维甲酸受体激动剂AM80抗阿尔治海默症最新研究进展

目的综述AM80他米巴罗汀(tamibarotene,AM80)抗阿尔治海默症(Alzheimer's Disease,AD)药理作用及其作用机制、不良反应以及临床用药安全等最新研究进展。方法通过阅读近几年国内外的相关文献,对AM80抗阿尔治海默症最新研究报道进行详细的归纳总结。结果 AM80是一个合成的维甲酸受体激动剂,具有很好的抗阿尔治海默症作用。AM80作为一个多靶点药物,它通过转录调控多种与AD发病相关的基因;能够减少β淀粉样肽在脑部的沉积;还能够改善AD小鼠的学习记忆功能;有效弥补脑内乙酰胆碱的减少;并且能够增加小胶质细胞对Aβ(beta amyloid)的降解功能并伴随脑部炎症的减少。结论 AM80有望成为一个安全和有效的预防和治疗AD的药物,具有广泛的临床应用前景。     

Convulsant action of a benzodiazepine receptor agonist/inverse agonist Ro 19-4603 in developing rats

An inverse benzodiazepine receptor agonist Ro 19-4603, administered intraperitoneally, was found to induce two types of motor seizures, i.e. minimal, predominantly clonic and major, generalized tonic-clonic, in rats at all developmental stages studied (7, 12, 18 and 25 days old). The developmental profile of the two types of seizure was different. Minimal seizures could be induced easily in the two youngest groups, whereas there were no marked differences in the induction of major seizures between the age groups. A lethal outcome was more common in 18- and 25-day-old rats than in younger animals. The convulsant action of the benzodiazepine agonist/inverse agonist Ro 19-4603 shows only quantitative changes during post-natal development in the rat.Abbreviations DPPC Diplamitoylphosphat     

骨立拮抗维甲酸所致大鼠骨质疏松的实验研究

目的　观察骨立对维甲酸所致骨质疏松大鼠的股骨骨密度、骨矿含量的影响。方法　采用ig维甲酸造成大鼠骨质疏松模型 ,使用骨立高、中、低 3种剂量分别进行治疗 ,观察其结果并与空白对照组和阳性对照药物组进行比较。结果　骨立 3个剂量治疗的骨质疏松大鼠的股骨骨密度和骨钙、骨磷含量均明显高于骨质疏松模型组大鼠 (P <0 .0 1或 0 .0 5 ) ,骨立高、中剂量组大鼠的尿钙排泄量明显低于骨质疏松模型组大鼠 (P <0 .0 1) ,其中以高剂量组疗效最佳。结论　骨立可明显提高骨质疏松大鼠的骨密度并升高其骨钙、骨磷的含量 ,降低尿钙排泄量 ,从而拮抗维甲酸所致的大鼠骨质疏松症。     

高效液相色谱法测定大鼠血清中视黄醇和视黄酸

目的 建立高效液相色谱法测定大鼠血清中视黄醇和视黄酸浓度的方法。方法 色谱柱为Phenomenex Luna C₁₈柱（150 mm×4.6 mm,5 μm）;流动相为甲醇-10 mmol/L乙酸铵缓冲盐（90：10,乙酸调整水相pH值至4）;体积流量为1.0 mL/min;检测波长为340 nm;柱温为40℃;进样量为20 μL。结果 大鼠血清样品中视黄醇和视黄酸均分离良好,视黄醇和视黄酸质量浓度在31.25～1 000 ng/mL（r=0.999 9）与峰面积均呈良好的线性关系。平均回收率大于90%,RSD值均小于10%。结论 本法操作简便、准确、灵敏、专属性强,为建立无干扰的测定大鼠血清中视黄醇和视黄酸的方法及其在大鼠体内药动学研究提供参考。     

Differential effects of retinoic acid on growth and apoptosis in human colon cancer cell lines associated with the induction of retinoic acid receptor beta

Retinoids are well known as potential chemopreventive and chemotherapeutic agents against a variety of human cancers. Here, we report that retinoic acid (RA) induced differential growth inhibition in human colon cancer cell lines: while DLD-1, HT-29, and WiDr were relatively resistant, HCT-15 and Colo201 were relatively sensitive. All-trans-retinoic acid caused morphological and biochemical changes such as membrane shrinkage, chromatin condensation, and DNA cleavage, which are typical features of cells undergoing apoptosis in sensitive cell lines. Although retinoic acid receptor (RAR)alpha, beta, gamma and retinoid X receptor alpha were expressed in all cell lines examined, a significant induction of RARbeta by all-trans-RA was observed only in sensitive cell lines, suggesting important roles of RARbeta in RA sensitivity. When a vector containing the RARbeta gene was introduced into a relatively resistant cell line, DLD-1, the cells acquired RA sensitivity. Further, we found that the RARbeta transfectants of DLD-1 expressed an enhanced level of c-Myc and Bax proteins, which may result in the increased susceptibility of the cells to all-trans-RA-induced apoptosis. In summary, our data demonstrated that RA induced growth inhibition and apoptosis in human colon cancer cells and that the induction of RAR3 may mediate the retinoid action.     

