Drug-Cannabinoid Interactions in Selected Therapeutics for Symptoms Associated with Epilepsy, Autism Spectrum Disorder, Cancer, Multiple Sclerosis, and Pain.

Clinical practice entails a translation of research that assists in the use of scientific data and therapeutic evidence for the benefit of the patient. This review critically summarizes the potential impact of cannabinoids in conjunction with other drugs when associated with treatments for epilepsy, autism spectrum disorder, cancer, multiple sclerosis, and chronic pain. In these associations, potential drug interactions may occur and alter the predicted clinical results. Therefore, the potential for drug interactions must always be assessed to avoid therapeutic failures and/or increased side effects. Some effects may be additive, synergistic, or antagonistic, but changes in absorption, distribution, metabolism, particularly through cytochrome P450 (CYP) isoenzymes (e.g., CYP2C9 and CYP3A4), and excretion may also occur. For example, the combination of cannabis-derived compounds and the antifungal drug ketoconazole, a CYP3A4 inhibitor, increases the plasma concentration of Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). In contrast, rifampicin, a CYP3A4 inducer, stands out for reducing plasma THC levels by approximately 20-40% and 50% to 60% for CBD. Other CYP3A4 inhibitors and inducers are likely to have a similar effect on plasma concentrations if co-administered. Pharmacokinetic interactions with anticonvulsant medications have also been reported, as have pharmacodynamic interactions between cannabinoids and medications with sympathomimetic effects (e.g., tachycardia, hypertension), central nervous system depressants (e.g., drowsiness, ataxia), and anticholinergics (e.g., tachycardia and somnolence). Although further studies are still pending, there is currently clinical evidence supporting drug interactions with cannabinoids, requiring doctors to evaluate the risk of drug combinations with cannabinoids and vice versa. The tables provided here were designed to facilitate the identification of biorelevant interactions that may compromise therapeutic efficacy and toxicity.

Analytical methods for honeybee venom characterization.

The discovery of new drugs has benefited significantly from the development of research in venomics, increasing our understanding of the envenomation processes. It has been previously reported that honeybee venom (HBV) exhibits several pharmacological activities such as anti-inflammatory, antibacterial, antimutagenic, radioprotective, and anticancer activity and may inclusively act as a complementary treatment for SARS-CoV-2. It composition consists mainly on melittin, phospholipase A2, and apamin but other constituents such as hyaluronidase, mast cell degranulating peptide and secapin are also relevant for its bioactivity. However, and because HBV is not officially recognized as a drug, until now, the international community did not establish quality standards for it. To uncover its exact composition, and boost the discovery of HBV-derived drugs, a significant number of techniques were developed. In this review, a relevant overview of the so far published analytical methods for HBV characterization is organized with the aim to accelerate its future standardization. The literature search was performed within PubMed, Google Scholar, and Science Direct by selecting specific documents and exploring HBV evaluation.

Chemical, Cytotoxic, and Anti-Inflammatory Assessment of Honey Bee Venom from Apis mellifera intermissa.

The venom from Apis mellifera intermissa, the main honey bee prevailing in Morocco, has been scarcely studied, despite its known potential for pharmacological applications. In the present work, we investigated the composition, the anti-inflammatory activity, and the venom's cytotoxic properties from fifteen honey bee venom (HBV) samples collected in three regions: northeast, central, and southern Morocco. The chemical assessment of honey bee venom was performed using LC-DAD/ESI/MSn, NIR spectroscopy and AAS spectroscopy. The antiproliferative effect was evaluated using human tumor cell lines, including breast adenocarcinoma, non-small cell lung carcinoma, cervical carcinoma, hepatocellular carcinoma, and malignant melanoma. Likewise, we assessed the anti-inflammatory activity using the murine macrophage cell line. The study provides information on the honey bee venom subspecies' main components, such as melittin, apamin, and phospholipase A2, with compositional variation depending on the region of collection. Contents of toxic elements such as cadmium, chromium, and plumb were detected at a concentration below 5 ppm, which can be regarded as safe for pharmaceutical use. The data presented contribute to the first study in HBV from Apis mellifera intermissa and highlight the remarkable antiproliferative and anti-inflammatory effects of HBV, suggesting it to be a candidate natural medicine to explore.

Advances on Natural Polyphenols as Anticancer Agents for Skin Cancer.

