The role of serotonin in the NMDA receptor antagonist models of psychosis and cognitive impairment

Objective

To review the evidence that agents which preferentially affect serotonin (5-HT) attenuate the ability of N-methyl-D-aspartate (NMDA) receptor non-competitive antagonists (NMDA-RA), e.g., phencyclidine (PCP), dizocilpine (MK-801), and ketamine, to stimulate locomotor activity (LA), and to impair novel object recognition (NOR).

Rationale

NMDA-RA-induced increased LA and impairment of NOR are widely used models of the pathophysiology of schizophrenia, the mechanism of action of antipsychotic drugs (APDs), and the identification of novel treatments. Serotonin (5-HT) plays an important role in attenuating these effects of NMDA-RA.

Results

Selective 5-HT_2A inverse agonists, e.g., M100907 and ACP-103, and atypical APDs, which are more potent 5-HT_2A than D₂ antagonists, e.g., clozapine and lurasidone, are more effective than selective D₂ receptor antagonists to attenuate NMDA-RA-induced increased LA. 5-HT_2A inverse agonists alone are not effective to improve NMDA-RA-impaired NOR, but augment the effects of atypical, but not typical APDs, to improve NOR. The 5-HT_1A receptor partial agonist tandospirone alone and the 5-HT_1A agonist effects of atypical APDs may substitute for, or contribute to, the effects of D₂ and 5-HT_2A receptor antagonism to reverse the NMDA-RA impairment in NOR. 5-HT₆ and 5-HT₇ receptor antagonists may also attenuate these NMDA-RA-induced behaviors. 5-HT_2C receptor inverse agonist, but not neutral antagonists, block NOR in na?ve rats and the effects of atypical APDs to restore NOR in PCP-treated rats, suggesting the importance of the constitutive activity of 5-HT_2C receptors in NOR.

Conclusions

Multiple 5-HT receptors contribute to effective treatments to reverse adverse effects of NMDA-RA which model psychosis and cognitive impairment.     

A 4-week versus a 3-week schedule of gemcitabine monotherapy for advanced pancreatic cancer: a randomized phase II study to evaluate toxicity and dose intensity

Background

This randomized phase II study compared the efficacy and toxicity between 4-week and 3-week schedules of gemcitabine monotherapy in advanced pancreatic cancer.

Methods

Patients with advanced pancreatic cancer were randomly assigned to either a 4-week schedule (gemcitabine at 1000?mg/m2 as a 30-min infusion weekly for 3 consecutive weeks every 4?weeks) or a 3-week schedule (gemcitabine at 1000?mg/m2 as a 30-min infusion weekly for 2 consecutive weeks every 3?weeks). The primary endpoint was the compliance rate during the first 8?weeks between the two groups.

Results

A total of 90 patients were enrolled. The compliance rate during the first 8?weeks was the same (53.3%). For the 4- and 3-week schedules, the tumor response rates were 14.2 and 17.1% (p?=?0.92), median progression free survival was 112 and 114?days (p?=?0.82), and median overall survival was 206 and 250?days (p?=?0.84), respectively. Grade 3?? neutropenia was the major adverse event in both schedules: 37.7 and 35.5% (p?=?0.82). In contrast, thrombocytopenia (platelet count <70000/mm3) was significantly higher for the 4-week schedule: 26.6 and 4.4% (p?=?0.008). The mean received dose intensity was equal: 588 and 550?mg/m2/week (p?=?0.14).

Conclusions

The 3-week schedule of gemcitabine did not improve the compliance rate during 8?weeks compared with the 4-week schedule, but it attained a comparable efficacy with lower toxicity. Further investigation will be needed to introduce it into daily practice. Clinical trial registration number: UMIN ID 974.     

Influence of Esculetin on Incidence, Proliferation, and Cell Kinetics of Mammary Carcinomas Induced by 7,12-Dimethylbenz[α]anthracene in Rats on High- and Low-fat Diets

The effects of a high-fat diet and esculetin were investigated on 7,12-dimethylbenz[α]anthracene (DMBA)-induced mammary carcinogenesis in female Sprague-Dawley rats. Rats were given a 5-mg dose of DMBA. Seven days later, they were fed either a high-fat (20% soybean oil) or low-fat (0.5% soybean oil) diet. A half of the rats received diets containing 0.03% esculetin. Esculetin significantly inhibited tumor incidence, growth and cell kinetics of the tumor in the rats fed the high-fat and the low-fat diets. Our findings indicate that DMBA-induced mammary tumorigenesis is affected by lipoxygenase products.     

