Central Nervous System Effects Research Articles

The Precious Potential of the Sacred Tree Chamaecyparis obtusa (Siebold & Zucc.) Endl. as a Source of Secondary Metabolites with Broad Biological Applications.

Chamaecyparis obtusa (Siebold & Zucc.) Endl., which belongs to the Cupressaceae family, occurs naturally in North America and Asia, especially in Korea, Taiwan and Japan, where it is an evergreen, coniferous, sacred, ethnic tree. It has many useful varieties that are widespread throughout the world and grown for decorative purposes. It is most commonly used as an ornamental plant in homes, gardens or parks. It is also widely used in many areas of the economy; for example, its wood is used in architecture as well as furniture production. In addition, oil extracted from Chamaecyparis obtusa is increasingly used in cosmetology for skin care. Due to its wide economic demand, mainly in Japan, it represents the largest area of plantation forest. Despite this, it is on the red list of endangered species. Its use in ethnopharmacology has led to more and more research in recent years in an attempt to elucidate the potential mechanisms of its various biological activities, such as antimicrobial, antioxidant, anticancer, antidiabetic, antiasthmatic, anti-inflammatory, antiallergic, analgesic and central nervous system effects. It has also been shown that Chamaecyparis obtusa can be used as an insect repellent and an ingredient in plant disease treatment. This thesis provides a comprehensive review of the biological studies to date, looking at different areas of the economic fields of potential use of Chamaecyparis obtusa.

Suppressive Effects of Neuromedin U Receptor 2-Selective Peptide Agonists on Appetite and Prolactin Secretion in Mice.

Neuromedin U receptor 2 (NMUR2), which is expressed in the central nervous system (CNS) including the hypothalamus, has been noted as a therapeutic target against obesity. We previously reported that intranasal administration of CPN-219, a NMUR2-selective hexapeptide agonist, suppresses body weight gain in mice; however, there is no detailed information regarding its CNS effects. Recently, in addition to appetite suppression, stress responses and regulation of prolactin (PRL) secretion have also attracted attention. NMUR2 expressed in the hypothalamic tuberoinfundibular dopaminergic neurons has emerged as an alternative target for treating hyperprolactinemia. Here, CPN-219 decreased food intake up to 24 h after administration at a dose of 200 nmol, resulting in body weight gain suppression, although grooming and anxiety-like behaviors were transiently induced. Interestingly, the restraint stress-induced increase in plasma PRL levels was significantly suppressed at a lower dose of 20 nmol, indicating the potential for drug development as an anti-PRL agent of NMUR2-selective agonists.

Mental Health of School-Aged Children Treated with Propranolol or Atenolol for Infantile Hemangioma and Their Parents

Background: Infants with infantile hemangioma (IH) have been effectively treated with propranolol or atenolol. Concerns were raised about the mental health of these children at school age, due to central nervous system effects of propranolol and visible nature of IH. Objective: This study aimed to compare the mental health at school age of children treated with propranolol to children treated with atenolol for IHs and their parents. Methods: This two-centered cross-sectional study included children aged ≥6 years and treated with either propranolol or atenolol for IH during infancy. Children’s outcomes were performance-based affect recognition (Dutch version of the Developmental Neuropsychological Assessment-II [NEPSY-II-NL]), parent-reported emotional and behavioral functioning (Child Behavioral Checklist [CBCL]), and health-related quality of life (KIDSCREEN-27). Parents’ outcome was parenting stress (Parenting Stress Questionnaire [OBVL]). Results: Data of 105 children (36 propranolol, 69 atenolol; 6.0–11.8 years) were analyzed. Mental health outcomes did not differ between both β-blocker groups. Although overall functioning was in line with norms, children presented specific problems concerning affect recognition, parent-reported attention, and social quality of life. Parents showed increased physical symptoms, depressive symptoms, and parent-child relationship problems. Conclusion: No difference in mental health at school age was found between children treated with propranolol or atenolol for IH. Although few overall mental health problems were found, specific problems require follow-up. Follow-up of children should be directed toward affect recognition, attention, and social functioning in daily life. Problems reported by parents could be ameliorated by mental health support during and after their infant’s β-blocker treatment.

Food-Derived Peptides: Beneficial CNS Effects and Cross-BBB Transmission Strategies.