Polyphenols are one of most important phytochemicals distributing in herb plants, vegetables and fruits, which known as important anticancer agents. Given the high incidence and mortality of skin cancer, this study aimed to uncover the chemopreventive effects of polyphenols against skin cancer metastasis. Electronic databases including Scopus, PubMed, and Cochrane library were used to compile the literature from 2000 to August 2019. Only in vivo mechanistic studies with English full-texts were chosen for this review. Polyphenols were included in this study if they were administered in purified form; while total extract and fractions were excluded. Among the 8254 primarily selected papers, only a final number of 34 studies were included. The chemopreventive effects of polyphenols as anthocyanins, ellagitanins, EGCG, oleuropeindihydroxy phenyl, punicalagin, quercetin, resveratrol and theaflavin, were mainly examined in treatment of melanoma as the highly metastatic form of this cutaneous cancer. Those properties are mediated by modulation of angiogenesis, apoptosis, inflammation, metastasis, proliferation, pathways such as EGFR/MAPK, mTOR/PI3K/Akt, JAK/STAT, FAK/RTK2, PGE-2/VEGF, PGE-1/ERK/HIIF-1α, and modulation of related signals including NF-κB, P21WAF/CIP1, Bim, Bax, Bcl2, Bclx, Bim, Puma, Noxa, ILs and MMPs. Chemopreventive effects of polyphenols are mediated by several signaling pathways against skin carcinogenesis and metastasis, implying the importance of polyphenols to open up new horizons in development of anti-skin cancer therapeutic strategies.

Endocrine disrupting chemicals: Impact on human health, wildlife and the environment.

Endocrine disrupting chemicals are a group of pollutants that can affect the endocrine system and lead to diseases and dysfunctions across the lifespan of organisms. They are omnipresent. They are in the air we breathe, in the food we eat and in the water we drink. They can be found in our everyday lives through personal care products, household cleaning products, furniture and in children's toys. Every year, hundreds of new chemicals are produced and released onto the market without being tested, and they reach our bodies through everyday products. Permanent exposure to those chemicals may intensify or even become the main cause for the development of diseases such as type 2 diabetes, obesity, cardiovascular diseases and certain types of cancer. In recent years, legislation and regulations have been implemented, which aim to control the release of potentially adverse endocrine disrupting chemicals, often invoking the precautionary principle. The objective of this review is to provide an overview of research on environmental aspects of endocrine disrupting chemicals and their effects on human health, based on evidence from animal and human studies. Emphasis is given to three ubiquitous and persistent groups of chemicals, polychlorinated biphenyls, polybrominated diphenyl ethers and organochlorine pesticides, and on two non-persistent, but ubiquitous, bisphenol A and phthalates. Some selected historical cases are also presented and successful cases of regulation and legislation described. These led to a decrease in exposure and consequent minimization of the effects of these compounds. Recommendations from experts on this field, World Health Organization, scientific reports and from the Endocrine Society are included.

Bee Collected Pollen and Bee Bread: Bioactive Constituents and Health Benefits.

Bee products were historically used as a therapheutic approach and in food consumption, while more recent data include important details that could validate them as food supplements due to their bioproperties, which support their future use as medicines. In this review data, data collected from bee pollen (BP) and bee bread (BB) essays will be discussed and detailed for their nutritional and health protective properties as functional foods. Dietary antioxidants intake derived from BP and BB have been associated with the prevention and clinical treatment of multiple diseases. The beneficial effects of BP and BB on health result from the presence of multiple polyphenols which possess anti-inflammatory properties, phytosterols and fatty acids, which play anticancerogenic roles, as well as polysaccharides, which stimulate immunological activity. From the main bioactivity studies with BP and BB, in vitro studies and animal experiments, the stimulation of apoptosis and the inhibition of cell proliferation in multiple cell lines could be one of the major therapeutic adjuvant effects to be explored in reducing tumor growth. Tables summarizing the main data available in this field and information about other bio-effects of BP and BB, which support the conclusions, are provided. Additionally, a discussion about the research gaps will be presented to help further experiments that complete the tree main World Health Organization (WHO) Directives of Efficiency, Safety and Quality Control for these products.

Gamma Irradiated Rhodiola sachalinensis Extract Ameliorates Testosterone-Induced Benign Prostatic Hyperplasia by Downregulating 5-Alpha Reductase and Restoring Testosterone in Rats.

