Synergistic Antinociceptive Effect of ß-Caryophyllene Oxide in Combination with Paracetamol, and the Corresponding Gastroprotective Activity.

Pain is the most frequent symptom of disease. In treating pain, a lower incidence of adverse effects is found for paracetamol versus other non-steroidal anti-inflammatory drugs. Nevertheless, paracetamol can trigger side effects when taken regularly. Combined therapy is a common way of lowering the dose of a drug and thus of reducing adverse reactions. Since ß-caryophyllene oxide (a natural bicyclic sesquiterpene) is known to produce an analgesic effect, this study aimed to determine the anti-nociceptive and gastroprotective activity of administering the combination of paracetamol plus ß-caryophyllene oxide to CD1 mice. Anti-nociception was evaluated with the formalin model and gastroprotection with the model of ethanol-induced gastric lesions. According to the isobolographic analysis, the anti-nociceptive interaction of paracetamol and ß-caryophyllene oxide was synergistic. Various pain-related pathways were explored for their possible participation in the mechanism of action of the anti-nociceptive effect of ß-caryophyllene oxide, finding that NO, opioid receptors, serotonin receptors, and K+ATP channels are not involved. The combined treatment showed gastroprotective activity against ethanol-induced gastric damage. Hence, the synergistic anti-nociceptive effect of combining paracetamol with ß-caryophyllene oxide could be advantageous for the management of inflammatory pain, and the gastroprotective activity should help to protect against the adverse effects of chronic use.

Bayesian Analysis Used to Identify Clinical and Laboratory Variables Capable of Predicting Progression to Severe Dengue among Infected Pediatric Patients.

The current contribution aimed to evaluate the capacity of the naive Bayes classifier to predict the progression of dengue fever to severe infection in children based on a defined set of clinical conditions and laboratory parameters. This case-control study was conducted by reviewing patient files in two public hospitals in an endemic area in Mexico. All 99 qualifying files showed a confirmed diagnosis of dengue. The 32 cases consisted of patients who entered the intensive care unit, while the 67 control patients did not require intensive care. The naive Bayes classifier could identify factors predictive of severe dengue, evidenced by 78% sensitivity, 91% specificity, a positive predictive value of 8.7, a negative predictive value of 0.24, and a global yield of 0.69. The factors that exhibited the greatest predictive capacity in the model were seven clinical conditions (tachycardia, respiratory failure, cold hands and feet, capillary leak leading to the escape of blood plasma, dyspnea, and alterations in consciousness) and three laboratory parameters (hypoalbuminemia, hypoproteinemia, and leukocytosis). Thus, the present model showed a predictive and adaptive capacity in a small pediatric population. It also identified attributes (i.e., hypoalbuminemia and hypoproteinemia) that may strengthen the WHO criteria for predicting progression to severe dengue.

The Additive Antinociceptive Effect of Resveratrol and Ketorolac in the Formalin Test in Mice.

Pain represents one of the leading causes of suffering and disability worldwide. Currently available drugs cannot treat all types of pain and may have adverse effects. Hence, the use of pharmacological combinations is an alternative treatment strategy. Therefore, this study aimed to evaluate the combination of resveratrol and ketorolac through isobolographic analysis. CD1 mice were used to study the antinociceptive effect of this combination using the formalin test and the study was divided into two phases. In the first phase, four individual doses of each drug were evaluated, totaling eight testing groups. From these data, the median effective doses (ED50) of each drug were calculated. In the second phase, four testing groups were used to evaluate the combination of sub-doses of both drugs and obtain the experimental ED50. To evaluate gastric damage, five groups were employed, including indomethacin, vehicle, resveratrol, ketorolac, and combined resveratrol and ketorolac groups. Stomach samples from the mice were taken after 5 h of treatment, and the area of the ulcers was determined. Resveratrol plus ketorolac elicited a reduction in nociceptive behavior during both phases of the formalin test, and isobologram analysis revealed that the theoretical and experimental ED50 values of resveratrol and ketorolac did not differ significantly, implying an additive interaction between the drugs. Additionally, the drug combination did not generate gastric ulcers, thus enhancing the desired effects without increasing the adverse effects. Consequently, these findings substantiate the efficacy of the resveratrol and ketorolac combination in the formalin test, thereby highlighting its potential as a viable alternative for alleviating pain.