Food-derived peptides, as dietary supplements, have significant effects on promoting brain health and relieving central nervous system (CNS) diseases. However, the blood-brain barrier (BBB) greatly limits their in-brain bioavailability. Thus, overcoming the BBB to target the CNS is a major challenge for bioactive peptides in the prevention and treatment of CNS diseases. This review discusses improvement in the neuroprotective function of food-derived active peptides in CNS diseases, as well as the source of BBB penetrating peptides (BBB-shuttles) and the mechanism of transmembrane transport. Notably, this review also discusses various peptide modification methods to overcome the low permeability and stability of the BBB. Lipification, glycosylation, introduction of disulfide bonds, and cyclization are effective strategies for improving the penetration efficiency of peptides through the BBB. This review provides a new prospective for improving their neuroprotective function and developing treatments to delay or even prevent CNS diseases.

Effect of psychostimulant medications on physical function in children with cerebral palsy: scoping review.

The aim of this scoping review is to examine the extent and depth of the literature on effects of central nervous system (CNS) stimulant medications on physical function in children with cerebral palsy (CP). A systematic search for relevant peer-reviewed studies was conducted of PubMed, CINAHL, Cochrane, SPORTDiscus, Embase, & Scopus (January 2002 & August 2022). We included studies that examined the effects of CNS stimulants on physical function in children with CP. Four studies met our selection criteria. All studies explored the effect of Modafinil on physical function outcomes. Three studies of the four included studies reported positive effects of Modafinil on spasticity, motor performance, and gait, whereas one study reported no significant effects of Modafinil. Our findings suggest that there is very low-quality evidence that suggests that Modafinil may enhance physical improvements in body structure and function, including reduction in spasticity and improvements in gait parameters. IMPACT: Central nervous system stimulants were examined for efficacy on physical function and spasticity in children with cerebral palsy. The evidence on the effects of central nervous system stimulants on physical function in children with CP is limited and inconsistent.

Various of Chemical and Pharmacological Applications of 1,3,4-Thiadiazole and It’s Derivative

1,3,4-Thiadiazole is a heterocyclic compound that has been widely studied for its diverse pharmacological activities. The compound is synthesized using different methods, including cyclization of linear organic derivative. The compound has been shown to exhibit various bioactivity, including its property as anticancer toward human cancers, antibacterial, diuretic, antitubercular, antifungal, and leishmanicidal agents, additionally, 1,3,4-thiadiazole derivatives have been shown to influence the central nervous system, displaying anti-inflammatory, anticonvulsant, analgesic, anxiolytic and antidepressant effects. 1,3,4-thiadiazole and its derivatives have been a subject of extensive research in the field of medicinal chemistry. These compounds exhibit a wide range of pharmacological activities, making them valuable candidates for drug development. The structural versatility of 1,3,4-thiadiazole derivatives allows for the fine-tuning of their pharmacological effects. The 1,3,4-thiadiazole moiety in a molecule enhances its bioactivity. Medicinal chemists have explored the SAR (Structure-Activity Relationship) of these derivatives to understand how different substitutions and modifications impact their pharmacological profiles. Synthesis and pharmacological activities of 1,3,4-thiadiazole and also its derivatives represent a vibrant area of research with promising implications for the progress of new therapeutic agents across various medical domains.

Optimizing and characterizing 4-methyl substituted pyrazol-3-carboxamides leading to the peripheral cannabinoid 1 receptor inverse agonist TM38837

Several series of diverse pyrazole-3-carboxamides functionalized with 4-methylamides, 4-methylcarboxylic acids and 4-methyltetrazoles were prepared from the corresponding 4-cyanomethylpyrazoles and investigated as Cannabinoid receptor 1 (CB1) antagonists and inverse agonists with the aim of making compounds with less CNS (Central Nervous System) mediated side-effects compared to rimonabant. The compounds were evaluated and optimized with respect to lipophilicity, solubility, CB1 potency, metabolism, distribution to brain and liver, effect on weight loss in diet-induced mice models. A few carboxylic acids and tetrazoles were selected as especially promising with the tetrazole TM38837 subsequently demonstrating impressive efficacy in various animal models of obesity, producing considerable weight loss and improvements on plasma markers of inflammation and glucose homeostasis, at doses apparently producing negligible brain exposure. TM38837 became the first peripherally restricted CB1 antagonist or inverse agonist to enter clinical trials supporting its lack of CNS effects and it is now believed that the non-CNS mediated efficacy is linked to high liver exposure. This opens opportunities to be explored in other indications such as nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH). Note that this is a first-time disclosure of the structure of TM38837 and other structures appearing in literature are not connected with this program.