Risk of internal mammary lymph node metastases and its prognostic value in breast cancer patients

The risk of an internal mammary lymph node (IMN) metastasis and its prognostic value for patients with invasive breast cancer were assessed by evaluating 142 patients who had either a mastectomy with lymph node dissection or a biopsy of the IMN. By univariate analysis, overall survival significantly correlated with the patient's age, clinical axillary node status, tumor size, and DNA ploidy, as well as histologically confirmed axillary and IMN metastases. By multivariate analysis, however, only the presence of axillary and IMN metastases appeared to be an important independent factor affecting survival. However, the incidence of IMN metastases was associated significantly with age, clinical tumor and axillary node status, tumor size, axillary lymph node metastases, and DNA ploidy. Accordingly, the patient's age, tumor size, DNA ploidy, and axillary lymph node metastases proved to be effective variable for discrimination. Consequently, in predicting the presence of IMN metastases, a diagnostic accuracy of 82%, a sensitivity of 84%, and a specificity of 82% can be achieved by a discriminant function. We conclude that the discriminant function with these four variables is effective in assessing the risk of IMN metastases. © 1993 Wiley-Liss, Inc.     

Expression of thymidylate synthase, orotate phosphoribosyltransferase and dihydropyrimidine dehydrogenase in thymic epithelial tumors

Background

It remains unclear whether thymidylate synthase (TS), orotate phosphoribosyltransferase (OPRT) and dihydropyrimidine dehydrogenase (DPD) expressions are associated with the pathogenesis of thymic epithelial tumors. Therefore, we investigated the expression of TS, OPRT and DPD in thymic epithelial tumors.

Patients and methods

Fifty-six patients with thymic epithelial tumors were included in this study. Tumors sections were stained by immunohistochemistry for TS, OPRT, DPD, microvessel density (MVD) determined by CD34, and p53. We also conducted in vitro study of TS, OPRT and DPD expression using thymic carcinoma, thymic tumor and thymic fibroblast cell lines.

Results

TS, OPRT and DPD were expressed in 61%, 48% and 41%, respectively. High grade malignancy is significantly associated with higher expression of TS, OPRT and DPD in thymic epithelial tumors. These biomarkers were closely associated with p53 and MVD, and the overexpression of TS and DPD was a prognostic marker for predicting poor outcome in univariate analysis. Our in vitro study showed that marked overexpression of TS and OPRT was observed in thymic carcinoma cells, but not in thymic tumor cells, or thymic fibroblast cells.

Conclusions

The expression of TS, OPRT and DPD was closely related to the grade of malignancy in thymic epithelial tumors. A positive expression of TS, DPD and OPRT might be an important factor in predicting the effectiveness of 5-FU based chemotherapy in this disease.     

Internal mammary sentinel node biopsy for breast cancer: is it practicable and relevant? (Review)

Sentinel lymph node (SLN) biopsy is a useful way of assessing axillary nodal status and obviates unnecessary axillary lymph node dissection for patients with node-negative breast cancer. However, SLN can also be located in the internal mammary lymph node (IMN) chain or elsewhere. The practicability and relevance of internal mammary SLN is reviewed and discussed. Axillary and IMN status have similar predictive value for survival, and the involvement of IMNs has prognostic value for both axillary node-negative and node-positive patients. Although parasternal recurrence is fortunately rare after modified radical mastectomy or breast conserving surgery, if left untreated it develops not infrequently as a clinically evident disease in patients with histologic involvement of IMNs. Internal mammary SLNs can be identified by means of lymphoscintigraphy and gamma-detection probe after peritumoral injection of radioisotopes. A positive internal mammary SLN biopsy would be an indication for internal mammary radiotherapy as well as adjuvant systemic treatment. However, the reported incidence of positive internal mammary SLNs is still lower than expected, because the spread of radioisotope activity is not synonymous with nodal positivity. Internal mammary SLN biopsy is considered to be still in the investigative stage. More data are needed on the correction of a internal mammary SLN and pathologic positivity, so that further clinical investigation is clearly warranted.     

