevented the alopecia in neonatal rats induced by the anticancer agent etoposide. The anti-alopecia effect of fMLP was not inhibited at all by Boc-FLFLF, a selective antagonist of formylpeptide receptor (FPR), which is the high affinity subtype of the fMLP receptor, but it was partly inhibited by Trp-Arg-Trp-Trp-Trp-Trp-NH(2) (WRW(4)), an antagonist of FPRL1 receptor. On the other hand, the anti-alopecia effect of MMK-1 was completely abolished by WRW(4). The anti-alopecia effects of fMLP and MMK-1 were also inhibited by Lys-D-Pro-Thr (K(D)PT) and pyrrolidine dithiocarbamate, which are inhibitors of interleukin-1 (IL-1) and nuclear factor-kappaB (NF-kappaB) respectively. Hence, we suggest that the anti-alopecia mechanisms of intraperitoneally administered fMLP and MMK-1 include activation of NF-kappaB via IL-1 release downstream of the FPRL1 receptor homolog in rats.     

帕妥珠单抗生物类似药SMMU-27 静脉注射对食蟹猴的重复给药毒性探索研究

目的:观察帕妥珠单抗生物类似药SMMU-27四周静脉注射对食蟹猴的安全性。方法:20只健康食蟹猴按体重随机分为阳性对照组、SMMU-27低、中、高剂量组和辅料对照组,每组4只,雌雄各半。低、中、高剂量组剂量分别为15、150和450 mg/kg,阳性对照组给予150 mg/kg帕妥珠单抗(Pertuzumab),辅料对照组给予空白溶剂(0 mg/kg)。各组动物按相应体重慢速静脉注射给药,给药体积为15 m L/kg,给药速度约5 m L/min。每周给药1次,共给药4周,恢复期4周,期间进行各项毒理学指标检测。结果:一般症状结果显示给药期间与给药后,低、中、高剂量组和阳性对照组陆续有动物出现腹泻症状。高剂量组1只动物在d40时濒死剖解,其最早出现稀便,停药后腹泻状态也未见好转,生化指标显示在d28时碱性磷酸酶(Alkaline Phosphatase,ALP)升高,在d14和d40时尿素(Blood Urea,BU)升高,总蛋白(Total Protein,TP)、白蛋白(Albumin,ALB)降低。低、高剂量组和阳性对照组均有部分动物白细胞(White Blood Cell,WBC)给药后数值降低,各给药组在d14时及高剂量组和阳性对照组在d28时BU升高或有升高的趋势,恢复期时有恢复趋势。高剂量濒死动物骨髓检查发现核红细胞较多,各阶段粒细胞减少,出现较多裸核;病理检查发现肾脏可见散在多发的中度肾小管扩张,近曲小管上皮轻度变性。其余指标包括一般症状、体重、尿液、心电图、免疫学指标等未见明显与供试品相关的异常变化。结论:SMMU-27主要毒性靶部位是胃肠道(腹泻)、肾脏(血清BU升高)和血液系统(WBC下降),应与这些部位表达供试品结合的相关受体有关,属供试品的药理作用放大和延伸。因此本实验条件下食蟹猴的安全剂量(NOAEL)为150 mg/kg,致死剂量为450 mg/kg。SMMU-27与等剂量阳性对照药物毒性反应基本类似。     

The use of ally-trenbolone as a progestational agent to maintain pregnancy in ovariectomized bitches

The administration of the synthetic progestogen, allytrenbolone, at a dose of 0.088 mg/kg/d per os successfully maintained pregnancy in 3 of 3 bitches ovariectomized at 34 to 42 d of gestation and in 1 of 3 ovariectomized on Day 8 or 9 of gestation. However, a dose of 0.044 mg/kg/d per os maintained pregnancy in only 2 of 6 bitches ovariectomized in mid-gestation. Two bitches that had ovariectomies performed on Day 9 of gestation and were supplemented with ally-trenbolone at a dose of 0.088 mg/kg/d per os did not establish a pregnancy that was detectable by mid-gestation. Although inhibited the first 2 d post partum in some bitches, lactation increased sufficiently to successfully maintain pups.     

Contrary action of khingamin on the rejection of a skin allograft and on the level of antibody-producing cells in mice

The effect of antimalarial drug khingamin preinjection on skin allograft rejection and the level of antibody forming cells (AFC) in Jerne reaction has been investigated. The drug at the doses of 30, 40, 50 mg/kg inhibited skin allograft rejection. The dose of 20 mg/kg proved ineffective. A single preinjection at a dose of 20 mg/kg had a stimulating effect on antibody formation, whereas the dose of 40 mg/kg induced no effect. When the latter dose was injected simultaneously with sheep red blood cells, it caused a significant inhibition of AFC levels. Fourfold preliminary injection of khingamin at doses 40 and 20 mg/kg had a stimulating effect. The reverse effect of khingamin may be accounted for by the diverse action of the drug itself and its metabolites.     

