Behavioral effects of intracerebral administration of luteinizing hormone releasing hormone (LHRH) in rats

The effects of LHRH intracerebrally infused on acquisition of conditioned avoidance responses (CARs) and spontaneous motility were studied in adult male rats. The results were the following: 1) LHRH (1 and 2.5 micrograms/rat) administered through a cannula stereotaxically implanted into the lateral ventricle induced an impairment in the acquisition of CARs along with an increase in global motility, rearing, head shaking and grooming behavior; 2) LHRH 1 microgram/rat injected into the hippocampus or nucleus accumbens induced also an impairment in acquisition which is evident 15 min after treatment. In contrast, intrastriatal injection induced an immediate disruption of this behavior; and 3) there is a good dose-response relationship for intrastriatal LHRH between 7.8 and 62.5 ng/rat. The results suggest that the estriatum could be the locus of the LHRH-induced inhibition of CARs. Then the possibility of an involvement of the dopamine nigrostriatal system is discussed.     

Influence of luteinizing hormone releasing hormone (LHRH) on the behavioral effects of amphetamine in rats

The influence of luteinizing hormone releasing hormone (LHRH) on the behavioral effects induced by several doses of D-amphetamine (0.25, 0.5, 1.0 and 2.0 mg/kg IP) was studied. A dose response relation was previously established for the effects of LHRH (50, 100 and 200 micrograms/kg SC) on acquisition and retention of conditioned avoidance responses (CARs). The neuropeptide impaired acquisition and improved retention of CARs, without modifying spontaneous motor activity. Pretreatment with 100 micrograms/kg of LHRH antagonizes the enhancement in acquisition of CARs due to D-amphetamine 0.5, 1.0 and 2.0 mg/kg, the impairment in retention induced by amphetamine 1.0 and 2.0 mg/kg, and the hypermotility and the increased rearing behavior induced by amphetamine 1.0 and 2.0 mg/kg. These results suggest that brain catecholamines, particularly dopamine, could play a role in the behavioral effects of LHRH. Interactions between LHRH and central dopaminergic mechanisms are discussed.     

Effects of pretreatment with luteinizing hormone releasing hormone (LHRH) on behaviors induced by apomorphine in rats

The influence of LHRH on the behavioral effects induced by apomorphine (APO) was studied in male rats. Several doses of apomorphine (31.25, 62.5, 125, 250 and 500 micrograms/kg) were administered subcutaneously (SC) after LHRH 100 micrograms/kg or solvent. Low doses of apomorphine induced hypomotility and impaired acquisition of a conditioned avoidance response (CAR). High doses produced hypermotility, stereotyped sniffing and a short lasting increase, followed by a decrease in the acquisition of CARs. Pretreatment with LHRH potentiated the hypomotility induced by low doses of apomorphine (62.5 and 125 micrograms/kg) and the hypermotility, stereotyped sniffing and the enhancement in acquisition of CARs produced by higher doses of apomorphine (250 and 500 micrograms/kg). These findings suggest that LHRH could indirectly regulate dopamine activity through an increase in sensitivity of dopamine receptors (pre- and postsynaptic), which mediate the behavioral effects of APO. It is postulated that this hypersensitivity of DA receptors could be the consequence of an inhibition of presynaptic dopaminergic transmission, induced by LHRH.     

Investigational luteinizing hormone releasing hormone (LHRH) agonists and other hormonal agents in early stage clinical trials for prostate cancer

Introduction: The treatment and management of prostate cancer continues to evolve; newer classes of agents and combination therapies are being developed and some are being investigated in early phase clinical trials.

Areas covered: We discuss investigational hormonal agents for the treatment of prostate cancer and focus primarily on luteinizing hormone releasing hormone (LHRH) agonists in early stage trials. We look at agents that target the hormonal axis, including anti-androgens, gonadotropins, estrogenic agents and progestogenic agents and other non-hormonal agents often used in combination with LHRH agonists. We review these candidates in the specific clinical niche in which they might find utility.