Dye-guided sentinel lymphadenectomy in clinically node-negative and node-positive breast cancer patients

Background  Sentinel lymphadenectomy has been used to assess the axillary nodal status in patients with breast cancer in an attempt to avoid unnecessary axillary dissection. Most studies have examined the utility of this procedure in clinically node-negative patients. However, the clinical evaluation of axillary nodes is often inaccurate for both clinically node-negative and clinically node-positive patients. Methods  We performed dye-guided sentinel lymphadenectomy in both clinically node-negative and clinically node-positive patients with breast cancer. All patients also underwent a formal axillary dissection. The results of imprint cytology, frozen sections, and permanent sections of the sentinel lymph node (SLN) were compared with each other and with histologic findings of the nonsentinel nodes. Results  The SLN was identified in 30 (79%) of 38 patients with clinically negative nodes, and in 11 (92%) of 12 patients with clinically positive nodes. For clinically node-negative patients, SLN evaluation yielded a diagnostic accuracy of 90%, a sensitivitiy of 72%, and a specificity of 100%. For clinically node-positive patients, these values were 100%, 100% and 100%, respectively. These values were not significantly different for the two groups of patients. Conclusions  Sentinel lymphadenectomy may be useful in assessing the axillary nodal status of both clinically node-positive and clinically node-negative breast cancer patients.     

Visualization of the thymus with therapeutic doses of radioiodine in patients with thyroid cancer

Two cases of papillary carcinoma of the thyroid are presented in which whole-body scans following therapeutic doses of iodine-131 revealed intense anterior mediastinal uptake. In both cases, the mediastinal uptake was absent from scans obtained after removal of the entire thymus. Histologically, the resected thymus glands showed hyperplasia and contained neither thyroid tissue nor metastatic foci of thyroid carcinoma. We therefore concluded that anterior mediastinal uptake of radioiodine may be caused by hyperplasia of the thymus.     

Serotonin potentiates high-glucose-induced endothelial injury: the role of serotonin and 5-HT(2A) receptors in promoting thrombosis in diabetes

To clarify the involvement of 5-hydroxytryptamine (5-HT) in promotion of thrombogenesis in diabetes, we examined the inhibitory effect of sarpogrelate, a 5-HT(2A) receptor antagonist, on thrombus formation in diabetic rats. In streptozotocin-induced diabetic rats, polyethylene tube-induced thrombus formation was enhanced compared with that in normal rats. The thrombogenesis was inhibited by sarpogrelate; cilostazol, a PDE3 inhibitor; and aspirin, a COX inhibitor, by 75.8%, 42.3%, and 34.3%, respectively. The inhibition by sarpogrelate was more pronounced in diabetic rats than normal ones. High glucose and 5-HT increased the expression of vascular cell adhesion molecule-1 (VCAM-1) in human umbilical vein endothelial cells (HUVECs) and combination of both high glucose and 5-HT further potentiated the effect. Sarpogrelate but not aspirin inhibited the increase in VCAM-1 expression induced by high glucose and 5-HT. These findings suggest that 5-HT mediates the enhanced thrombogenesis in diabetes and suggests that a 5-HT(2A) receptor antagonist may have novel therapeutic potential for the treatment of diabetic complications.     

Localization of Ang-1, -2, Tie-2, and VEGF expression at endothelial-pericyte interdigitation in rat angiogenesis

Endothelial cells and pericytes play critical role in angiogenesis, which is controlled, in part, by the angiopoietin (Ang)/Tie-2 system and vascular endothelial growth factor (VEGF). Here, we investigated Ang, Tie-2, and VEGF expression within endothelial cells and pericyte interdigitations (EPI), which consist of cytoplasmic projections of pericytes and corresponding endothelial indentations. After subcutaneous implantation of a thermoreversible gelation polymer disc in rats, the capillary density was low on day 5, increased to a peak on day 7, and then decreased on days 10-20. A small number of EPI were observed on day 5, then increased sharply to a peak on day 10, but had decreased on day 20. Light and electron microscopy immunohistochemical and RNA in situ hybridization analyses revealed that Tie-2 localized at endothelial cells, and Ang-2 localized at endothelial cells and pericytes, while Ang-1 and VEGF localized at pericytes, and Ang-1 was most intensely observed at EPI of pericytes. Conventional quantitative RT-PCR and Western blot analyses revealed that the level of Ang-1 was low on days 5-7, then increased on days 10-20, while the level of VEGF was high on days 5-10, but had decreased on day 20. The level of Ang-2 remained high and Tie-2 remained at the level of the control on days 5-20. The present study showed that the angiogenic phase might be initiated by increases in Ang-2 and VEGF, while the microvessel maturation phase might be initiated by a relative increase in Ang-1 and a decrease in VEGF. Moreover, EPI might serve as a pathway for the Ang-1/Tie-2 system, with VEGF promoting pericyte recruitment for microvascular integrity.