Termination of pregnancy in dogs by oral administration of dexamethasone

Dexamethasone was administered orally for 7.5 or 10 d to each of 20 pregnant bitches beginning at an estimated 28 to 51 d of gestation, using 1 of 2 dose regimens. Five bitches were given dexamethasone 3 times a day for 10 d, with the highest dose of 0.2 mg/kg for 5 d and then at progressively decreasing doses of 0.16-0.02 mg/kg for 5 d. The 15 remaining bitches were given dexamethasone 2 times a day for 7.5 d, increasing from 0.1 to 0.2 mg/kg over the first 3 administrations, then remaining at 0.2 mg/kg on Days 2 to 5, and decreasing from 0.16 to 0.02 mg/kg over the last 5 administrations. The side effects, including mild polydipsia and polyuria, disappeared when treatment was discontinued. Depending on the stage of pregnancy, uterine contents were either resorbed or aborted, or both. Pregnancy was terminated within 2 to 16 d after the start of treatment in all treated bitches, at 2 to 5 d of treatment in 2 of 3 bitches treated at 40 to 51 d of pregnancy, and at 0 to 4 d after the end of treatment in most of the 17 bitches treated at 28 to 35 days of pregnancy. Oral administration of dexamethasone appears to be a potentially useful pharmacologic treatment for the termination of unwanted pregnancy in the bitch.     

A teratogenicity study on hydroxyurea and diphenylhydantoin in cats

Hydroxyurea, an antitumor drug and known teratogen in rat, miniature swine and dog, and diphenylhydantoin, a teratogen in mouse and rat, were assessed for teratogenic effects in cat. Pregnancies were induced, by synchronizing gonadotropin-stimulated estrus and ovulation with natural copulations. Hydroxyurea at 50 or 100 mg/kg, and sodium diphenylhydantoin at 1 or 2 mg/kg dosages, were administered orally in single daily doses from gestation days 10-22. Appropriate controls given empty capsules, were included for each drug. Cats were necropsied on gestation day 43. Fetuses were examined for external, visceral and skeletal malformations. Hydroxyurea at 50 mg/kg dose produced a low teratogenic activity and at 100 mg/kg a high incidence of non-pregnancy and resorptions with, consequently, fewer live fetuses. Diphenylhydantoin gave no clear evidence of teratogenicity at any test dose but was embryolethal at the maternally toxic dose of 2 mg/kg. So far, studies conducted suggest that the cat is a useful species for screening drugs and chemicals for their teratogenic potential.     

Central effects of citral, myrcene and limonene, constituents of essential oil chemotypes from Lippia alba (Mill.) n.e. Brown.

Citral, myrcene and limonene (100 and 200 mg/kg body wt., i.p.), constituents of essential oils from Lippia alba chemotypes, decreased not only the number of crossings but also numbers for rearing and grooming, as measured by the open-field test in mice. Although muscle relaxation detected by the rota rod test was seen only at the highest doses of citral (200 mg/kg body wt.) and myrcene (100 and 200 mg/kg body wt.), this effect was observed even at the lowest dose of limonene (50 mg/kg body wt.). Also, citral and myrcene (100 and 200 mg/kg body wt.) increased barbiturate sleeping time as compared to control. Limonene was also effective at the highest dose, and although citral did not increase the onset of sleep, it increased the duration of sleep, which is indicative of a potentiation of sleeping time. Citral (100 and 200 mg/kg body wt.) increased 2.3 and 3.5 times, respectively, the barbiturate sleeping time in mice. Similar effects were observed for myrcene and limonene at the highest dose (200 mg/kg body wt.) which increased the sleeping time around 2.6 times. In the elevated-plus maze, no effect was detected with citral up to 25 mg/kg body wt., while at a high dose it decreased by 46% the number of entries in the open arms. A smaller but significant effect was detected with limonene (5 mg/kg body wt.). While myrcene (10 mg/kg body wt.) decreased only by 22% the number of entries in the open arms, this parameter was decreased by 48% at the highest dose. Our study showed that citral, limonene and myrcene presented sedative as well as motor relaxant effects. Although only at the highest dose, they also produced a potentiation of the pentobarbital-induced sleeping time in mice, which was more intense in the presence of citral. In addition, neither of them showed an anxiolytic effect, but rather a slight anxiogenic type of effect at the higher doses.     

Specific binding sites on human phagocytic blood cells for Gly-Leu-Phe and Val-Glu-Pro-Ile-Pro-Tyr, immunostimulating peptides from human milk proteins.