Systematic Review of the Serotonergic System in the Pathophysiology of Severe Dengue: The Theory of Thrombocytopenia and Vascular Extravasation.

BACKGROUND: Severe dengue is characterized by thrombocytopenia, hemorrhaging, and/or capillary extravasation and may be linked to a reduced plasma concentration of serotonin (5-hydroxytriptamine, or 5-HT). OBJECTIVE: The aim of the current contribution was to conduct a systematic bibliographic review of reports on the role of the peripheral serotonergic system in the pathophysiology of severe dengue. METHODS: A bibliographic review was carried out of in vivo/in vitro models, clinical trials, and case series studies from 2010-2019. The selective criteria were the use of treatments with serotonin reuptake inhibitors and/or agonists/antagonists of 5-HT receptors and their impact on inflammation, coagulation, and endothelium. Moreover, cross-sectional and cohort studies on the relationship between intraplatelet and plasma 5-HT levels in patients with dengue were also included. The risk of bias in the selected reports was examined with domain-based assessment utilizing Cochrane-type criteria. The main results are summarized in Tables and Figures. RESULTS: Based on descriptions of the effect of serotonergic drugs on 5-HT levels and the findings of clinical trials of dengue treatment, most receptors of the peripheral serotonergic system, and especially 5-HT2A, seem to participate in regulating serum 5-HT during severe dengue. Therefore, the peripheral serotonergic system probably contributes to thrombocytopenia and capillary extravasation. CONCLUSION: Regarding dengue, 5-HT may be a key parameter for predicting severity, and an understanding of 5-HT-related mechanisms could possibly facilitate the development of new therapies. These proposals require further research due to the limited number of publications on the role of serotonergic receptors at the peripheral level.

In Vivo and In Silico Study of the Antinociceptive and Toxicological Effect of the Extracts of Petiveria alliacea L. Leaves.

Petiveria alliacea L. is an herb used in traditional medicine in Mexico and its roots have been studied to treat pain. However, until now, the antinociceptive properties of the leaves have not been investigated, being the main section used empirically for the treatment of diseases. For this reason, this study aimed to evaluate the antinociceptive and toxoicological activity of various extracts (aqueous, hexanic, and methanolic) from P. alliacea L. leaves in NIH mice and to perform an in silico analysis of the phytochemical compounds. Firstly, the antinociceptive effect was analyzed using the formalin model and the different doses of each of the extracts that were administered orally to obtain the dose-response curves. In addition, acute toxicity was determined by the up and down method and serum biochemical analysis. Later, the phytochemical study of extracts was carried out by thin layer chromatography (TLC) and visible light spectroscopy, and the volatile chemical components were analyzed by gas chromatography-mass spectrometry (GC/MS). Moreover, the most abundant compounds identified in the phytochemical study were analyzed in silico to predict their biological activity (PASSonline) and toxicology (OSIRIS Property Explorer). As a result, it was known that all extracts at doses from 10 to 316 mg/kg significantly reduced the pain response in both phases of the formalin model, with values of 50-60% for the inflammatory response. The toxicological studies (DL50) exhibited that all extracts did not cause any mortality up to the 2000 mg/kg dose level. This was corroborated by the values in the normal range of the biochemical parameters in the serum. Finally, the phytochemical screening of the presence of phenolic structures (coumarins, flavonoids) and terpenes (saponins and terpenes) was verified, and the highest content was of a lipid nature, 1.65 ± 0.54 meq diosgenin/mL in the methanolic extract. A total of 54 components were identified, 11 were the most abundant, and only four (Eicosane, Methyl oleate, 4-bis(1-phenylethyl) phenol, and Ethyl linolenate) of them showed a probability towards active antinociceptive activity in silico greater than 0.5. These results showed that the P. alliacea L. leaf extract possesses molecules with antinociceptive activity.

Effect of Long-Term Intake of Nutritive and Non-Nutritive Sweeteners on Metabolic Health and Cognition in Adult Male Rats.