Effect of hepatotoxic or nephrotoxic agents on the induction of colon cancers in rats by 1,2-dimethylhydrazine

The effects of liver injury induced by p,p′-diaminodiphenylmethane (DDPM) and of kidney injury induced by N-(3,5-dichlorophenyl)succinimide (NDPS) on 1,2-dimethylhydrazine (DMH) colon carcinogenesis were examined in rats. Prior administration of either DDPM or NDPS before DMH injection resulted in no significant differences in tumor incidences, but differences were noted in histological pattern, tumor size, and extent of invasion.     

淫羊藿苷对维甲酸致大鼠骨质疏松影响的研究

目的观察淫羊藿苷对维甲酸致大鼠骨质疏松的影响。方法大鼠分为对照组、模型组、淫羊藿苷低、中、高剂量组,每组10只。70ms／kg维甲酸灌胃2周制备大鼠骨质疏松模型。淫羊藿苷组灌胃给予50、100、200mg／kg淫羊藿苷,连续4周。测定血和骨中相关指标;测定骨密度;骨物理学指标和生物力学指标。结果与模型组比较,淫羊藿苷组可不同程度的升高血清中Ca2＋、P3＋浓度（P〈0．01）,降低ALP（P〈0．01）;升高骨中Ca2＋、P3＋、Hyp含量（P〈0．05或〈0．01）;升高骨密度、湿重、干重（P〈0．01）;增加骨中最大弯曲力、抗弯强度、断裂挠度、弹性段终点荷。结论淫羊蓉苷对维甲酸致大鼠骨质疏松有一定的防治作用。     

Influence of chenodeoxycholic acid on serum triglycerides in patients with primary hypertriglyceridemia.

Administration of chenodeoxycholic acid (CDCA) to patients with primary hypertriglyceridemia caused the diminution of serum triglyceride concentrations of 54.31% and 46.04% at dosages of 500 mg/day and of 250 mg/day, respectively. Results after 1 month of treatment with 250 mg/day are not statistically different from those obtained with 500 mg/day. Administration of CDCA did not change the serum cholesterol, SGOT, SGPT, total bilirubin, gammaGT or alkaline phosphatase levels.     

阿仑膦酸钠抗维甲酸骨质疏松的实验研究

目的观察和分析阿仑膦酸钠(ALN)对维甲酸所致实验性骨质疏松大鼠的防治作用。方法观察ALN(1.8、3.6 mg.kg-1.d-1)对维甲酸所致实验性骨质疏松大鼠股骨头和股骨干部位的骨矿密度、股骨头的钙磷含量以及强迫游泳时间的影响。结果与模型对照组相比,ALN可明显增加维甲酸所致实验性骨质疏松大鼠股骨头和股骨干部位的骨矿密度(P<0.05,P<0.01),钙、磷含量(P<0.05)及强迫游泳时间(P<0.01)。结论ALN可使维甲酸所致实验性骨质疏松大鼠骨钙、磷含量的提高,骨矿密度的增加,运动能力的提高,有明显的防治骨质疏松作用。     

Elevation of serum corticosterone in rats by bremazocine, a kappa-opioid agonist

Bremazocine at doses of 0.01 mg kg-1 s.c., and higher, increased serum corticosterone concentration several-fold in rats. The increase occurred within 20 min, was maximum at 40-60 min and subsided after 120 min. Pretreatment with naloxone (1-10 mg kg-1 s.c.) antagonized the corticosterone increase. These data support the view that kappa-opioid agonist activity of bremazocine mediated the corticosterone increase.     