The effect of Rhodiola sachalinensis Boriss extract irradiated with 50 kGy gamma rays (HKC) on benign prostatic hyperplasia (BPH) was investigated. Seven-week-old male SD rats received a subcutaneous injection of 20 mg/kg of testosterone propionate (TP) to induce BPH. Then, the testosterone only group received testosterone, the testosterone + finasteride group received testosterone and finasteride (5 mg/kg), the testosterone + HKC group received testosterone and HKC extract (500 mg/kg). Prostate weight and the dihydrotestosterone (DHT) levels in serum or prostate tissue were determined. The mRNA expressions of 5-alpha reductase (AR) in prostate tissue were also measured. Compared to the control group, prostate weight was significantly improved in the TP group and decreased in the HKC and finasteride-treated groups. Furthermore, the mRNA expression of 5-AR in the prostate was significantly reduced in the HKC and finasteride-treated groups. Similarly, the expression levels of α-smooth muscle actin (α-SMA) and cytokeratin, which are associated with prostatic enlargement in the HKC and finasteride groups, were much lower than in the TP group. HKC treatment showed similar efficacy to finasteride treatment on rats with testosterone-induced BPH. HKC may be explored as a potential new drug for BPH treatment.

Polyphenolic characterisation and bioactivity of an Oxalis pes-caprae L. leaf extract.

The present work is focused on the characterisation of the polyphenolic content of an Oxalis pes-caprae L. leaf extract and on the evaluation of its bioactivity with particular interest on its vascular activity and antioxidant potential. The polyphenolic content was characterised by HPLC-DAD and LC-MS/MS. The vascular activity was evaluated according to the influence on the serotonergic and adrenergic systems of the human internal mammary artery (HIMA). Antioxidant and neuroprotective studies were also conducted. Several luteolin and apigenin derivatives were identified as main constituents of the extract, which did not present any contractile effect nor had any effect on the serotonergic system of HIMA. However, it showed antagonistic effect on the adrenergic system, inhibiting the contraction to noradrenaline (reduction of 58.44% of maximum contraction). The extract showed antioxidant activity and standardised luteolin and apigenin derivatives showed neuroprotective potential, particularly homoorientin.

Lewis, Fischer 344, and sprague-dawley rats display differences in lipid peroxidation, motor recovery, and rubrospinal tract preservation after spinal cord injury.

The rat is the most common animal model for the preclinical validation of neuroprotective therapies in spinal cord injury (SCI). Lipid peroxidation (LP) is a hallmark of the damage triggered after SCI. Free radicals react with fatty acids causing cellular and membrane disruption. LP accounts for a considerable amount of neuronal cell death after SCI. To better understand the implications of inbred and outbred rat strain selection on preclinical SCI research, we evaluated LP after laminectomy sham surgery and a severe contusion of the T9 spinal cord in female Sprague-Dawley (SPD), Lewis (LEW), and Fischer 344 (F344) rats. Further analysis included locomotor recovery using the Basso, Beattie, and Bresnahan (BBB) scale and retrograde rubrospinal tract tracing. LEW had the highest levels of LP products 72 h after sham surgery and SCI, significantly different from both F344 and SPD. SPD rats had the fastest functional recovery and highest BBB scores; these were not significantly different to F344. However, LEW rats achieved the lowest BBB scores throughout the 2-month follow-up, yielding significant differences when compared to SPD and F344. To see if the improvement in locomotion was secondary to an increase in axon survival, we evaluated rubrospinal neurons (RSNs) via retrograde labeling of the rubrospinal tract and quantified cells at the red nuclei. The highest numbers of RSNs were observed in SPD rats then F344; the lowest counts were seen in LEW rats. The BBB scores significantly correlated with the amount of positively stained RSN in the red nuclei. It is critical to identify interstrain variations as a potential confound in preclinical research. Multi-strain validation of neuroprotective therapies may increase chances of successful translation.

Neutrophilia induced by histamine challenge in guinea pig: The role of IL-5, IL-10 and IL-17A, but not CXCL8

Background: Histamine is widely used as a pharmacological tool for the evaluation of airway responsiveness. Nevertheless, undesirable and contradictory effects have been described after histamine provocation tests. In previous evaluations of airway responsiveness in a guinea pig asthma model, the control groups consistently showed high neutrophil counts in bronchoalveolar lavage fluid (BALF) immediately after the histamine challenge. The changes in cytokine and chemokine levels in guinea pig lung associated with histamine induced-neutrophilia are described in this paper. Methods: Immediately and 24 h after histamine challenge, airway wall and BALF eosinophil and neutrophil counts as well as lung cytokines (IL-5, IL-10, IL-17A, TNFα and TGFβ) and chemokines (CCL11 and CXCL8) levels were evaluated. Results: Histamine inhalation generated an all-or-none bronchial response, and the dose inducing airway obstruction was similar in all guinea pigs. Immediate increases in neutrophil counts in airway wall and BALF and in IL-5, IL-10 and IL-17A levels in the lung homogenate were observed after histamine challenge. Significant correlations were found between neutrophil counts from airway wall and IL-5, IL-10 and IL-17A levels in the lung homogenate. Conclusions: Histamine inhalation induced rapid neutrophil LBA and airway wall infiltration that was not associated with CXCL8 expression but with a Th2 and Th17 cytokines that probably are involved in the recruitment and activation of neutrophils.