Expert opinion: Of all candidate compounds being evaluated in clinical trials, very few will receive FDA approval. Few, if any of the investigational agents discussed here will be used routinely in clinical practice for treating prostate cancer. Recognizing the reasons for the failure of agents to advance to later stage trials is important. Furthermore, a thorough understanding of the mechanisms underlying prostate cancer pathogenesis, including various points in the HGPA and parallel pathways, will help identify potentially actionable targets.     

Development of luteinizing hormone releasing hormone (LHRH) delivery systems for vaginal mucosal route

The objective of this study was to find a rational dosage form for vaginal mucosal delivery of LHRH. Vaginal absorption of LHRH was estimated by measuring its ovulation inducing effect in rat and in vitro vaginal membrane permeation study in rabbit. The effectsof different hydrogel bases, such as Polycarbophil and Pemulen compared with solutions on vaginal membrane permeation of LHRH were investigated. Sodium laurate, disodium ethylenediamine tetraacetate (EDTA) and sodium tauro-24,25-dihydrofusidate (STDHF), which are effective peptidase inhibitors were chosen as additives to a LHRH hydrogel delivery system and LHRH solutions. A Polycarbophil hydrogel formulation showed 3.4 times increase in LHRH vaginal membrane permeability compared with a solution formulation. Vaginal membrane permeability from the Polycarbophil was greater than that from Pemulen hydrogels. This may be due to the larger bioadhesive values. LHRH solution with EDTA(2%), STDHF(1%) and sod. laurate(0.5%) showed 4.1 times, 4.8 times and 6.0 times of ovulation inducing activity compared with control. These results suggest that enzyme inhibition effect of EDTA, STDHF and sod. laurate may result in substantial enhancement of vaginal absorption. By administration of Polycarbophil hydrogels containing LHRH the ovulation inducing activity was 3.3 times greater than the solutions. This result indicates the bioadhesive hydrogels as well as peptidase inhibition significantly improved absorption of LHRH. By coadministration with these inhibitors the ovulation inducing activity of Polycarbophil hydrogel containing LHRH was comparable with subcutaneous administration in ovulation inducing activity.     

Oral absorption studies of lipid-polylysine conjugates of thyrotropin releasing hormone (TRH1) and luteinizing hormone releasing hormone (LHRH1)

The lipoamino acids and their oligomers provide an excellent means of enhancing peptide lipophilicity and also helping to increase the stability of the peptide and protect it from enzymatic degradation. Thyrotropin releasing hormone (TRH) and luteinizing hormone releasing hormone (LHRH) were extended on the N-terminal with one and two lipoamino acids and labelled with the ³H-acetyl group. TRH and LHRH conjugates were also prepared where the compounds were extended with two lipoamino acids, a polylysine unit and the N-terminal labelled with the ³H-acetyl group. The higher lipophilicity resulted in a higher Caco-2 cell association and also a higher rate of oral uptake. The addition of the polylysine system increased the water solubility, as well as the oral uptake of the conjugates. The conjugates developed have been absorbed and detected after oral administration and appear to be stable for a considerable time in vivo.     

Oral absorption studies of lipid-polylysine conjugates of thyrotropin releasing hormone (TRH1) and luteinizing hormone releasing hormone (LHRH1)

The lipoamino acids and their oligomers provide an excellent means of enhancing peptide lipophilicity and also helping to increase the stability of the peptide and protect it from enzymatic degradation. Thyrotropin releasing hormone (TRH) and luteinizing hormone releasing hormone (LHRH) were extended on the N-terminal with one and two lipoamino acids and labelled with the ³H-acetyl group. TRH and LHRH conjugates were also prepared where the compounds were extended with two lipoamino acids, a polylysine unit and the N-terminal labelled with the ³H-acetyl group. The higher lipophilicity resulted in a higher Caco-2 cell association and also a higher rate of oral uptake. The addition of the polylysine system increased the water solubility, as well as the oral uptake of the conjugates. The conjugates developed have been absorbed and detected after oral administration and appear to be stable for a considerable time in vivo.     