Potentiation of the teratogenic effects induced by coadministration of retinoic acid or phytanic acid/phytol with synthetic retinoid receptor ligands

Previous studies in our laboratory identified retinoid-induced defects that are mediated by RAR-RXR heterodimerization using interaction of synthetic ligands selective for the retinoid receptors RAR and RXR in mice (Elmazar et al. 1997, Toxicol Appl Pharmacol 146:21–28; Elmazar et al. 2001, Toxicol Appl Pharmacol 170:2–9; Nau and Elmazar 1999, Handbook of experimental pharmacology, vol 139, Retinoids, Springer-Verlag, pp 465–487). The present study was designed to investigate whether these RAR-RXR heterodimer-mediated defects can be also induced by interactions of natural and synthetic ligands for retinoid receptors. A non-teratogenic dose of the natural RXR agonist phytanic acid (100 mg/kg orally) or its precursor phytol (500 mg/kg orally) was coadministered with a synthetic RAR-agonist (Am580; 5 mg/kg orally) to NMRI mice on day 8.25 of gestation (GD8.25). Furthermore, a non-teratogenic dose of the synthetic RXR agonist LGD1069 (20 mg/kg orally) was also coadministered with the natural RAR agonist, all-trans-retinoic acid (atRA, 20 mg/kg orally) or its precursor retinol (ROH, 50 mg/kg orally) to NMRI mice on GD8.25. The teratogenic outcome was scored in day-18 fetuses. The incidence of Am580-induced resorptions, spina bifida aperta, micrognathia, anotia, kidney hypoplasia, dilated bladder, undescended testis, atresia ani, short and absent tail, fused ribs and fetal weight retardation were potentiated by coadministration of phytanic acid or its precursor phytol. Am580-induced exencephaly and cleft palate, which were not potentiated by coadministration with the synthetic RXR agonists, were also not potentiated by coadministration with either phytanic acid or its precursor phytol. LGD1069 potentiated atRA- and ROH-induced resorption, exencephaly, spina bifida, aperta, ear anotia and microtia, macroglossia, kidney hypoplasia, undescended testis, atresia ani, tail defects and fetal weight retardation, but not cleft palate. These results suggest that synergistic teratogenesis can be induced by coadministration of a natural RXR ligand (phytanic acid) with a synthetic RAR agonist (Am580). Thus, certain potentially useful therapeutic agents or nutritional factors such as phytanic acid should be tested for teratogenic risk by coadministration with other retinoid receptor agonists.     

Differential induction of hepatic drug-metabolizing enzymes by fenvaleric acid in male rats.

Racemic fenvaleric acid [2-(4-chlorophenyl)-3-methyl-butanoic acid], the principal metabolite of fenvalerate, was administrated orally at 0.75, 1.5, and 3.0 mmol/kg body weight/day to Fisher-344 male rats for 7 days. Both pure enantiomers of fenvaleric acid were administered at 1.5 mmol/kg body weight/day; the clofibric acid at the same concentration was used as a positive control. Hepatic enzyme activities were measured. Results obtained clearly show that fenvaleric acid induced numerous hepatic drug metabolism enzymes in F344 rats. The (R) enantiomer of this compound induces a proliferation of peroxisomes, whereas the (S) enantiomer induces CYP2B and mEH activities. Therefore, high exposure to pyrethroid insecticides could interact with the normal metabolism of drugs or xenobiotics.     

Changes in adrenal function as a possible mechanism for elevation of serum glucose by a single large dose of fluoride

Serum glucose was elevated immediately after ip administration of a single large dose of fluoride (NaF 35 mg/kg) to rats. Moreover, elevation of serum glucose following ip administration of 35 mg/kg of fluoride to rats was suppressed by adrenalectomy, dibenamine, or propranolol, but not by thyroid-parathyroidectomy. The elevation of serum glucose was associated with enhancement of glucose-6-phosphatase activities in liver and kidney in fluoride-treated rats.     

Selective potentiation of gabapentin-mediated antinociception in the rat formalin test by the nicotinic acetylcholine receptor agonist ABT-594

The treatment of chronic pain is hampered by various issues including multiple underlying mechanisms contributing to disease pathology and treatment-related toxicity concerns. These can be partially circumvented by combining mechanistically distinct drugs with the aim of selectively potentiating analgesia as opposed to side-effects. This approach has been used to assess the antinociceptive efficacy of the nicotinic acetylcholine (nACh) receptor agonist ABT-594 when combined with the antiepileptic drug gabapentin, the μ-opioid receptor agonist morphine or the antidepressant drug duloxetine in the rat formalin test. Alone, ABT-594 (0.01-0.3 mg/kg) dose-dependently attenuated spontaneous flinching behaviour during first (P1) and second (P2) phase. Similarly, P1, interphase and P2 flinching were variously attenuated by gabapentin (25-200 mg/kg), morphine (0.3-3 mg/kg) and duloxetine (3-60 mg/kg). Remarkably, a completely inactive dose of ABT-594 reduced the dose of gabapentin required to produce antinociception during P1 by 4-8 fold and during P2 by 8-16 fold. This striking potentiation was blocked by mecamylamine and indicative of analgesic synergy. Similar, albeit less consistent results (3-10 fold potency increase) were obtained with morphine/ABT-594. Although a 3 fold increase in P2 antinociceptive potency was obtained with duloxetine in the presence of ABT-594, a corresponding increase in efficacy was lacking. Indeed, a mechanistically relevant reduction in antinociceptive efficacy and potency of duloxetine/ABT-594 occurred during interphase. Thus, activation of the nicotinic cholinergic system differentially modulates the antinociceptive actions of distinct mechanism of action compounds, and provides a novel framework for nACh receptor modulators mediating analgesia in the putative absence of adverse events associated with this mechanism of action.     