Antigen-induced airway hyperresponsiveness in absence of broncho-obstruction in sensitized guinea pigs.

BACKGROUND: Airway obstruction after antigen challenge is not always observed in patients with allergic asthma, even if they develop hyperresponsiveness. A similar event is observed in our guinea pig model of allergic asthma. Our aim was to study this phenomenon. METHODS: Sensitized guinea pigs were challenged with ovalbumin (OVA) 3 times every 10 days. Animals were divided into 2 groups: (1) Guinea pigs exhibiting airway obstruction after antigen challenge (R = responders), and (2) guinea pigs lacking airway obstruction response (NR = nonresponders). After the third antigen challenge, antigen-induced airway hyperresponsiveness (AI-AHR), serum OVA-specific immunoglobulins, bronchoalveolar lavage fluid (BALF) inflammatory cells, histamine, cysteinyl leukotrienes and thromboxane A2 (TxA2) BALF levels, and in vitro tracheal contraction induced by contractile mediators and OVA were evaluated. RESULTS: R group consistently displayed a transient antigen-induced airway obstruction (AI-AO) as well as AI-AHR, high T×A2, histamine, OVA-IgG1, OVA-IgE and OVA-IgA levels, and intense granulocyte infiltration. NR group displayed no AI-AO and no changes in BALF measurements; nevertheless, AI-AHR and elevated OVA-IgG1 and OVA-IgA levels were observed. In all groups, histamine, TxA2 and leukotriene D4 induced a similar contraction. Tracheal OVA-induced contraction was observed only in R group. AI-AHR magnitude showed a direct association with OVA-IgG1 and OVA-IgA levels. The extent of AI-AO correlated directly with OVA-IgE and inversely with OVA-IgA levels. CONCLUSIONS: Our data suggest that TxA2 and histamine participate in AI-AO likely through an IgE mechanism. AI-AHR might occur independently of AI-AO, contractile mediators release, and airway inflammatory cell infiltration, but IgA and IgG1 seem to be involved.

Chronic administration of tibolone modulates anxiety-like behavior and enhances cognitive performance in ovariectomized rats.

Hormone replacement therapy (HRT) may be prescribed to prevent the symptoms of menopause. This therapy may include estrogenic and/or progestin components and may increase the incidence of endometrial and breast cancers. Tibolone (TIB), which is also made up of estrogen and progestin components, is often used to reduce the impact of HRT. However, the effect of TIB on the processes of learning, memory and anxiety has yet to be fully elucidated. The aim of this study was to evaluate the long-term effect on learning, memory processes and anxiety in ovariectomized rats caused by different doses of TIB (0 mg/kg, 0.01 mg/kg, 0.1 mg/kg 1.0 mg/kg and 10 mg/kg, administered daily via the oral route for 18 weeks). Two behavioral animal models, the autoshaping and T maze models were employed. The concentrations of acetyl choline transferase (ChAT) and tryptophan hydroxylase (TPH) in the hippocampus were directly measured by Western blot. No significant changes were observed in the autoshaping model and spontaneous activity test. In the T maze, increased latency was observed with TIB doses of 1 and 10 mg/kg compared to the vehicle. We observed that the ChAT content decreased with increasing doses of TIB, whereas TPH content increased with doses of 1 and 10 mg/kg of TIB. These data indicate that high doses of TIB improved emotional learning, which may be related to the modulation of the cholinergic and serotonergic systems by TIB.

Aerosolized polymerized type I collagen reduces airway inflammation and remodelling in a guinea pig model of allergic asthma.