Two immunostimulating peptides were isolated from human milk proteins by enzymatic digestion, the tripeptide GLF and the hexapeptide VEPIPY. These peptides increased the phagocytosis of human and murine macrophages and protected mice against Klebsiella pneumoniae infection. The present study showed that this activity may be correlated to the presence of specific binding sites on human blood phagocytic cells. The receptor molecules implicated were different for the two peptides. [3H]GLF specifically bound to PMNL and monocytes, whereas [3H]VEPIPY only bound to monocytes. The leukemic promyelocytic cell line HL-60 differentiated into granulocytes or into macrophages (depending on inducer used) coroborated these results. Specific binding of [3H]GLF on plasma membrane preparations of human PMNL (20 degrees C) was saturable and Scatchard analysis indicated two classes of binding sites: high-affinity sites of Kd 2.3 +/- 1.0 nM and Bm 60 +/- 9 fmol/mg protein and low-affinity sites of Kd 26.0 +/- 3.5 nM and Bm 208 +/- 45 fmol/mg protein. [3H]GLF binding was inhibited in a concentration-dependent manner by various analogous peptides, such as LLF, GLY, LLY and RGDGLF, but not by RGD, RGDS, VEPIPY and the chemotactic peptide f-Met-Leu-Phe (f-MLF). Only at high concentrations the direct analog MLF competed with labeled GLF. An important inhibitory effect was also observed with C1q component of the complement whereas C3 and BSA were uneffective. Specific binding of [3H]VEPIPY on monocyte membranes (20 degrees C) was saturable and Scatchard analysis was consistent with one class of binding sites of Kd 3.7 +/- 0.3 nM and Bm 150 +/- 6 fmol/mg protein.     

Sodium selenite stimulates neurobehavior and neurochemical activities in rats

The effect of 0.05, 0.1, and 0.2 mg sodium selenite/kg body weight ip on the activities of neurobehavioral, acetyl cholinesterase, monoamine oxidase, and the content of dopamine and its metabolites in circadian rhythm centers of male Wistar rats was studied after 7 d of treatment. The results show an appreciable increase in locomotion, stereo-events, distance traveled, and average speed at the dose of 0.1 and 0.2 mg sodium selenite/kg. The data have shown hyperactivity of animals with various doses of sodium selenite, and it was significant and dose-dependent after 3 d of treatment. The activity of acetylcholinesterase (AChE) was inhibited dose dependently, and it was significant in preoptic area with 0.1 or 0.2 mg sodium selenite/kg. Conversely, in the posterior hypothalamus its activity was significantly elevated with the dose of 0.2 mg sodium selenite/kg, but its alteration in brain stem was not significant. Monoamine oxidase (MAO) activity was increased in preoptic area with the dose of 0.1 mg sodium selenite/kg, but its alteration in posterior hypothalamus and brain stem was not significant. The content of dopamine (DA), 3,4-dihydroxyphenyl acetic acid (DOPAC), and homovanilic acid (HVA) was elevated dose dependently and it was significant with the doss of 0.1 and 0.2 mg sodium selenite/kg, but the content of DOPAC and HVA in posterior hypothalamus was not significant with the dose of 0.1 mg sodium selenite/kg.     

Central mechanisms of action involved in cocaine-induced tachycardia

The present study was designed to determine the central effects of cocaine on heart rate and blood pressure in Wistar Kyoto rats (WKY) and to evaluate mechanisms involved in the response. Cocaine (0.025-4 mg/kg) was administered to unanesthetized, unrestrained rats via a cannula placed into the lateral ventricle. Procaine (0.1 and 4 mg/kg) was also administered centrally. Cocaine did not significantly alter blood pressure at doses of 0.025, 0.1, or 0.5 mg/kg, icv. Only the highest dose, 4 mg/kg, icv produced a significant pressor response. Cocaine produced significant dose-dependent tachycardia, with the maximum increase in heart rate occurring within 5 min. Procaine (4 mg/kg, icv) produced tachycardia, but the effect was significantly less than that produced by cocaine (4 mg/kg, icv). Cocaine also produced tachycardia at a dose of 0.1 mg/kg, but procaine did not significantly alter heart rate at the same dose. Central phentolamine pretreatment (0.1 mg/kg, icv) significantly attenuated the increase in heart rate produced by cocaine. These results indicate that the centrally mediated tachycardia produced by cocaine is partly due to its local anesthetic activity and to indirect stimulation of alpha receptors.     