히스타민 증후군, 음식 불내성, 부신 피로 동반 환자 2예

Histamine is known as a substance that causes allergies and anaphylaxis, but, in fact, it is a kind of inflammatory cytokine which is involved in immune and inflammatory responses that protect from external materials, such as dust, parasites, and bacteria. Histamine mainly plays a role in physically washing or sterilizing these substances through vasodilation, increasing mucus secretion and expectoration, smooth muscle contraction, and gastric acid secretion. In addition, histamine has central nervous system effects such as arousal and memory, because it is necessary to remember and avoid harmful exposures. Like other cytokines, histamine must be produced, released, and degraded in a balance for proper action. When this balance is broken, various non-specific symptoms from histamine excess, such as rhinitis, urticarial, itching sense, abdominal cramp, diarrhea, epigastric burning, chronic cough, headache, dizziness, edema, insomnia, nervousness, and irritability can be appeared. It is defined as “histamine imbalance” in functional medicine, and some researchers are called it as “histamine syndrome”. This complexity of symptoms often complicates accurate diagnosis, leading to partial or symptomatic treatments. Consequently, histamine syndrome can escalate healthcare burden and decrease quality of life. An integrative and functional medicine approach is important due to this situation. Moreover, histamine syndrome often coexists with food intolerance and adrenal fatigue (functional adrenal insufficiency), necessitating a comprehensive approach that addresses all these aspects simultaneously. In this report, we present two cases of patients with histamine syndrome, accompanied by food intolerance and adrenal fatigue, to explore appropriate directions for functional medicine diagnosis and treatment strategies.

Unmasking hidden risks: The surprising link between PDE5 inhibitors and seizure susceptibility.

Phosphodiesterase 5 inhibitors (PDE5i) are the first line treatment for erectile dysfunction; however, several articles and case reports have shown central nervous system effects, that can cause seizures in susceptible patients. This study aims to describe the changes caused by the use of Sildenafil and Tadalafil through the analysis of abnormalities expressed in the electrocorticogram (ECoG) of rats and evaluate the seizure threshold response and treatment of seizures with anticonvulsants. The study used 108 rats (Wistar). Before surgery for electrode placement in dura mater, the animals were randomly separated into 3 experiments for electrocorticogram analysis. Experiment 1: ECoG response to using PD5i (Sildenafil 20mg/kg and Tadalafil 2.6mg/kg p.o.). Experiment 2: ECoG response to the use of PD5i in association with Pentylenetetrazole (PTZ-30 mg/kg i.p.), a convulsive model. Experiment 3: ECoG response to anticonvulsant treatment (Phenytoin, Phenobarbital and Diazepam) of seizures induced by association IPDE5 + PTZ. All recordings were made thirty minutes after administration of the medication and analyzed for ten minutes, only once. We considered statistical significance level of *p<0.05, **p<0.01 and ***p < 0.001. After administration of Sildenafil and Tadalafil, there were increases in the power of recordings in the frequency bands in oscillations in alpha (p = 0.0920) and beta (p = 0.602) when compared to the control group (p<0.001). After the use of Sildenafil and Tadalafil associated with PTZ, greater potency was observed in the recordings during seizures (p<0.001), however, the Sildenafil group showed greater potency when compared to Tadalafil (p<0.05). Phenobarbital and Diazepam showed a better response in controlling discharges triggered by the association between proconvulsant drugs. PDE5i altered the ECoG recordings in the rats' motor cortexes, demonstrating cerebral asynchrony and potentiating the action of PTZ. These findings demonstrate that PDE5i can lower the seizure threshold.