Collagen-polyvinylpyrrolidone (Collagen-PVP) has been demonstrated to elicit immunomodulatory properties in different chronic inflammatory diseases. Nevertheless, its effects on asthma are still unknown. We have evaluated whether collagen-PVP could modulate airway inflammation and remodelling in a guinea pig model of allergic asthma. Sensitized guinea pigs were challenged with the allergen (ovalbumin) six times (at 10-day intervals). From the third challenge on, animals were treated every 5 days with saline aerosols containing 0.16, 0.33, or 0.66 mg/ml of collagen-PVP (n = 5, respectively). Some guinea pigs, sensitized and challenged with saline as well as treated with 0 or 0.66 mg/ml collagen-PVP, were included in the study as control (n = 7) and sham groups (n = 5), respectively. From the first challenge on, ovalbumin induced a transient airway obstruction, measured by barometric plethysmography, which was not modified by collagen-PVP treatments. After the last allergen challenge, guinea pigs were anesthetized to obtain bronchoalveolar lavage (BAL) and the left lung caudal lobe. As expected, BAL cell count from allergen-challenged guinea pigs showed abundant neutrophils and eosinophils, as well as numerous tumor necrosis factor (TNF)-alpha-expressing granulocytes and macrophages in airway wall (determined by immunohistochemical assay). Neutrophilia and TNF-alpha-expressing leukocytes, from collagen-PVP treated animals, diminished from 0.16 mg/ml, and eosinophilia from 0.66 mg/ml of collagen-PVP doses. Histological changes induced by allergen challenges include thickening of connective tissue below airway epithelium and vascular wall widening of airway adjacent vessels; these changes were reduced by collagen-PVP treatment. Collagen-PVP seems to have anti-inflammatory and antifibrotic properties in this guinea pig asthma model.

Capacitative Ca2+ entry during Ca2+ undershoot in bovine airway smooth muscle.

In numerous cells, Ca2+ undershoot is commonly observed after withdrawing stimulus that release Ca2+ from intracellular stores. In airway smooth muscle (ASM), the fast intracellular Ca2+ concentration ([Ca2+]i) drop during undershoot is produced by sarcoplasmic reticulum (SR) reloading, but the mechanisms involved in the long lasting basal [Ca2+]i recovery are unknown. We investigated the post-caffeine Ca2+ undershoot recovery in ASM isolated cells from bovine trachea. [Ca2+]i determination was done by a ratiometric method by incubating cells with Fura-2/AM. After inducing a transient response, caffeine withdrawn generated a Ca2+ undershoot. SR-Ca2+ content during maximum undershoot drop was approximately 40% of SR caffeine-releasable Ca2+ (SR-Ca2+ load). Undershoot recovery rate increased in presence of cyclopiazonic acid (CPA, a SR-Ca2+ ATPase inhibitor), but SR-Ca2+ load was reduced. Genistein (a tyrosine kinase inhibitor) slowed down the Ca2+ undershoot drop and the SR-Ca2+ load but did not affect the undershoot recovery rate. Ni2+ (a capacitative Ca2+ inhibitor), but neither SKF-96365 (a passive Ca2+ entry inhibitor) nor econazole (a capacitative Ca2+ inhibitor in non-excitable cells), inhibited Ca2+ undershoot recovery and SR-Ca2+ load. Our data suggest that capacitative Ca2+ entry is involved in bovine ASM Ca2+ undershoot recovery, and that changes in Ca2+ undershoot have an impact on SR-Ca2+ loading which might affect in turn ASM excitability.

Sesquiterpenoids from antidiabetic Psacalium decompositum block ATP sensitive potassium channels.

ETHNOPHARMACOLOGICAL RELEVANCE: The hypoglycemic effect of root and rhizome aqueous decoction of Psacalium decompositum (Asteraceae), a medicinal herb from Mexico, has been experimentally demonstrated, leading to the identification of several hypoglycemic sesquiterpenoids, such as cacalol, and the mixture of 3-hydroxycacalolide, and epi-3-hydroxycacalolide; however, the mechanism of action of these compounds is unknown. AIM OF THE STUDY: To establish whether cacalol, cacalone epimer mixture and cacalol acetate may block adenosine triphosphate-sensitive potassium channels (K(ATP) channels) in a similar way to the antidiabetic drug glibenclamide. MATERIALS AND METHODS: Cacalol, cacalone epimer mixture, and cacalol acetate were tested on the diazoxide-induced relaxation of male rat aortic rings precontracted with phenylephrine (3.2x10(-6)M). RESULTS: Cacalol (10(-5)M), cacalol acetate and the cacalone epimer mixture (10(-4)M) inhibited the diazoxide effect, in a similar manner and concentration as glibenclamide (10(-5)M). Cacalone epimer mixture exerted this effect in a concentration-dependent manner (P<0.01). Cacalol (10(-4)M), irreversibly inhibited the diazoxide-induced relaxation, and displayed activity at a lower concentration (10(-5)M) than cacalone epimer mixture and cacalol acetate. CONCLUSIONS: These results suggest that the studied compounds block K(ATP) channels in a similar way to glibenclamide in rat aorta. However, controversial data indicate that Psacalium decompositum sesquiterpenoids are less effective than glibenclamide in lowering plasma glucose levels, suggesting that cacalol and cacalone epimer mixture, as well as cacalol acetate, may display a higher affinity to SUR2 subunit of K(ATP) channels in aortic smooth muscle than to SUR1 subunit in pancreatic beta-cells.

