Assessment of the inbred C57BL/6 and outbred CD1 mouse strains using a progressive ratio schedule during development.

Inbred strains have a genetic similarity of at least 98.6% compared to their outbred counterparts. Several studies have shown that inbred C57BL/6 mice and outbred ICR (CD1) mice differ in locomotion, cognitive flexibility, and aggression. However, their performance in operant paradigms is not well understood. A progressive ratio (PR) schedule of reinforcement is a method of quantitative estimation of the incentive state of an animal for a reward by increasing response requirements for reinforcer delivery, which is relevant to assess the breakpoint (amount of response effort an animal is willing to invest for a single unit of reward). This study tested male and female C57BL/6 and CD1 mice with an open field to analyze locomotion. Then, we used conditioning chambers with a PR3 schedule for ten consecutive days (P30-P40). PR performance was measured with the breakpoint, and the mathematical principles of reinforcement (MPR) were used to estimate motivation, impulsivity, and motor skills to manipulate the operandum. We found that CD1 mice showed higher locomotor activity than C57BL/6 independently of sex. CD1 mice had a higher breakpoint. However, male CD1 mice gradually increased breakpoint until the last session. In the MPR model, CD1 mice showed decreased fixed paused parameter (impulsivity) than C57BL/6, independent of sex. Our data suggest that the higher breakpoint in CD1 strain may partially be related to impulsivity. Therefore, the MPR model can help identify factors that affect performances, such as motivation, impulsivity, and motor skills during a PR in adolescent CD1 and C57BL/6 mice. These findings are essential to characterize the differences in the behavioral performance between C57BL/6 and CD1 strains and their potential as animal models.

Raman spectroscopy to assess the differentiation of bone marrow mesenchymal stem cells into a glial phenotype.

Background: Mesenchymal stem cells (MSCs) are multipotent precursor cells with the ability to self-renew and differentiate into multiple cell linage, including the Schwann-like fate that promotes regeneration after lesion. Raman spectroscopy provides a precise characterization of the osteogenic, adipogenic, hepatogenic and myogenic differentiation of MSCs. However, the differentiation of bone marrow mesenchymal stem cells (BMSCs) towards a glial phenotype (Schwann-like cells) has not been characterized before using Raman spectroscopy. Method: We evaluated three conditions: 1) cell culture from rat bone marrow undifferentiated (uBMSCs), and two conditions of differentiation; 2) cells exposed to olfactory ensheathing cells-conditioned medium (dBMSCs) and 3) cells obtained from olfactory bulb (OECs). uBMSCs phenotyping was confirmed by morphology, immunocytochemistry and flow cytometry using antibodies of cell surface: CD90 and CD73. Glial phenotype of dBMSCs and OECs were verified by morphology and immunocytochemistry using markers of Schwann-like cells and OECs such as GFAP, p75 NTR and O4. Then, the Principal Component Analysis (PCA) of Raman spectroscopy was performed to discriminate components from the high wavenumber region between undifferentiated and glial-differentiated cells. Raman bands at the fingerprint region also were used to analyze the differentiation between conditions. Results: Differences between Raman spectra from uBMSC and glial phenotype groups were noted at multiple Raman shift values. A significant decrease in the concentration of all major cellular components, including nucleic acids, proteins, and lipids were found in the glial phenotype groups. PCA analysis confirmed that the highest spectral variations between groups came from the high wavenumber region observed in undifferentiated cells and contributed with the discrimination between glial phenotype groups. Conclusion: These findings support the use of Raman spectroscopy for the characterization of uBMSCs and its differentiation in the glial phenotype.

Normal pressure hydrocephalus decreases the proliferation of oligodendrocyte progenitor cells and the expression of CNPase and MOG proteins in the corpus callosum before behavioral deficits occur.