Recirculating bioavailable nicotine metabolite using ascorbic acid: A pragmatic approach for treating nicotine dependence

Nicotine undergoes metabolism, converting into the oxidized metabolite cotinine, which can persist in the body for several weeks and potentially lead to fatal conditions, such as cancer. Conventional nicotine replacement therapy provides additional nicotine to the body, thereby increasing the chance of accumulating the toxic metabolite cotinine. Consequently, we proposed a hypothesis: converting cotinine back into nicotine using a suitable reducing agent, such as ascorbic acid, could be a practical approach. This conversion would allow cotinine to be reutilized for its central nervous system effects before its eventual elimination from the body. In the current study, we examined this hypothesis by using plasma samples from smokers. Volunteers (both non-smokers and smokers) were screened and recruited for this study. In the initial time- and dose-dependent studies, we incubated plasma samples from non-smokers with cotinine and ascorbic acid. Changes in cotinine and nicotine levels were quantified using HPLC-PDA. Based on the findings of these experiments, we selected a concentration of 1 µM ascorbic acid and incubated it with plasma samples from 25 smokers for 10 min. A time-dependent study revealed that nicotine was detected in non-smokers' plasma samples after a 10-minute incubation with 28.38 µM of both cotinine and ascorbic acid. In a subsequent dose-dependent study, the maximum concentration of nicotine was observed at 1 µM ascorbic acid. Among the 25 samples of smokers’ plasma, the mean nicotine concentration increased from 0.565 ± 0.196 to 1.937 ± 0.622 µM (P = 0.0081), while cotinine levels decreased from 1.278 ± 0.253 to 0.754 ± 0.137 µM (P = 0.0087). This study conclusively demonstrated that ascorbic acid, at a specified concentration, effectively converts cotinine back into nicotine in smokers' plasma. Importantly, this conversion did not occur in water or in the absence of ascorbic acid in the plasma, indicating enzyme involvement.

Bioavailable central nervous system disease-modifying therapies for multiple sclerosis.

Disease-modifying therapies for relapsing multiple sclerosis reduce relapse rates by suppressing peripheral immune cells but have limited efficacy in progressive forms of the disease where cells in the central nervous system play a critical role. To our knowledge, alemtuzumab, fumarates (dimethyl, diroximel, and monomethyl), glatiramer acetates, interferons, mitoxantrone, natalizumab, ocrelizumab, ofatumumab, and teriflunomide are either limited to the periphery or insufficiently studied to confirm direct central nervous system effects in participants with multiple sclerosis. In contrast, cladribine and sphingosine 1-phosphate receptor modulators (fingolimod, ozanimod, ponesimod, and siponimod) are central nervous system-penetrant and could have beneficial direct central nervous system properties.

CNS Prophylaxis Among Patients with HIV-Associated Diffuse Large B-Cell Lymphoma - a Single Center Retrospective Study

Title: CNS Prophylaxis Among Patients with HIV-Associated Diffuse Large B-Cell Lymphoma - A Single Center Retrospective Study Introduction: Patients with Human Immunodeficiency Virus (HIV) are known to develop Lymphoma at a higher rate compared with the general population, with Diffuse Large B-Cell Lymphoma (DLBCL) being the most common subtype. Historically, before the advent of HIV treatment with antiretroviral therapy (ART), HIV-associated DLBCL was considered a more aggressive type of lymphoma and all patients were treated with central nervous system (CNS) prophylaxis. However, since ART has been widely adopted, there is some data to suggest that HIV-associated DLBCL among those taking ART more closely resembles de-novo DLBCL and may not need to be universally treated with CNS prophylaxis. There are no good prospective trials evaluating which patients who develop HIV-associated DLBCL while on ART should receive CNS prophylaxis. Furthermore, studies that tried to predict which DLBCL patients are at greater risk for CNS relapse explicitly excluded patients with HIV. Despite the absence of data, guidelines have shifted and current NCCN guidelines now recommend that HIV patients with DLBCL should be risk stratified as de-novo DLBCL patients with respect to CNS directed therapy. In this study, patients with HIV-associated DLBCL were retrospectively analyzed to understand the patterns of CNS prophylaxis and effects on relapse free survival. Methods: The Electronic Medical Record was queried at a large academic medical center in New York City for patients with HIV-associated DLBCL between the years of 2012 and 2021 using ICD-10 codes. Other subtypes of Lymphoma such as Burkitt's or Plasmablastic Lymphoma were excluded. Patients who did not receive their entire treatment course within the institution were also excluded. Clinical characteristics at diagnosis, treatment type, CNS prophylaxis, and survival data was collected and analyzed. Results: A total of 38 patients were identified according to the inclusion criteria. 26 patients (68%) underwent screening lumbar punctures (LPs) for CNS disease while 12 patients (32%) did not. The two groups were not statistically different within any categories except for LDH, where the LP group had a median LDH of 492 units/L and the non-LP group had a median LDH of 241 units/L (p-value: 0.031). The two groups were not statistically different in cell of origin subtypes, stage, bone marrow involvement, kidney/adrenal involvement, the use of ART prior to diagnosis, IPI or CNS-IPI scores. In addition, among the group that had an LP done with no CNS involvement (n=25), there was no statistical difference in relapse-free survival among those who received adequate CNS prophylaxis and those who did not (p-value 0.886). Conclusions: Among patients with HIV-associated DLBCL in a large academic medical center in New York City, there is no reliable indicator to predict which were offered screening lumbar punctures and which were not. Clinicians may be using additional measures of aggressiveness not accounted for in standard IPI and CNS-IPI scoring algorithms. Furthermore, there was no clear benefit in relapse free survival among high-risk patients who received adequate CNS prophylaxis versus those who did not in this limited sample size. Further research is needed to determine whether patients with HIV-associated DLBCL should be risk stratified similarly to de-novo DLBCL patients with respect to CNS prophylactic therapy.