Regulation of the phosphoinositide-3 kinase and mitogen-activated protein kinase signaling pathways by progesterone and its reduced metabolites in the rat brain.

Several growth factors, such as vascular endothelial growth factor, brain-derived neurotrophic factor, and insulin-like growth factor-I are involved in the actions of progesterone in the central nervous system. Previous studies in neuronal and glial cultures have shown that progesterone may regulate growth factor signaling, increasing the phosphorylation of extracellular-signal regulated kinase (ERK) and the phosphorylation of Akt, components of the mitogen-activated protein kinase (MAPK) and the phosphoinositide-3 kinase (PI3K) signaling pathways, respectively. In this study, we have evaluated whether progesterone and its reduced metabolites, dihydroprogesterone and tetrahydroprogesterone, regulate PI3K and MAPK signaling in the brain of ovariectomized rats in vivo. Significant increases in the phosphorylation of ERK, in the expression of the catalytic (p110) and the regulatory (p85) subunits of PI3K and in the phosphorylation of Akt were observed in the hypothalamus, the hippocampus, and the cerebellum 24 hr after progesterone administration. Progesterone metabolites partially mimicked the effect of progesterone and had a stronger effect on MAPK and PI3K signaling in the hypothalamus than in the other brain regions. These findings suggest that progesterone regulates MAPK and PI3K signaling pathways in the central nervous system in vivo by direct hormonal actions and by mechanisms involving progesterone metabolites.

Histological and sex steroid hormone receptor changes in testes of immature, mature, and aged chickens.

Sex steroid hormone receptors play a central role in the regulation of reproduction in male chickens. In this work, we evaluated by histomorphometric methods and Western blot analysis changes in the number of the different cell populations and in the content of sex steroid hormone receptors in testes from immature (1.5-month-old), mature (12-month-old), and aged (48-month-old) chickens. The number of Sertoli cells, germ cells, and Leydig cells per area of testicular tissue markedly changed according to chicken age. The highest number of Sertoli and Leydig cells was found in testes of immature chickens, with a dramatic decrease in those of mature chickens; however, the number of germ cells was the highest in mature chickens in comparison with other ages. The content of androgen receptor diminished in testes of mature and aged animals in comparison with that of immature chickens. In contrast, the content of estrogen receptor alpha and progesterone receptor was higher in testes of mature animals than in other ages. Both progesterone receptor isoforms were expressed in a similar proportion in testes of immature and mature animals. Interestingly, progesterone receptor isoform A was the predominant isoform in aged animals. These results suggest that there are marked age-dependent changes in chicken testes histology and in sex steroid hormone receptors content that should contribute to sex steroid hormone actions, in this tissue throughout the lifespan of chickens.

Chemical composition and antispasmodic effect of Casimiroa pringlei essential oil on rat uterus.

The Casimiroa pringlei essential oil was analyzed to determine its chemical composition. Its effect on rat uterine smooth muscle was studied and compared with verapamil. Pure commercial piperitone, eucalyptol, and alpha-terpineol, the major constituents of C. pringlei essential oil, were tested on the uterine tonic contraction induced by high-potassium depolarizing solution (KCl 60 mM).