This study evaluated the effects of long-term intake of nutritive sweeteners (NSs) and non-nutritive sweeteners (NNSs) on body weight, food and energy intake, blood pressure, metabolic parameters, and memory retention in rats. Sixty male Sprague-Dawley rats were randomly divided into six groups (n = 10 per group): control (water),10% sucrose (SUC), aspartame (ASP), sucralose (SCA), stevia (STV), and 5% xylitol (XYL). Pure NSs (SUC and XYL) and NNSs were added to the drinking water for 18 weeks. ASP, SCA, and STV dosage was based on the estimated daily intake limit: 4.1, 2.0, and 3.4 mg/kg/day, respectively. Chronic access to NNSs did not result in any difference in total weight gain of the rats, while it was significantly elevated in the SUC group compared with the control and NNSs groups. Food intake was significantly lower in all NNSs groups compared with SUC and control groups. Sweetened beverage intake volumes were significantly diminished in all NNSs groups compared with intake in SUC and control groups. Total calories consumed were lower for the STV and XYL groups compared with all other groups. Blood pressure and glucose metabolism did not differ significantly between the groups. All sweeteners increased total cholesterol, low-density lipoprotein, and triglyceride levels. Short-term memory was significantly impaired in the ASP group in the novel object recognition task, while long-term memory was impaired in SUC and STV groups. These metabolic and behavioral results suggest that the long-term intake of NSs or NNSs can be associated with peripheral and central effects.

Comparative analysis of anthropometric indicators for diagnosing obesity and predicting cardiometabolic risk in Mexican adolescents.

Introduction: Introduction: obesity is a cardiometabolic risk (CMR) factor in adolescents. It represents a public health problem that requires simple diagnostic strategies based on the determination of anthropometric indicators (AIs) such as body mass index (BMI), waist circumference (WC), conicity index (CONI), waist-to-height ratio (WHtR), and body fat percentage (BFP). The purpose of the current contribution was to analyze the utility of the aforementioned AIs for evaluating obesity as a CMR factor in Mexican adolescents. Materials and methods: the design of the study is descriptive and cross-sectional. Nutritional status was established by using various AIs and as a CMR factor under the criteria of WHtR. Participating in the present investigation were 2,000 adolescents from 15 to 17 years of age, of which 1,079 (53.9 %) were female and 921 (46.1 %) were male. All were high school students in Tuxtla Gutiérrez, Chiapas, Mexico. Results and conclusion: the prevalence of obesity was influenced by gender. With the WHtR and BFP, male students exhibited a greater prevalence of obesity, while with the BMI and CONI, the percentage of obesity was similar between the two genders. BMI was significantly correlated with BFP, WC and WHtR, and was one of the AIs with the greatest area under the curve, showing a good capacity to predict cardiometabolic risk. BMI is a simple and adequate tool for diagnosing obesity and predicting CMR in adolescents.

Introducción: Introducción: la obesidad es un factor de riesgo cardiometabolico (RCM) en los adolescentes y representa un problema de salud pública que requiere estrategias diagnosticas sencillas, basadas en la determinación de indicadores antropométricos (IA) como el índice de masa corporal (IMC), la circunferencia de la cintura (CC), el índice de conicidad (ICONI), el índice de cintura-talla (ICT) y el porcentaje de grasa corporal (PGC). El propósito del presente estudio fue analizar la utilidad de diversos IA (IMC, CC, ICONI, ICT y PGC) para evaluar la obesidad como factor de RCM en adolescentes mexicanos. Materiales y métodos: el diseño del estudio fue descriptivo y transversal. Se analizó el estado nutricional mediante varios IA y el factor de RCM bajo los criterios del ICT. Este estudio fue conducido en 2000 adolescentes de entre 15 y 17 años, de los cuales 1079 (53,9 %) eran mujeres y 921 (46,1 %) varones, todos ellos estudiantes de nivel medio superior de Tuxtla Gutiérrez, Chiapas, México. Resultados y conclusión: la prevalencia de la obesidad estuvo influenciada por el género: los varones presentaron una mayor prevalencia de obesidad con ICT y PGC, mientras que con IMC e ICONI, el porcentaje de obesidad fue similar entre ambos géneros. El IMC se correlacionó significativamente con el PGC, la CC y el ICT, y fue uno de los IA con mayor área bajo la curva, mostrando una buena capacidad para predecir el RCM. El IMC representa una herramienta sencilla y adecuada para el diagnóstico de obesidad y predecir el RCM en adolescentes.