Normal pressure hydrocephalus (NPH) compromises the morphology of the corpus callosum (CC). This study aims to determine whether 60- or 120-day NPH disrupts the cytoarchitecture and functioning of white matter (WM) and oligodendrocyte precursor cells (OPCs) and establish whether these changes are reversible after hydrocephalus treatment. NPH was induced in CD1 adult mice by inserting an obstructive lamina in the atrium of the aqueduct of Sylvius. Five groups were assembled: sham-operated controls (60 and 120 days), NPH groups (60 and 120 days), and the hydrocephalus-treated group (obstruction removal after 60-d hydrocephalus). We analyzed the cellular integrity of the CC by immunohistochemistry, TUNEL analysis, Western blot assays, and transmission electron microscopy (TEM). We found a reduction in the width of the CC at 60 and 120 days of NPH. TEM analysis demonstrated myelin abnormalities, degenerative changes in the WM, and an increase in the number of hyperdense (dark) axons that were associated with significant astrogliosis, and microglial reactivity. Hydrocephalus also caused a decrease in the expression of myelin-related proteins (MOG and CNPase) and reduced proliferation and population of OPCs, resulting in fewer mature oligodendrocytes. Hydrocephalus resolution only recovers the OPC proliferation and MOG protein density, but the rest of the WM abnormalities persisted. Interestingly, all these cellular and molecular anomalies occur in the absence of behavioral changes. The results suggest that NPH severely disrupts the myelin integrity and affects the OPC turnover in the CC. Remarkably, most of these deleterious events persist after hydrocephalus treatment, which suggests that a late treatment conveys irreversible changes in the WM of CC.

Phenytoin promotes the proliferation of oligodendrocytes and enhances the expression of myelin basic protein in the corpus callosum of mice demyelinated by cuprizone.

Oligodendrocyte loss and myelin sheet destruction are crucial characteristics of demyelinating diseases. Phenytoin promotes the proliferation of endogenous neural precursor cells in the ventricular-subventricular zone in the postnatal brain that help restore the oligodendroglial population. This study aimed to evaluate whether phenytoin promotes myelin recovery of the corpus callosum of demyelinated adult mice. CD1 male mice were exposed to a demyelinating agent (0.2% cuprizone) for 8 weeks. We assembled two groups: the phenytoin-treated group and the control-vehicle group. The treated group received oral phenytoin (10 mg/kg) for 4 weeks. We quantified the number of Olig2 + and NG2 + oligodendrocyte precursor cells (OPCs), Rip + oligodendrocytes, the expression level of myelin basic protein (MBP), and the muscle strength and motor coordination. The oligodendroglial lineage (Olig2 + cells, NG2 + cells, and RIP + cells) significantly increases by the phenytoin administration when compared to the control-vehicle group. The phenytoin-treated group also showed an increased expression of MBP in the corpus callosum and better functional scores in the horizontal bar test. These findings suggest that phenytoin stimulates the proliferation of OPCs, re-establishes the oligodendroglial population, promotes myelin recovery in the corpus callosum, and improves motor coordination and muscle strength.

Chronic exposure to cyclohexane induces stereotypic circling, hyperlocomotion, and anxiety-like behavior associated with atypical c-Fos expression in motor- and anxiety-related brain regions.

Recreational abuse of solvents continues, despite cyclohexane (CHX) is used as a safe replacement in gasoline or adhesive formulations. Increasing evidence indicates that CHX inhalation affects brain functioning; however, scanty information is available about its effects on behavior and brain activity upon drug removal. In this study, we used CD1 adult mice to mimic an intoxication period of recreational drugs for 30 days. During the CHX exposure (~30,000 ppm), we analyzed exploratory and biphasic behaviors, stereotypic circling, and locomotion. After CHX removal (24 h or a month later), we assessed anxiety-like behaviors and quantified c-Fos cells in motor- and anxiety-related brain regions. Our findings indicate that the repeated inhalation of CHX produced steady hyperactivity and reduced ataxia, sedation, and seizures as the exposure to CHX progressed. Also, CHX decreased grooming and rearing behaviors. In the first week of CHX inhalation, a stereotypic circling behavior emerged, and locomotion increased gradually. One month after CHX withdrawal, mice showed low activity in the center zone of the open field and more buried marbles. Twenty-four hours after CHX removal, c-Fos expression was low in the dorsal striatum, ventral striatum, motor cortex, dorsomedial prefrontal cortex, basolateral amygdala, lateral hypothalamus, and ventral hippocampus. One month later, c-Fos expression remained low in the ventral striatum and lateral hypothalamus but increased in the dorsomedial prefrontal cortex and primary motor cortex. This study provides a comprehensive behavioral characterization and novel histological evidence of the CHX effects on the brain when is administered in a recreational-like mode.