Antiedematogenic and Analgesic Activities of Abietic Acid in Mice.

Exacerbated inflammatory responses to harmful stimuli can lead to significant pain, edema, and other complications that require pharmacological intervention. Abietic acid (AA) is a diterpene found as a significant constituent in pine species, and evidence has identified its biological potential. The present study aimed to evaluate abietic acid's antiedematogenic and anti-inflammatory activity in mice. Swiss mice (Mus musculus) weighing 20-30 g were treated with AA at 50, 100, and 200 mg/kg. The central nervous system (CNS) effects were evaluated using open-field and rotarod assays. The antinociceptive and anti-inflammatory screening was assessed by the acetic acid and formalin tests. The antiedematogenic activity was investigated by measuring paw edema induced by carrageenan, dextran, histamine, arachidonic acid, and prostaglandin, in addition to using a granuloma model. The oral administration of abietic acid (200 mg/Kg) showed no evidence of CNS effects. The compound also exhibited significant antiedematogenic and anti-inflammatory activities in the carrageenan and dextran models, mostly related to the inhibition of myeloperoxidase (MOP) activity and histamine action and, to a lesser extent, the inhibition of eicosanoid-dependent pathways. In the granuloma model, abietic acid's effect was less expressive than in the acute models investigated in this study. In conclusion, abietic acid has analgesic and antiedematogenic activities related to anti-inflammatory mechanisms.

Update on Central Nervous System Effects of the Intersection of HIV-1 and SARS-CoV-2.

Research has shown myriad neurologic and mental health manifestations during the acute and subsequent stages of COVID-19 in people with HIV (PWH). This review summarizes the updates on central nervous system (CNS) outcomes following SARS-CoV-2 infection in PWH and highlight the existing knowledge gaps in this area. Studies leveraging electronic record systems have highlighted the excess risk of developing acute and lingering neurological complications of COVID-19 in PWH compared to people without HIV (PWoH). However, there is a notable scarcity of neuroimaging as well as blood and cerebrospinal fluid (CSF) marker studies that can confirm the potential synergy between these two infections, particularly in PWH receiving suppressive antiretroviral therapy. Considering the unclear potential interaction between SARS-CoV-2 and HIV, clinicians should remain vigilant regarding new-onset or worsening neurological symptoms in PWH following COVID-19, as they could be linked to either infection.

Effects of thermal exposure to disposable plastic tableware on human gut microbiota and metabolites: A quasi-experimental study

The aim of this quasi-experimental study was to determine the alterations in gut microbiota and metabolism in humans who consume hot food served in disposable plastic tableware (DPT). Participants in the exposure and control groups were provided three hot meals in DPT (n = 30) or non-DPT (n = 30), respectively. After a month of observation, individuals in the exposure group discontinued the three meals provided in DPT (n = 27) for 1 month as the post-exposure group. Fecal samples were collected and tested for microplastics (MPs) detection using LDIR and gut microbiota identification based on the 16 S rRNA. Urine samples were used for metabolite analysis using LC-MS/MS. Results showed that the level of MPs in feces was lower in the post-exposure group compared with the exposure group. Furthermore, the abundance of the phyla Actinobacteria, Proteobacteria, Firmicutes, and Bacteroidota in the exposure and post-exposure groups were significantly different compared with the control group. Changes in microbiota abundance and metabolite levels were mainly associated with central nervous system effects, energy metabolism, and inflammation, suggesting that thermal exposure to DPT for 1 month has considerable health effects.