Tryptophan and serotonin in blood and platelets of depressed patients: Effect of an antidepressant treatment

Abstract: Platelets llave serotonin (5-HT) uptake and storage mechanisms similar to those from neurons. In addition, they represent nearly 99% of blood 5-HT concentration. For these characteristics, platelets are considered useful biomarkers of the serotonergic synaptic neurotransmission, particularly in psychiatric disturbances such as depression. However, most studies which have evaluated platelet 5-HT concentrations in depression have not shown similar findings. It has been suggested that changes in plasma tryptophan (TRP) concentrations might modify 5-HT concentration in the brain, as well as in platelets. Likewise, decreased plasma concentrations of TRP have been found in depressed patients, and the selective 5-HT reuptake inhibitors (SSRIs) induce changes in platelet 5-HT concentration. Considering the controversy surrounding platelet 5-HT concentrations in depressed patients, and the fact that blood 5-HT and TRP have not been studied in the Mexican population, we decided to study 5-HT and tryptophan concentrations in blood and platelets from depressed and control Mexican subjects to evaluate a possible correlation with the severity of depression. The effect of fluoxetine and citalopram treatment on blood and platelet 5-HT and TRP concentrations in depressed patients was also studied. Material and methods Depressed patients The patients of this study were carefully selected and evaluated. Scales based on semi-structured interviews were applied (MINI and SCID-II) by clinical investigators to reduce any possible bias in patient selection. The influence of the seasonal variability on the 5-HT or TRP blood concentrations was controlled by pairing depressed patients and healthy subjects according to age, gender and, in the case of women, menstrual cycle phase. Patients with a complete remission of depression symptoms (defined as a score not higher than 5 points in the Hamilton's scale, and lower than 7 points in Beck's scale) were asked for a blood sample to measure platelet and blood concentrations of 5-HT and TRP. The patients were weighted before the treatment and after their improvement. Control subjects The control group was integrated by 30 healthy subjects, 24 women and 6 men, with an average age of 32.3 ± 10.8 years. Participants were recruited from the overall Mexican population, interviewed by a psychiatrist, and evaluated with the structured interview MINI and the SCID-II, all these to discard any psychiatric diagnose. None of them had received any pharmacological treatment during the three weeks prior to the study. Control and depressed women were paired according to their menstrual cycle phase. All participants received a detailed explanation of the study, and those who voluntarily accepted the stipulations signed an informed consent document. Control and patient subjects were clinically examined and studied with routine laboratory tests (blood count, blood chemistry, urinalysis, and thyroid function test). Blood sample procedures 5-HT and TRP measurements in total blood preparation were carried out according to the method described by Anderson, and were quantified by high performance liquid chromatography (HPLC). Statistical analysis The differences were statistically determined through an analysis of variance (ANOVA), with the assistance of the SPSS 12.00 (Statistical Software by SPPS Inc.). Results Results from laboratory tests, such as blood count, blood chemistry, thyroid function (T3, T4 and TSH) and urinalysis were normal in depressed subjects, as well as in healthy volunteers. Platelet number, blood 5-HT concentration, platelet content of 5-HT, and blood tryptophan concentration showed no significant differences in depressed patients in comparison to control subjects. 5-HT values in blood and platelet were significantly lower than the initial concentrations in patients after antidepressant treatment. Discussion and conclusions Discrepancies between our study and those found in the literature can be explained with three different approaches: ethnical, physiological, and methodological, as is further discussed. The significant decrease produced by the antidepressant treatment in blood and platelet serotonin concentration may be a consequence of the action of SSRIs, due to a 5-HT diminished uptake by the platelet. Considering our results, we conclude that: Blood and platelet 5-HT concentrations were not different between depressed patients and healthy volunteers. Blood TRP concentrations were not different between depressed patients and healthy volunteers. SSRIs (fluoxetine or citalopram) used in the treatment of depressed patients induced a significant decrease in blood and platelet content of 5-HT, and had no effect in TRP concentrations. Based on these results, neither blood/platelet 5-HT nor blood tryptophan concentrations seem to be good biological markers of depressive patients status. However, 5-HT, but not tryp-tophan, might be a reference point for pharmacological treatment effect.

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El sistema serotoninérgico en el paciente deprimido. Segunda parte