Glycine modulates N-methyl-D-aspartic acid induced learning facilitation in rats

Summary Pretraining i.p. administration of N-methyl-D-aspartic acid (NMDA) at doses of 10 and 20mg/kg dose-dependently facilitated performance in a water T-maze learning task in rats. The effect of NMDA was inhibited by the competitive NMDA receptor antagonist CGP37849 [(DL)-E(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid] (CGP) at a dose of 6mg/kg, and by the NMDA receptor complex glycine site antagonist 1-hydroxy-3-amino-2-pyrrolidone (HA-966) at a dose of 10mg/kg. The NMDA site antagonist, when given alone, did not impair learning. The glycine precursor milacemide (2-N-pentylaminoacetamide HCl), at doses of 5 and 10mg/kg accelearted learning acquisition and its effect was antagonized by HA-966. The learning rate was impaired following the administration of NMDA 10mg/kg together with milacemide 5mg/kg when compared with the effect of 10mg/kg NMDA alone.The administration of 5mg/kg NMDA was associated with an elevated tissue concentration of aspartate in the hippocampus, an effect which was antagonized by 6mg/kg of CGP. NMDA at doses of 10 and 20mg/kg elevated the concentration of glycine but decreased the concentration of aspartate, glutamate and glutamine in the cortex and aspartate in the hippocampus. The cortical effects of NMDA 10mg/kg were antagonized by 6mg/kg of CGP. Milacemide at the dose of 10mg/kg elevated glycine, aspartate, glutamate and taurine concentrations. The coadministration of 5 mg/kg NMDA with 5mg/kg milacemide elevated the concentrations of glycine, glutamate and glutamine in the cortex and taurine in the hippocampus. These amino acid levels were higher than after administration of 5mg/kg either agent alone. The results demonstrate a dose-dependent facilitation effect on learning performance by NMDA and glycine receptor agonists. Antagonists at the NMDA and glycine sites counteracted the learning improvement of NMDA, and the glycine site antagonist the effect of milacemide.     

Mechanism of the Protective Effect of Intraperitoneally Administered Agonists for Formyl Peptide Receptors against Chemotherapy-Induced Alopecia

Previously, we found that an intraperitoneally administered chemotactic peptide, N-formyl-Met-Leu-Phe (fMLP), and MMK-1, a selective agonist of formyl peptide receptor-like 1 (FPRL1) receptor, the low affinity subtype of the fMLP receptor, prevented the alopecia in neonatal rats induced by the anticancer agent etoposide. The anti-alopecia effect of fMLP was not inhibited at all by Boc-FLFLF, a selective antagonist of formylpeptide receptor (FPR), which is the high affinity subtype of the fMLP receptor, but it was partly inhibited by Trp-Arg-Trp-Trp-Trp-Trp-NH₂ (WRW⁴), an antagonist of FPRL1 receptor. On the other hand, the anti-alopecia effect of MMK-1 was completely abolished by WRW⁴. The anti-alopecia effects of fMLP and MMK-1 were also inhibited by Lys-D-Pro-Thr (K(D)PT) and pyrrolidine dithiocarbamate, which are inhibitors of interleukin-1 (IL-1) and nuclear factor-κB (NF-κB) respectively. Hence, we suggest that the anti-alopecia mechanisms of intraperitoneally administered fMLP and MMK-1 include activation of NF-κB via IL-1 release downstream of the FPRL1 receptor homolog in rats.     

Dose–Response Effects of Diphenylhydantoin on Pregnant Dams and Embryo‐Fetal Development in Rats

Despite the widespread use of diphenylhydantoin (DPH), there is a lack of reliable information on the teratogenic effects, correlation with maternal and developmental toxicity, and dose–response relationship of DPH. This study investigated the dose–response effects of DPH on pregnant dams and embryo‐fetal development as well as the relationship between maternal and developmental toxicity. DPHwas orally administered to pregnant rats from gestational days 6 through 15 at 0, 50, 150, and 300 mg/kg/day. At 300 mg/kg, maternal toxicity including increased clinical signs, suppressed body weight, decreased food intake, and increased weights of adrenal glands, liver, kidneys, and brain were observed in dams. Developmental toxicity, including a decrease in fetal and placental weights, increased incidence of morphological alterations, and a delay in fetal ossification delay also occurred. At 150 mg/kg, maternal toxicity manifested as an increased incidence of clinical signs, reduced body weight gain and food intake, and increased weights of adrenal glands and brain. Only minimal developmental toxicity, including decreased placental weight and an increased incidence of visceral and skeletal variations, was observed. No treatment‐related maternal or developmental effects were observed at 50 mg/kg. These results show that DPH is minimally embryotoxic at a minimal maternotoxic dose (150 mg/kg/day) but is embryotoxic and teratogenic at an overt maternotoxic dose (300 mg/kg/day). Under these experimental conditions, the no‐observed‐adverse‐effect level of DPH for pregnant dams and embryo‐fetal development is considered to be 50 mg/kg/day. These data indicate that DPH is not a selective developmental toxicant in the rat.