Screening of the action mechanisms involved in the antinociceptive effect of isopulegol and its complex in cyclodextrin using acute nociception models in mice

Isopulegol, a terpene compound commonly present in the essential oils of several aromatic plants, may present a number of important pharmacological activities. Besides the screening of the antinociceptive effect of the monoterpene isopulegol (ISO) and its inclusion complex in β-cyclodextrins (ISO/CD), this study also aimed at investigating the signaling pathways involved in the antinociceptive response. The effects of ISO and ISO/CD on the central nervous system (CNS) were evaluated through open-field and rota-rod assays and the antinociceptive effects in formalin models, abdominal contortions by acetic acid, hot-plate and plantar mechanical hypernociception. Male and female mice (Mus musculus), weighing between 20–30 g, were divided into 6-animal groups. The oral administration of isopulegol and its complex showed significant antinociceptive effects in the 10, 5 and 1 mg/kg doses for both the formalin and abdominal contortion assays, with highlights on the 10 mg/kg dose of ISO and ISO/CD in both assays. Likewise, the 10 mg/kg dose was selected for the evaluation of the effects on the CNS, central and peripheral antinociceptive effect and screening of the signaling pathways involved in the analgesic potential. ISO and ISO/CD, both in the 10 mg/kg dose v.o., did not show any alteration to the parameters evaluated of the CNS and the results pointed to a possible acute antinociceptive action in the tests of formalin, abdominal contortion, hot-plate and plantar mechanical hypernociception, suggesting the involvement of these signaling pathways: opioid, potassium channel, cholinergic, nitric oxide, cyclic guanosin monophosphate, vaniloid and glutamatergic. The results suggest that ISO and ISO/CD carry a promising antinociceptive potential as a possible alternative to the pharmacological treatment of pain, showing that the inclusion of ISO in cyclodextrins enhance its pharmacological properties, once that the complexation process involves much lower amounts of the compound – what contributes to a better bioavailability and weaker probability for the development of undesired effects.

An Unusual Case of Loperamide Toxicity in a Neonate - A Case Report

Introduction: Loperamide is an antidiarrheal agent approved by the Food and Drug Administration for the treatment of various forms of diarrhea in adults, including traveler’s diarrhea, irritable bowel syndrome associated with chronic diarrhea, and acute nonspecific diarrhea in patients 2 years of age and older, and reducing ileostomy output. The drug has, however, been shown to be toxic at therapeutic doses and causes serious cardiac adverse reactions, central nervous system (CNS) effects such as decreased level of consciousness, coordination abnormality, muscular hypertonia, miosis, respiratory depression, urinary retention, paralytic ileus, abdominal distension, and fecal impaction in infants and toddlers. Methods: We report an unusual case of suspected loperamide toxicity in a 22-day-old baby who presented with respiratory and CNS depression after consuming a single therapeutic dose of loperamide. Results: The neonate’s respiratory depression was attributed to ingestion of loperamide, prescribed by a local quack, as all other causes were ruled out. There was a significant improvement in the baby’s respiratory efforts after IV naloxone, an effective antidote. Conclusion: Special caution should be taken when administering loperamide to pediatric patients due to their greater variability in response. Loperamide is often given by local quacks as a nonprescription medicine for immediate relief, even to infants and toddlers, without complete knowledge about its potential side effects at therapeutic doses. To address this, it is imperative that strict measures should be taken.