Effect of permeation enhancer pretreatment on the iontophoresis of luteinizing hormone releasing hormone (LHRH) through human epidermal membrane (HEM)

A 2 x 2 factorial design was performed to determine the effect of a permeation enhancer (oleic acid/propylene glycol), iontophoresis (2 V), and the combination of the two treatments on the permeation enhancement of a model peptide, LHRH (luteinizing hormone releasing hormone), through human epidermal membrane (HEM). In parallel studies, TEAB (tetraethylammonium bromide, a small ionic solute) and sucrose (an electroosmotic flow marker) were also investigated. Structural changes in the HEM were monitored via conductance measurements, differential scanning calorimetry (DSC), and infrared (IR) spectroscopy experiments. LHRH enhancement due to enhancer in combination with iontophoresis (I + E; 29.5 times passive permeability, P), was greater than during iontophoresis alone (I; 14.3) and enhancer treatment alone (E; 3.5). I + E had an additive effect of I and E, indicating the mechanisms of action of the individual enhancement strategies were likely to be located at different sites in the skin. Also, no synergistic enhancement was observed with I + E for either TEAB or sucrose. For TEAB, permeability enhancement due to I (approximately 1400) was much higher than that due to E (14.9), and no additive effect could be detected. For sucrose, E had no effect on either passive or iontophoretic permeability, eliminating the possibility that electroosmosis could explain increases in LHRH permeability. Evidence of synergy between E and I was found, with conductance measurements indicating that I + E synergistically increased the membrane permeability to conducting ions (Na+ and Cl-). It appears these pathways were not available for transport for the solutes used in the current study. DSC and IR investigations showed significant changes in stratum corneum lipid structure following E treatment but not following I. These findings probably arise from the localized action of iontophoresis compared with the bulk action of enhancer. In summary, increased LHRH delivery through HEM in vitro can be achieved using an enhancer in combination with iontophoresis.     

NMR studies on the structure of some cyclic and linear antagonists of luteinizing hormone-releasing hormone (LHRH)

The structure of cyclic antagonists of luteinizing hormone-releasing hormone (LHRH), Ac-D-Phe(p-Cl)¹-D-Phe(p-C1)²-Trp³-Ser⁴-c(Asp⁵-D-Arg⁶-Leu⁷-Lys⁸)-Pro⁹-D-Ala¹⁰-NH₂ ( I ), Ac-D-Phe(p-Cl⁾l-D-Phe(p-Cl)²-D-Trp³-Ser⁴-c(Glu⁵-Arg⁶-Leu⁷-Lys⁸)-Pro⁹-D-Ala¹⁰-NH₂ ( II ) and their linear analogues, Ac-D-Phe(p-Cl)¹-Phe(p-C1)²-Trp³-Ser⁴-Asp⁵-D-Arg⁶-Leu⁷-Lys⁸-Pro⁹-D-Ala¹⁰-NH₂ ( III ) and Ac-D-Phe(p-Cl)¹-D-Phe(p-C1)²-Trp³-Ser⁴-Glu⁵-D-Arg⁶-Leu⁷-Lys⁸-Pro⁹-D-Ala¹⁰-NH₂ ( IV ), have been studied by NMR spectroscopy. The cyclic peptides I and II are more potent antagonists than the corresponding linear peptides in an in vivo assay. All the peptides show propensity of an unusual type II′β-turn involving residues 3–6. Cyclic analogues also show some additional structure around residues 7 and 8 which is absent in the linear peptides. This additional structure in the cyclic peptides may be due to a minor conformation with a β-turn between residues 5 and 8. © Munksgaurd 1995.     