Coordinate regulation of xenobiotic and bile acid homeostasis by pregnane X receptor.

Identification and characterization of the pregnane X receptor (PXR) as a key regulator of cytochrome P450 3A (CYP3A) gene expression has led to an increased understanding of the molecular basis of many drug-drug interactions. Mice lacking PXR (PXR-KO) were used in the present study to delineate the role of PXR in regulating hepatomegaly and regulating the activity of CYP3A, organic anion transporting polypeptide-2 (Oatp2), and Cyp7a1 (cholesterol 7alpha-hydroxylase) gene products in vivo. Pregnenolone-16alpha-carbonitrile (PCN) produced hepatomegaly in the wild-type mice but not in the PXR-KO mice. PCN increased both the number of proliferating cell nuclear antigen immuno-positive nuclei and apparent cell size in the wild-type mice but not in the PXR-KO mice. To determine the role PXR plays in regulating CYP3A activity, 6beta-hydroxylation of testosterone and the duration of the loss of righting reflex following administration of the muscle-relaxant zoxazolamine were measured. PCN increased the level of testosterone 6beta-hydroxylation and decreased the duration of the loss of righting-reflex time following zoxazolamine administration in wild-type mice, but did not effect either of these parameters in PXR-KO mice. PCN increased the hepatic uptake of [(3)H]digoxin, an Oatp2 substrate, in wild-type mice but not in the PXR-KO mice. Similarly, PCN decreased bile acid excretion in wild-type mice but not in the PXR-KO mice. Taken together, these data demonstrate a pivotal role for PXR in the regulation of drug-induced hepatomegaly and in the metabolism (CYP3A), transport (Oatp2), biosynthesis (Cyp7a1), and excretion of xenobiotics and bile acids in vivo.     

An evaluation of tamoxifen as a partial agonist by classical receptor theory--an explanation of the dual action of tamoxifen

Tamoxifen is known to have both agonist and antagonist properties. Classical receptor theory predicts that given the relative concentrations of a partial agonist and full agonist acting on the same receptor, the partial agonist may reduce the effect of the full agonist. The immature rat uterine model is an excellent system to evaluate the interactions of estradiol and tamoxifen by application of receptor theory. Using this model, tamoxifen demonstrates both additive and antagonistic effects to estradiol in the fashion predicted by theory. The effects of tamoxifen are additive at low doses of estradiol and antagonistic over higher estradiol doses. It is possible that the dualism of agonism and antagonism seen in other target organs and species is a function of these basic characteristics of a partial agonist.     

Retinoyl beta-glucuronide: lack of binding to receptor proteins of retinoic acid as related to biological activity.

Retinoid beta-glucuronides have emerged as biologically active, water-soluble, natural retinoids with relatively few toxic and teratogenic effects. The mechanism of action of these glucuronides in the control of epithelial differentiation, growth, and tumorigenesis is unknown. Since retinoyl beta-glucuronide (RAG) contains a free carboxyl group, we studied the interactions of RAG with cellular retinoic acid-binding protein (CRABP) and nuclear receptors of retinoic acid (RARs), the possible mediators of the biological action of retinoic acid (RA). RAG did not exhibit any significant affinity to bind either CRABP or RARs. During 24- and 48-hr incubations of RAG in chick cytosol, detectable amounts of RA were generated which interacted with the RA receptors. In chick skin, the biological activity of RAG may be due to this slowly released RA. Other possible modes of action of RAG are suggested.     

Alteration of intravenous nicotine self-administration by opioid receptor agonist and antagonists in rats

Rationale  

The role played by endogenous opioids in mediating the reinforcing properties of nicotine is unclear. As with preclinical studies, clinical trials with naloxone, a prototypic opioid receptor antagonist have yielded equivocal findings with regard to its efficacy in reducing cigarette smoking.