Whole-Exome Sequencing Analysis of Idiopathic Hypogonadotropic Hypogonadism: Comparison of Varicocele and Nonobstructive Azoospermia

As a rare disease leading to male infertility, idiopathic hypogonadotropic hypogonadism (IHH) has strong heterogeneity of clinical phenotype and gene mutation. At present, there is no effective diagnosis and treatment method for this disease. This study is to explore the possible new pathogenic gene of idiopathic hypogonadotrophic hypogonadism and the pathological mechanism affecting its occurrence. We performed a whole-exome sequencing on 9 patients with normosmic idiopathic hypogonadotropic hypogonadism (nIHH), 19 varicocele patients with asthenospermia, oligospermia, or azoospermia, 5 patients with simple nonobstructive azoospermia, and 13 normal healthy adult males and carried out comparative analysis, channel analysis, etc. After preliminary sequencing screening, 309–431 genes harbouring variants, including SNPs and indels, were predicted to be harmful per single patient in each group. In genetic variations of nIHH patients’ analysis, variants were detected in 10 loci and nine genes in nine patients. And in co-analysis of the three patient groups, nine nIHH patients, 19 VC patients, and five SN patients shared 116 variants, with 28 variant-harbouring genes detected in five or more patients. We found that the NEFH, CCDC177, and PCLO genes and the Gene Ontology pathways GO:0051301: cell division and GO:0090066: regulation of anatomical structure size may be key factors in the pathogenic mechanism of IHH. Our results suggest that the pathogenic mechanism of IHH is not limited to the central nervous system effects of GnRH but may involve other heterogeneous pathogenic genetic variants that affect peripheral organs.

LPS-Induced Garcia Effect and Its Pharmacological Regulation Mediated by Acetylsalicylic Acid: Behavioral and Transcriptional Evidence.

Lymnaea stagnalis learns and remembers to avoid certain foods when their ingestion is followed by sickness. This rapid, taste-specific, and long-lasting aversion-known as the Garcia effect-can be formed by exposing snails to a novel taste and 1 h later injecting them with lipopolysaccharide (LPS). However, the exposure of snails to acetylsalicylic acid (ASA) for 1 h before the LPS injection, prevents both the LPS-induced sickness state and the Garcia effect. Here, we investigated novel aspects of this unique form of conditioned taste aversion and its pharmacological regulation. We first explored the transcriptional effects in the snails' central nervous system induced by the injection with LPS (25 mg), the exposure to ASA (900 nM), as well as their combined presentation in untrained snails. Then, we investigated the behavioral and molecular mechanisms underlying the LPS-induced Garcia effect and its pharmacological regulation by ASA. LPS injection, both alone and during the Garcia effect procedure, upregulated the expression levels of immune- and stress-related targets. This upregulation was prevented by pre-exposure to ASA. While LPS alone did not affect the expression levels of neuroplasticity genes, its combination with the conditioning procedure resulted in their significant upregulation and memory formation for the Garcia effect.

Drugs possessing aryloxypropanamine pharmacophore, duloxetine, dapoxetine and propranolol, increase allopregnanolone in rat brain: Possible involvement of allopregnanolone in their central nervous system effects

Allopregnanolone (AP) is a neurosteroid synthesized in the brain and a positive allosteric modulator of γ-aminobutyric acid (GABA) type A receptors. Some drugs possessing the aryloxypropanamine (AOPA) pharmacophore, such as fluoxetine, exert their central nervous system (CNS) effects by increasing the brain AP. Although duloxetine (DLX), dapoxetine (DPX), atomoxetine (ATX) and propranolol (PRL) also possess the AOPA pharmacophore and are used to treat some psychiatric disorders, the capabilities of these drugs to increase the brain AP and the possible involvement of AP in their CNS effects remain to be fully elucidated. To clarify these points, we first developed a method for quantifying AP in the rat brain by liquid chromatography/electrospray ionization-tandem mass spectrometry. Analysis of the changes in the brain AP levels using this method revealed that the intraperitoneal administration of DLX (10 mg/kg), DPX (10 mg/kg) and PRL (20 mg/kg) significantly increased the brain AP (DLX: < 0.40–2.74 ng/g tissue, DPX: 1.48–3.83 ng/g tissue and PRL: < 0.40–2.09 ng/g tissue) compared to the saline administration (<0.40 ng/g tissue). These results suggested the possible involvement of the GABAergic neurosteroid, AP, in the central actions of DLX, DPX and PRL. In contrast, ATX (10 mg/kg) did not affect the AP levels in the brain. In addition, the brain and serum AP levels had a remarkably high positive correlation after the administration of DLX, DPX and PRL. Thus, this study proposed the AP-related novel mechanism of actions of DLX, DPX and PRL in the CNS.