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Abstract: Nowadays there are increasing number of studies to support the crucial role of monoamines in depressive disorders. Among them are studies such as long-term treatment of antidepressants whose mechanism of action regulates monoamine metabolism, monoamine receptor density and post-mortem studies. An acute increase in monoamine concentration at the synaptic cleft might induce desensitization of brain auto- and hetero-receptors which explains the therapeutic antidepressive response. This has been proved by monoamine depletion studies in which an antidepressant effect or a patient relapse has been observed. Likewise, the antidepressive therapeutic response occurs earlier when auto-receptors are pharmacologically blocked at nervous and somatodendritic terminals. In the first part of this review, post-mortem studies related with the serotoninergic system were analyzed, as well as the usefulness of measuring serotonin, triptophan, and serotonin metabolite levels in different biological fluids of depressed patients. In this second part, alterations in platelet transporter and serotonin receptors are discussed as platelet is considered a neural serotoninergic model. Platelets are capable of storing and releasing serotonin in a similar manner as serotoninergic synaptosomes. Thus, platelets and serotoninergic synaptic terminals share biochemical and morphological properties. Serotonin transporter in platelets of depressed patients Due to the difficulty to obtain human brain samples and disagreements in the post-mortem studies, platelets have been suggested as a peripheral model to study neural serotonin uptake. The model is supported by the fact that platelet properties are similar to those of neuronal serotoninergic synaptic terminals. Serotonin studies in platelets have been useful in clinical aspects such as depressive disturbances. Radioligand studies in platelets from untreated depressed patients have shown a decrease in [H]-imipramine binding sites, compared to the binding in platelets from control subjects. Since that decrease has been consistently confirmed in studies on affective subjects, it has been proposed as a specific biomarker of depressed patients. Nevertheless, some researchers have not found similar results, and no explanation of the variability in the density of [H]-imipramine binding sites has been proposed. Serotonin receptor changes in depressed patients The hypothesis on receptor adaptative changes proposes that there is a depletion of monoaminergic neurotransmitters in depressed subjects which induces a compensatory regulation in the number and/or function of receptors. To explore this different techniques as the following have been developed: • Techniques to evaluate receptor density and affinity, including post-mortem radioligand binding to serotonin receptors in brain tissue and in platelets from depressed patients. • Techniques to evaluate receptor regulation and sensitivity by using neuroendocrine tests described below. Somatodendritic 5HT 1A autoreceptor dysfunction in depressive disorders Dysfunction of presynaptic somatodendritic 5HTja autoreceptors has been found in behavioral changes related to anxiety, depression and alcoholism. Neuroendocrine tests after the administration of 5-HT1a agonists have been used as an index of 5-HTta receptor function. It seems that azapirodecanediones increase plasmatic concentrations of prolactin, somatotropin, and adrenocortico-tropin; they also seem to decrease body temperature. In depressed patients, the hypothermia response, following presynaptic 5-HTta receptor stimulation, and the neuroendocrine response, following hypothalamus postsynaptic 5-HTta receptor stimulation, were both diminished. These findings suggest a desensitization or down-regulation of pre- and post-synaptic 5-HTja receptors in depressed patients. Platelet 5-HT 2A receptors in depressed patients Density and affinity Most radioligand studies have found an increase of platelet 5-HT2a receptors either in major depression patients or in attempted suicide patients. However, Rosel et al. studied platelets from depressed patients, finding an increment in the 5-HT2a platelet receptors affinity for [H]-ketanserin, but not in the receptors density. Functional capacity The evaluation of receptor function and sensitivity in platelets is performed after serotonin stimulation by using neuroendocrine tests and some other functional tests, such as platelet aggregation, morphological changes, quantification of intracellular calcium, and second messengers quantification. Despite being widely used, neuroendocrine tests are not completely reliable because they could be influenced by factors such as: stress on the hypothalamus-hypophysis axis, the lack of stereo-selective agonists and antagonists for different subtype serotonin receptors, and the effect of the drugs on other neurotransmitter systems. Other methodological aspects, such as: population heterogeneity, small samples, lack of variable control (i.e. age, sex, doses, diet, menstrual cycle), and placebo effects, are limitations to the neuroendocrine tests related to a single neurotransmitter system (serotonin). Results from platelet functional studies are contradictory as well. Platelet aggregation assays in depressed patients suggested a down-regulation of 5-HT2A receptors, compared to platelets from healthy subjects. However, some other studies have found no differences. Other platelet function responses mediated by 5-HT2A receptors, such as morphology changes, intracellular calcium, and phosphatidyl inositol hydrolysis, suggest a receptor up-regulation or hypersensitivity in depressed patients. Despite some disagreement among the results of platelet 5-HT2A receptor studies in depressed patients, most of them have reported an increase in 5-HT2A receptors density in these patients. However, suicidal behavior is clearly correlated to such an increase. Similar results have been observed in most post-mortem studies reporting an increase of 5-HT2A receptors in the prefrontal cortex. Protein synthesis and mRNA for 5-HT2A receptors are increased in prefrontal cortex and hippocampus in adolescent and adult suicide victims. These findings suggest that changes in the brain serotonergic system are related to depressive states and suicidal behavior. Human brain imaging techniques as well as molecular genetics studies may be additional tools to support the understanding of the neurobiology of depressive states, and their treatment.