Effects of substrate temperature on patterns produced by dried droplets of proteins.

Rapid diagnosis provides better clinical management of patients, helps control possible outbreaks, and increases survival. The study of deposits produced by the evaporation of droplets is a useful tool in the diagnosis of some health problems. With the aim to improve diagnostic time in clinical practice where we use the evaporation of droplets, we explored the effects of substrate temperature on pattern formation of dried droplets in globular protein solutions. Three deposit groups were observed: "functional" patterns (from 25 to 37 ∘C), "transition" patterns (from 44 to 50 ∘C), and "eye" patterns (from 58 to 63 ∘C). The dried droplets of the first two groups show a ring structure ("coffee-ring") that confines a great diversity of aggregates such as needle-like structures, tiny blade-shape crystals, highly symmetrical crystallization patterns, and amorphous salt aggregates. In contrast, the "eye" patterns are deposits with a large inner aggregate surrounded by a coffee ring, and they can appear from the evaporation of droplets in protein binary mixtures and blood serum. Interestingly, the unfolding proteins correlates with the formation of "eye" patterns. We measured stain diameter, "coffee-ring" thickness, radial density profile, and entropy computed by GLCM-statistics to quantify the structural differences among deposit groups. We found that "functional" patterns are structurally indistinguishable among them, but they are clearly different from elements of the other deposit groups. An exponential decay function describes pattern formation time as a function of substrate temperature, which is independent from protein concentration. Patterns formation at 32 ∘C takes place up to 63% less time and preserves the structural characteristics of dried droplets in proteins formed at room temperature. Therefore, we argue that droplet evaporation at this substrate temperature could be an excellent candidate to make a more efficient diagnosis based on droplet evaporation of biofluids.

Impact of Exposure to Environmental Enrichment on the Anxiety-Like Behavior of Ovariectomized Mice.

Objective: The aim of this study was to explore the influence of short-term (2-week) exposure to social (SE) and/or physical enrichment (PE) on the anxiety-like behavior of ovariectomized (OVX) NIH Swiss mice. Method : One week after surgery, each OVX mouse was housed under one of 4 social conditions: (1) isolated, (2) accompanied by an intact female, (3) accompanied by an intact male, or (4) in a community of 10 OVX individuals. The animals in each of these environments were divided into 2 subgroups, consisting of the presence and absence of PE. Following a 2-week exposure to the respective conditions, each OVX mouse was subjected to either the light/dark exploration test (LDT) or the elevated plus maze (EPM) to examine anxiety-like behavior. Results: The LDT and EPM showed very similar patterns. Compared to an impoverished environment, PE elicited a significant anxiolytic effect for OVX mice housed alone or in companion of an intact female (F [1, 54] = 16.11, P = 0.001). By contrast, mice living in community but without PE displayed anxiogenic-like behavior, perhaps due to crowding, compared to the animals living in isolation (F [1, 36] = 5.64, P = 0.023). Conclusion: This study emphasized the importance of taking housing conditions into account during the screening of new anxiolytic agents and the critical role of OVX in the regulation of anxiety.

Cyclic changes and actions of progesterone and allopregnanolone on cognition and hippocampal basal (stratum oriens) dendritic spines of female rats.