Effect of luteinizing hormone-releasing hormone (LHRH) analogue treatment on a cytokine profile in prostate cancer patients

The aim of the study was to test serum concentrations of the chosen cytokines in patients with prostate cancer (PCa) treated with an luteinizing hormone-releasing hormone (LHRH) analogue. We tested interleukin (IL)-2, IL-10, tumor necrosis factor (TNF)-alpha, interferon (INF)-gamma in blood at three time points; I - before the injection, II - 10 days and III - 20 days after the injection in 14 men with PCa. Patients had one depot injection of the LHRH analogue monthly. The cytokine concentrations in serum samples were determined by ELISA method. Prostate specific antigen (PSA) level was examined before and after six months of the LHRH analogue treatment. After six months of the therapy, we observed normalization of serum PSA value from 16.48 ng/ml to 1.45 ng/ml. LHRH analogue injection resulted in a significant drop of the IL-2 concentration, and the value gradually returned to normal in the next 20 days. IL-10 concentration transiently increased and then was down-regulated. Serum TNF-alpha and INF-gamma concentrations in PCa patients were significantly lower compared to controls and were not affected by the treatment. LHRH analogue treatment in PCa patients modulates concentrations of the chosen cytokines which may result both in antitumor and a transient immunosuppressive effect.     

Luteinizing hormone-releasing hormone (LHRH) agonists in the treatment of breast cancer

This article reviews the use of luteinizing-hormone-releasing hormone (LHRH) agonists in pre- or perimenopausal women with hormone-receptor-positive breast cancer. Estimates of efficacy from systematic reviews, based on several randomized trials, are provided. These show that LHRH agonists can reduce the risk of recurrence and death, and can be an alternative to chemotherapy, particularly for women who would like to avoid early menopause. The benefits can be seen 10 or 15 years later. The main side effects – hot flashes and reduction in bone density – often recede once treatment stops. Ongoing research will provide information about LHRH agonists when used with modern chemotherapy regimens and aromatase inhibitors.     

雷公藤甲素聚乳酸纳米粒对大鼠睾丸组织的影响

目的　观察采用聚乳酸纳米粒能否减轻雷公藤甲素的大鼠睾丸毒性。方法　雄性Wistar大鼠分别ig 0 .2及 0 .6mg·kg- 1雷公藤甲素 (非纳米粒组 )及其聚乳酸纳米粒混悬液 (纳米粒组 ) ,连续给药 15d ,以ig生理盐水的大鼠为对照组 ,测定睾丸的脏器系数及其组织匀浆液中酸性磷酸酶 (ACP)活性和果糖含量 ,光镜观察睾丸组织的病理学变化。结果在 0 .6mg·kg- 1剂量下 ,非纳米粒组睾丸ACP活性和果糖的含量均明显低于纳米粒组 (P <0 .0 5 )。光镜观察显示 ,雷公藤甲素 0 .6mg·kg- 1可引起大鼠睾丸的损伤 ,非纳米粒组引起的病变程度明显重于纳米粒组 ,主要表现为睾丸萎缩 ,各级生精细胞变性、坏死、数量减少或消失 ,出现了多核巨细胞。结论以聚乳酸作为药物载体的纳米体系 ,可明显减轻雷公藤甲素对睾丸的毒性     

Effects of octamethylcyclotetrasiloxane (D4) on the luteinizing hormone (LH) surge and levels of various reproductive hormones in female Sprague-Dawley rats