Characterization of a mouse model of chronic hydrocephalus induced by partial occlusion of the aqueduct of Sylvius in the adult brain.

BACKGROUND: Hydrocephalus is a neurologic disturbance produced by the abnormal production, circulation, and absorption of cerebrospinal fluid (CSF). Late-onset idiopathic aqueductal stenosis induces normal pressure hydrocephalus (NPH) in adults. To date, no animal model replicating chronic NPH is available to study the pathophysiological changes observed in these subjects. NEW METHOD: We performed and characterized a model that induces chronic hydrocephalus in the adult mouse brain by producing a pre-aqueductal semiobstruction using an acetate lamina inserted into the atrium of the aqueduct of Sylvius. After surgical procedure, we analyzed the hydrocephalus development on days 60 and 120 and sham-operated animals were used as controls. We included an additional group of hydrocephalus resolution in which we removed the obstruction and analyzed the morphological changes in the brain. RESULTS: The hydrocephalus was fully established on day 60 after the obstruction and remained stable for 120 days. In all animals, the intracranial pressure remained ~4.08 mmHg and we did not find statistically significant differences between the hydrocephalus groups and controls. We did not find motor impairments and anxiety-like behaviors among groups and the analysis of microglia and astrogliosis revealed mild glial reactivity. COMPARISON WITH EXISTING METHODS: This model generates a long-term ventricular enlargement with normal intracranial pressure and moderate glial reactivity. Importantly, this model allows the reversibility of ventricular enlargement after the removal of the obstructive film from the brain. CONCLUSIONS: This mouse model may be useful to study the long-term cerebral alterations that occur during NPH or after its surgical resolution.

A comparison of passive surveillance and active cluster-based surveillance for dengue fever in southern coastal Ecuador.

BACKGROUND: Dengue is a major emerging infectious disease, endemic throughout the tropics and subtropics, with approximately 2.5 billion people at risk globally. Active (AS) and passive surveillance (PS), when combined, can improve our understanding of dengue's complex disease dynamics to guide effective, targeted public health interventions. The objective of this study was to compare findings from the Ministry of Health (MoH) PS to a prospective AS arbovirus research study in Machala, Ecuador in 2014 and 2015. METHODS: Dengue cases in the PS system were compared to laboratory confirmed acute dengue illness cases that entered the AS study during the study period. Variables of interest included age class and sex. Outbreak detection curves by epidemiologic week, overall cumulative incidence and age-specific incidence proportions were calculated. Descriptive statistics were tabulated for all variables of interest. Chi-square tests were performed to compare demographic characteristics between the AS and PS data sets in 2014 and 2015. RESULTS: 177 and 245 cases were identified from 1/1/2014 to 12/31/2015 by PS and AS, respectively; nine cases appeared in both systems. AS identified a greater number of laboratory-confirmed cases in 2014, accounting for more than 60% of dengue cases in the study area. In 2015, the opposite trend was observed with PS identifying 60% of the dengue cases in the study area. Peak transmission time in laboratory confirmed dengue illness, as noted by AS and PS was similar in 2014, whereas earlier detection (7 weeks) was observed by AS in 2015. Younger patients were more frequently identified by PS, while older patients were identified more frequently by AS. The cumulative incidence proportion for laboratory confirmed dengue illness reported via PS to the MoH was 4.12 cases per 10,000 residents in 2014, and 2.21 cases per 10,000 residents in 2015. CONCLUSIONS: Each surveillance system captured distinct demographic subgroups within the Machala population, possibly due to differences in healthcare seeking behaviors, access to care, emerging threats of other viruses transmitted by the same mosquito vector and/or differences in clinical presentation. Integrating AS with pre-existing PS can aid in identifying additional cases in previously underdiagnosed subpopulations, improving our understanding of disease dynamics, and facilitating the implementation of timely public health interventions.