Ovarian steroids modulate the neuronal structure and function during the estrous cycle, contrasting peak effects during the proestrus cycle and low effects during the metestrus cycle. An ovariectomy (OVX) decreases gonadal hormones and tests the effects of substitutive therapies. We studied female rats with a normal estrous cycle and we also studied the effects of systemic progesterone (P4, 4.0 mg/kg) or its reduced metabolite allopregnanolone (ALLO, 4.0 mg/kg, both for 10 days) in females who had had an OVX 16.5 weeks prior to the study (long-term OVX) with the novel object recognition test (NORT) for associative memory. The dendritic shape and spine density in Golgi-impregnated basal dendrites (stratum oriens) of hippocampal pyramidal neurons was also studied. Proestrus females had a better performance than metestrus or OVX females in short-term memory (tested 1 h after the acquisition phase). Proestrus and metestrus females showed better results than OVX females for long-term memory (24 h after the initial phase). Both P4 and ALLO recovered the cognitive impairment induced by long-term OVX. Also, proestrus females had a higher density of dendritic spines than metestrus females, OVX reduced the density of spines when compared to intact females, whereas both P4 and ALLO treatments increased the dendritic spine density, number of dendritic branches along the dendritic length, and branching order compared to vehicle. These data add the dendrites of the stratum oriens as an additional site for naturally occurring changes in spine density during the estrous cycle and evidence the actions of progestins in both behavioral recovery and the structural dendritic rearrangement of hippocampal pyramidal neurons in long-term OVX female rats.

Association of anthropometric indicators to evaluate nutritional status and cardiometabolic risk in Mexican teenagers / Asociación de indicadores antropométricos para evaluar el estado nutricional y el riesgo cardiometabólico en adolescentes mexicanos

Introduction: anthropometric indicators (AIs) such as waist circumference (WC), body mass index (BMI), waist/hip index (WHpI), waist/height index (WHtI) and body fat percentage (BFP) are useful tools for the diagnosis of nutritional status (NS) in adolescents. Each of these parameters has advantages and disadvantages. The purpose of the present study was to analyze the association of these AIs (WC, BMI, WHpI, WHtI, and BFP) to evaluate nutritional status and estimate the cardiometabolic risk (CMR) in Mexican adolescents. Material and method: in a cross-sectional descriptive study, the NS was analyzed through various AIs and CMR with the WHtI criteria. Nine hundred and seventeen adolescents between 15 and 17 years old participated in the study, of whom 488 (52.9%) were female and 429 (47.1%) male, all students of middle school in Tuxtla Gutiérrez, Chiapas, Mexico. Results and conclusion: women presented a higher prevalence of obesity according to most indicators. The WHtI was the parameter that detected the highest prevalence of obesity (31%), correlating with the BMI and the BFP. Moreover, there was evidence of a significant relation between NS (assessed by all the anthropometric indicators) and CMR. The WHtI could be considered as an adequate tool for the diagnosis of obesity associated with CMR in adolescents

Introducción: los indicadores antropométricos (IA) como la circunferencia de cintura (CC), el índice de masa corporal (IMC), el índice cintura/ cadera (ICC), el índice cintura/talla (ICT) y el porcentaje de grasa corporal (PGC) son herramientas útiles para el diagnóstico del estado nutricional (EN) en los adolescentes. Sin embargo, cada uno de estos IA presentan ventajas y desventajas. El propósito del presente estudio fue analizar la asociación de los IA (IMC, CC, ICC, ICT y PGC) para evaluar el EN y estimar el riesgo cardiometabólico (RCM) en adolescentes mexicanos. Material y método: el diseño del estudio fue descriptivo transversal. Se analizó el EN a través de diversos IA y el RCM bajo los criterios de ICT. Este estudio fue conducido en 917 adolescentes de entre 15 y 17 años, de los cuales 488 (52,9%) eran mujeres y 429 (47,1%) varones, todos estudiantes de nivel medio superior de Tuxtla Gutiérrez, Chiapas, México. Resultados y conclusión: las mujeres presentaron mayor prevalencia de obesidad con la mayoría de los IA utilizados. El ICT fue el IA que detectó mayor prevalencia de obesidad (31%), correlacionándose con el IMC y el PGC. Además, se evidenció una asociación significativa entre el EN valorado por todos los IA y el RCM. El ICT podría ser considerado como una herramienta adecuada para el diagnóstico de obesidad asociada a RCM en adolescentes

Association of anthropometric indicators to evaluate nutritional status and cardiometabolic risk in Mexican teenagers.