The objectives of this study were to assess the potential for D₄ to suppress the pre-ovulatory lutenizing hormone (LH) surge, to block or delay ovulation, and to evaluate potential effects on reproductive hormones in rats. Female Sprague–Dawley Crl:CD^® (SD) IGS BR rats received whole-body vapor inhalation exposure to D₄ (0, 700, or 900 ppm) 6 h per day for 3 days. Trunk blood obtained on proestrus at 10 a.m. was evaluated for levels of follicle stimulating hormone (FSH), estradiol (E2), estrone (E1), and progesterone (P4). Other rats had serial blood samples collected via cannula at 2, 4, 6, 8, and 10 p.m. on the day of proestrus and plasma evaluated for LH and prolactin (PRL). Trunk blood was collected at 8 a.m. of estrus and plasma evaluated for FSH, E2, E1, and P4. At 10 a.m. on proestrus, significant increases in E1 levels in the 700 and 900 ppm groups and significant increases in P4 levels in the 900 ppm group were noted. At 8 a.m. on estrus, significant increases in E1, E2, in the E1/E2 ratio and decreases in FSH were noted in the 700 and 900 ppm groups. The major effect on the LH profile was observed most clearly when the rats were grouped by ovulatory status, animals that did or did not ovulate. Regardless of treatment, suppression of the LH surge correlated with blocked ovulation. The percentage of rats that ovulated was (700 ppm, 42%; 900 ppm, 31%) compared to controls (79%). Overall, the data indicate that high exposures to D₄ attenuated the pre-ovulatory LH surge and significantly decreased the portion of female rats that ovulated.     

Influences of peripheral adrenocorticotropin 1–39 (ACTH) and human corticotropin releasing hormone (h-CRH) on human auditory evoked potentials (AEP)

Hormones of the hypothalamus-pituitary-adrenal (HPA) axis have been considered to form part of an efferent humoral system modulating central nervous stimulus processing. The present experiments were designed to compare the effects of iv bolus administrations of placebo, porcine ACTH 1–39 (1.5 U) and h-CRH (25 µg) on auditory evoked potentials (AEPs) in healthy men. Also, cardiovascular parameters, cortisol and self-reported mood were assessed. ACTH significantly reduced the amplitude of the N1 component of the AEP; P1 and P2 remained unchanged. The selective reduction of N1 amplitude defies an interpretation of the changes in terms of a reduced stimulus-induced cortical arousal following ACTH; the ACTH-induced changes may rather indicate an influence on frontocortical functions of directing attention. The effect of ACTH on N1 cannot be attributed to its adrenocorticotropic action or to cardiovascular changes, but appears to represent an intrinsic extraadrenal influence of the hormone. The data do not provide evidence for effects of h-CRH on central nervous stimulus processing in humans, after peripheral administration.     

Synthesis of conjugates between luteinizing hormone releasing hormone (LH-RH) and N-acetyl-muramyl-L-alanyl-D-isoglutamine (MDP) models of totally synthetic vaccines

Two glycopeptides associating the aminoacid sequence of LH-RH with MDP were prepared, using a Lys residue as a linker. These conjugates, Nα MDP N^e (LH-RH)-Lys and Nα MDP N^e (LH-RH)-Lys-NH₂ obtained by condensation of fragments were synthesized by liquid as well as solid phase methods. Both compounds were able to induce anti LH-RH antibodies and immunological castration. They retained the immuno-adjuvant activity of MDP. Such antigen-adjuvant constructs, devoid of carrier and obtained by chemically defined and reproducible synthetic methods could offer suitable tools for structure-activity relationship studies aiming at defining synthetic vaccines.     

Corticotropin releasing factor (CRF): studies in alcohol preferring and non-preferring rats

Electroencephalographic (EEG) responses to corticotropin releasing factor (CRF) as well as CRF concentrations in several brain regions were measured in two lines of rats which have been genetically selected for alcohol preferring (P) or non-preferring (NP) behaviors. Fifteen rats were implanted with chronic electrodes and EEG spectra were evaluated following intracerebroventricular (ICV) administration of CRF (0.15 nmol) or saline. P rats demonstrated a significantly increased EEG response to CRF in the theta frequency range (ANOVA: PREF × DRUG 4–6 Hz,P<0.03; 6–8 Hz,P<0.05) in frontal cortex. A significantly lower concentration of CRF was found in the P rats in hypothalamus (P<0.02), amygdala (P<0.003), prefrontal cortex (P<0.01), and cingulate cortex (P<0.02). The finding that P rats had an increased response to exogenously administered CRF, taken together with decreased CRF concentrations, suggests that CRF receptors may be up-regulated in these animals. Differences in the regulation of CRF neurons may contribute to the expression of behavioral preference for ethanol consumption in these rat lines.Presented in part at the 1990 RSA meeting, Toronto, Canada     