INTRODUCTION: Introduction: anthropometric indicators (AIs) such as waist circumference (WC), body mass index (BMI), waist/hip index (WHpI), waist/height index (WHtI) and body fat percentage (BFP) are useful tools for the diagnosis of nutritional status (NS) in adolescents. Each of these parameters has advantages and disadvantages. The purpose of the present study was to analyze the association of these AIs (WC, BMI, WHpI, WHtI, and BFP) to evaluate nutritional status and estimate the cardiometabolic risk (CMR) in Mexican adolescents. Material and method: in a cross-sectional descriptive study, the NS was analyzed through various AIs and CMR with the WHtI criteria. Nine hundred and seventeen adolescents between 15 and 17 years old participated in the study, of whom 488 (52.9%) were female and 429 (47.1%) male, all students of middle school in Tuxtla Gutiérrez, Chiapas, Mexico. Results and conclusion: women presented a higher prevalence of obesity according to most indicators. The WHtI was the parameter that detected the highest prevalence of obesity (31%), correlating with the BMI and the BFP. Moreover, there was evidence of a significant relation between NS (assessed by all the anthropometric indicators) and CMR. The WHtI could be considered as an adequate tool for the diagnosis of obesity associated with CMR in adolescents.

INTRODUCCIÓN: Introducción: los indicadores antropométricos (IA) como la circunferencia de cintura (CC), el índice de masa corporal (IMC), el índice cintura/cadera (ICC), el índice cintura/talla (ICT) y el porcentaje de grasa corporal (PGC) son herramientas útiles para el diagnóstico del estado nutricional (EN) en los adolescentes. Sin embargo, cada uno de estos IA presentan ventajas y desventajas. El propósito del presente estudio fue analizar la asociación de los IA (IMC, CC, ICC, ICT y PGC) para evaluar el EN y estimar el riesgo cardiometabólico (RCM) en adolescentes mexicanos. Material y método: el diseño del estudio fue descriptivo transversal. Se analizó el EN a través de diversos IA y el RCM bajo los criterios de ICT. Este estudio fue conducido en 917 adolescentes de entre 15 y 17 años, de los cuales 488 (52,9%) eran mujeres y 429 (47,1%) varones, todos estudiantes de nivel medio superior de Tuxtla Gutiérrez, Chiapas, México. Resultados y conclusión: las mujeres presentaron mayor prevalencia de obesidad con la mayoría de los IA utilizados. El ICT fue el IA que detectó mayor prevalencia de obesidad (31%), correlacionándose con el IMC y el PGC. Además, se evidenció una asociación significativa entre el EN valorado por todos los IA y el RCM. El ICT podría ser considerado como una herramienta adecuada para el diagnóstico de obesidad asociada a RCM en adolescentes.

Agonist E-6837 and antagonist SB-271046 of 5-HT6 receptors both reverse the depressive-like effect induced in mice by subchronic ketamine administration.

Major depression is one of the most common affective disorders caused by schizophrenia. The administration of N-methyl-D-aspartate receptor antagonists, such as ketamine, can reproduce the negative and affective symptoms of this disorder in animals. Preclinical studies have shown that 5-HT6 receptor (5-HT6R) agonists and antagonists have a considerable antipsychotic response. The aim of the present study was to evaluate the effect of an acute treatment with an agonist, E-6837, and an antagonist, SB-271046, of 5-HT6R on the immobility induced in mice by a subchronic ketamine regimen (5 days; 10 mg/kg/day, intraperitoneal). Repeated ketamine administration alone increased the immobility time in the forced-swimming test and the tail-suspension test. E-6837 at 10 and 20 mg/kg caused a significant reduction of immobility in the tail-suspension test and forced-swimming test, respectively. Interestingly, SB-271046 (10 mg/kg) also elicited an antidepressant-like effect in both tests. The current findings suggest an important role for these 5-HT6R ligands as mood modulators. However, it is necessary to explore the physiological mechanisms involved in this process in greater detail.

Effect of ketamine administration, alone and in combination with E-6837, on climbing behavior.

Some types of schizophrenia have been associated with repetitive movements lacking specific purpose, also known as stereotyped behavior. Dopamine agonists (D2) and noncompetitive N-methyl-D-aspartate receptor antagonists (e.g. ketamine) have been administered in rodent models to induce stereotyped behavior that resembles some motor symptoms of schizophrenia. Recently, a relationship has been found between 5-HT6 receptors (5-HT6Rs) and dopaminergic activity. The present study evaluates the effect of ketamine (5 and 10 mg/kg), alone and in combination with the 5-HT6R agonist E-6837, on the climbing behavior of male mice. Ketamine was administered with an acute (1 day) and subchronic (5 day) scheme. Later, these doses and schemes were combined with an acute scheme of E-6837 (5 and 10 mg/kg). With both the acute and the subchronic schemes, ketamine increased climbing behavior at a dose of 10 mg/kg, and this effect was reversed by E-6837 (at 5 and 10 mg/kg). The present results suggest that there is an interaction between N-methyl-D-aspartate and 5-HT6 receptors in the regulation of climbing behavior. Further research is necessary to provide more evidence on this interaction.

Interacción de los receptores NMDA - 5-HT6 en la investigación preclínica de las alteraciones cognitivas relacionadas con la esquizofrenia / Interaction of nmda AND 5-HT6 receptors in the preclinical investigation of schizophrenia-related cognitive changes

Diversos antagonistas del receptor N-metil-D-aspartato (RNMDA) como la fenciclidina o la ketamina estudiados en roedores han permitido inducir alteraciones cognitivas similares a las observadas en la esquizofrenia. Casualmente, uno de los receptores a serotonina, el 5-HT6, ha cobrado interés en la búsqueda de nuevos fármacos con propiedades procognitivas. Con la finalidad de comprender mejor la interacción de ambos receptores (NMDA y 5-HT6) en la regulación cognitiva se realizó una revisión exhaustiva en la literatura. Varios estudios con esquemas agudos o subcrónicos de los antagonistas NMDA en roedores fueron evaluados en distintas pruebas, en donde se encontró deterioro cognitivo. Fue común que el esquema agudo de diversos fármacos serotoninérgicos 5-HT6 revirtiera el deterioro cognitivo inducido por la administración previa de los antagonistas del RNMDA. Por el contrario y sorprendentemente, la inyección aguda y combinada tanto de los antagonistas NMDA como de los fármacos serotoninérgicos 5-HT6 lograron fortalecer la memoria. El esquema subcrónico de los antagonistas NMDA representa el modelo más integrador para el estudio de las alteraciones cognitivas asociadas a la esquizofrenia. Aunque el deterioro y el efecto procognitivo mediados por estos receptores pudieran ser explicados mediante la regulación conjunta que ejercen ambos receptores sobre la liberación de distintos neurotransmisores como el glutamato, es una situación compleja que se requiere continuar investigando para fundamentar mejor estas ideas (AU)

Diverse antagonists of the NMDA receptor studied in rodents, such as phencyclidine or ketamine, have enabled researchers to induce cognitive changes similar to those found in schizophrenia. Interestingly, one of the serotonin receptors, 5-HT6, has attracted much attention for the development of new drugs with pro-cognitive properties. With the aim of better understanding the interaction of both NMDA and 5-HT6 in cognitive regulation, an exhaustive review of the literature was carried out. Various studies have found cognitive impairment, evaluated in rodents using different tests, after applying acute or sub-chronic schemes of NMDA antagonists. An acute scheme of applying different serotogenic 5-HT6 receptors has often reversed the cognitive impairment induced by the previous administration of NMDA antagonists. Surprisingly, an acute injection of a combination of suboptimal doses of NMDA and 5-HT6 antagonists resulted in strengthening memory. The sub-chronic scheme of NMDA antagonists represents the most reliable model for the study of cognitive changes associated with schizophrenia. Cognitive impairment, as well as a pro-cognitive effect mediated by NMDA and 5-HT6, may be explained by a joint regulation of these receptors to modulate the release of distinct neurotransmitters, such as glutamate. This represents a complex interaction that requires ongoing research to clarify the mechanisms at play (AU)

Adrenalectomy modifies the hippocampal 5-HT(1A) receptors and the anxiolytic-like effect of 8-OH-DPAT in rats.