清风胶囊对长期染毒大鼠体重、红细胞及血液流变学的影响

目的：研究戒毒中药清风胶囊对长期吗啡依赖和戒断引起的体内气血变化的影响。方法：通过复制吗啡依赖大鼠反复成瘾和催促戒断动物模型,观察长期染毒大鼠体重、红细胞和血液流变学的改变,评价清风胶囊对长期吗啡依赖和戒断引起的体内气血变化的影响。结果：清风胶囊各剂量组能明显控制吗啡依赖大鼠由于长期躯体依赖和戒断所导致的体重下降,并明显降低全血粘度和血浆粘度,整体改善优于阳性药物组。结论：清风胶囊对长期吗啡依赖和戒断大鼠的血液学指标具有改善作用,并能缓解体重的下降,促进机体的康复。     

Effects of nicotine on body weight and food consumption in rats

Recent human and animal studies have found that cigarette smoking or nicotine administration is accompanied by decreased consumption of sweet-tasting, high caloric foods. Cessation of smoking or nicotine is accompanied by increased consumption of these foods. Changes in consumption of these specific foods may partially account for the inverse relationship between smoking or nicotine and body weight. The present research was designed to determine whether consumption of nonsweet food is affected by nicotine and whether continuous access to only nonsweet foods attenuates the body weight changes associated with nicotine administration and cessation of nicotine administration. Alzet miniosmotic pumps were implanted SC to administer saline or three different concentrations of nicotine to male Sprague-Dawley albino rats for 2–3 weeks. Two studies on a total of 80 rats found an inverse dose-response relationship between nicotine administration and body weight without changes in bland food or water consumption. After cessation of nicotine administration, there were no differences in food consumption or body weight changes between groups. The effects of nicotine on body weight, both during and after drug administration, were attenuated in comparison to the results of studies that provided sweet-tasting foods.     

Effects of nicotine on body weight and food consumption in female rats

Women often report that they smoke cigarettes to avoid weight gains and that they relapse after abstaining from tobacco because of weight gains. Men also report these concerns but to a lesser extent. This gender difference may reflect sociological and cultural pressures about physical appearance, or it may reflect sex differences in the effects of nicotine. The present research was designed to examine the effects of nicotine administration and cessation of nicotine on body weight, food consumption, and water consumption. Alzet miniosmotic pumps were implanted SC to administer saline or three different concentrations of nicotine to female Sprague-Dawley rats for 17 days. This paradigm has been used in previous studies of nicotine and body weight in male rats. Animals were used as subjects to avoid cultural factors and cognitive concerns about body weight. Nicotine administration decreased normal body weight gains and cessation of nicotine was accompanied by significant increases in body weight compared to controls. In contrast to previous studies of male rats, the nicotine-related changes in body weight were accompanied by changes in bland food and water consumption. These findings indicate that females are more sensitive than males to the effects of nicotine on body weight and feeding during and after drug administration.     

Influence of tetrahydrocannabinols (delta8-THC and delta9-THC) on body weight, food, and water intake in rats

Female Wistar rats, six to a group, were injected daily for a 23-day period with Δ⁸-THC (5.0 mg/kg), Δ⁹-THC (2.5 mg/kg) or vehicle. Body weight, food and water intake were recorded every second day. It was found that Δ⁸-THC caused a decrease of body weight, to a level maintained throughout the injection period, with only slight signs of recovery. Both drugs caused a marked decrease of water intake. Food intake was not significantly affected by the drugs. Factors in relation to the effects of THC on body weight, food and water intake are discussed.