Stress is closely related with levels of corticosteroid and corticotrophin releasing factor, which at the same time can modify 5-HT(1A) receptors and brain serotonin levels. Consequently, the absence of corticosteroids in rats induced by an adrenalectomy could be useful to understand the functionality of the brain serotonergic system after a stressing event. The influence of 15 min of forced swimming was explored on sham and adrenalectomized rats by measuring the 5-HT(1A) receptor density in raphe and hippocampus. Other previously stressed groups (sham and adrenalectomized) were tested in two anxiety models with the 5-HT(1A) agonist 8-OH-DPAT, the postsynaptic antagonist MM-77, and with a combination of these two compounds. It was found that the removal of adrenals in rats that were not previously stressed induced an increase in the postsynaptic 5-HT(1A) receptor density. On the other hand, an adrenalectomy in rats that were previously stressed induced a reduction in the same receptor density. Adrenal gland removal induced an anxiolytic-like effect. However, after the injection of 8-OH-DPAT, adrenalectomized rats showed anxiogenic-like actions, an effect which was reversed by MM-77. Data show that changes in 5-HT(1A) receptors density caused by a stressful session can have behavioral consequences, thus emphasizing the need to reconsider the clinical use of 5-HT(1A) ligands after traumatic events.

Alterations in GABAergic function following forced swimming stress.

Forced swimming induces alterations in the GABA brain concentration and could change the sensitivity of the GABA/benzodiazepine receptor-chloride ionophore complex to benzodiazepines. This change in sensitivity could be explained by the allopregnanolone release that takes place during stress. The current study was carried out to determine whether forced swimming is able to modify the anti-anxiety effect of diazepam and to explore the possible relation of this change to allopregnanolone, the GABA concentration or/and the GABA/benzodiazepine receptor density. Unstressed and stressed mice, injected with the vehicle or diazepam, were evaluated in the exploratory behavior test. Diazepam induced clear anxiolytic actions at all doses in unstressed animals, but such an effect was not observed in stressed animals. The injection of allopregnanolone 24 h before the anxiety test blocked the effect of this benzodiazepine. Forced swimming decreased GABA concentrations in the hippocampus and the thalamus-hypothalamus region, besides decreasing the [(3)H]flunitrazepam labeling in both the hypothalamus and amygdala. These results show that forced swimming abolishes the anti-anxiety effect of diazepam.

Influence of forced swimming stress on 5-HT1A receptors and serotonin levels in mouse brain.

Several stressful factors are able to modify 5-HT1A receptors; for example, different schemes of forced swimming-induced stress (FS) produce a variety of changes in synthesis as well as in 5-HT1A binding in the brain. In addition, it is known that the concentration of 5-HT in the brain is modified as a consequence of acute stressing. The main purpose of this study was to characterize the influence of 15 min of FS on 5-HT levels and on 5-HT1A receptor density in specific brain areas. Mice stressed 24 h before were sacrificed and their brains processed by means of a quantitative autoradiography technique. The following areas were studied: dorsal raphe nucleus (DRN); median raphe nucleus (MRN); thalamus; hypothalamus; amygdala, and hippocampus. 5-HT and 5-hydroxyindolacetic acid (5-HIAA) concentrations in the brainstem, thalamus-hypothalamus, and hippocampus of stressed (ST) mice were analyzed 24 h after stressing by high performance liquid chromatography (HPLC) with fluorometric detection. All data were compared with corresponding unstressed (UST) controls. A significant decrease in 5-HT1A receptor density in DRN, MRN, and hippocampus, accompanied by an increase in labeling of 5-HT1A receptor in thalamus, hypothalamus, and amygdala was observed in ST animals. FS induced a decrease in the 5-HT concentration in the thalamus-hypothalamus, accompanied by an increase in hippocampus areas without affecting 5-HT concentration in the brainstem. Additionally, 5-HIAA/5-HT ratio in the thalamus-hypothalamus area was increased. This study showed that stress alters both 5-HT concentration and 5-HT1A receptors in a region-specific manner.