Mamey sapote fruit and carotenoid formulations derived thereof are dietary sources of vitamin A - A comparative randomized cross-over study.

Mamey sapote is a fruit rich in specific keto-carotenoids, namely sapotexanthin and cryptocapsin. Their chemical structure suggests their provitamin A activity, although their absorption and conversion to vitamin A remained to be demonstrated in humans. Besides structure-related factors, the fruit matrix might also hamper absorption and conversion efficiency. Therefore, we monitored carotenoid and vitamin A levels in triacylglycerol-rich lipoprotein (TRL) fractions in plasma of human participants after consumption of fresh sapote and a carotenoid-rich "matrix-free" formulation derived thereof. A randomized 2-way cross-over study was conducted to compare the post-prandial bioavailability of 0.8 mg sapotexanthin and 1.2-1.5 mg cryptocapsin from the above-mentioned test meals. Seven blood samples were drawn over 9.5 h after test meal consumption. Carotenoids and retinoids were quantitated in TRL fractions using HPLC-DAD. Sapotexanthin was absorbed by all participants from all meals, being ca. 36% more bioavailable from the "matrix-free" formulation (AUCmedian = 73.4 nmol∙h/L) than from the fresh fruit (AUCmedian = 54.0 nmol∙h/L; p ≤ 0.001). Cryptocapsin was only absorbed by 4 of 13 participants. The appearance of retinyl esters was observed in all participants independent of the test meal. Although the fruit matrix hampered carotenoid in vivo-bioavailability from sapote, the fruit clearly represents a valuable source of vitamin A for humans.

Cyclohexane Inhalation Produces Long-Lasting Alterations in the Hippocampal Integrity and Reward-Seeking Behavior in the Adult Mouse.

Cyclohexane (CHX) is an organic solvent commonly used as a drug-of-abuse. This drug increases the oxidative stress and glial reactivity in the hippocampus, which suggests that this brain region is vulnerable to CHX effects. This study aimed to establish the behavioral changes and the pathological alterations that occur in the Cornu Ammonis 3 (CA3) and Dentate Gyrus (DG) after a long-lasting exposure to CHX. We exposed CD1 mice to a recreational-like dose of CHX (~ 30,000 ppm) for 30 days and explored its consequences in motor skills, reward-seeking behavior, and the CA3 and DG hippocampal subfields. Twenty-four hours after the last administration of CHX, we found a significant decrease in the number of c-Fos+ cells in the hippocampal CA3 and DG regions. This event coincided with an increased in NMDAR1 expression and apoptotic cells in the CA3 region. At day 13th without CHX, we found a persistent reduction in the number of c-Fos+ and TUNEL+ cells in DG. At both time points, the CHX-exposed mice showed a strong overexpression of neuropeptide Y (NPY) in the CA3 stratum lucidum and the hippocampal hilus. In parallel, we used an operant-based task to assess motor performance and operant conditioning learning. The behavioral analysis indicated that CHX did not modify the acquisition of operant conditioning tasks, but affected some motor skills and increased the reward-seeking behavior. Altogether, this evidence reveals that CHX exposure provokes long-lasting changes in the hippocampal subfields, induces motor impairments and increases the motivation-guided behavior. These findings can help understand the deleterious effect of CHX into the adult hippocampus and unveil its potential to trigger addiction-like behaviors.

Bioaccessibility of carotenoids from plant and animal foods.

The frequent consumption of carotenoid-rich foods has been associated with numerous health benefits, such as the supply of provitamin A. To exert these health benefits, carotenoids need to be efficiently liberated from the food matrix, micellized in the small intestine, taken up by the enterocytes and absorbed into the human blood stream. Enormous efforts have been made to better understand these processes. Because human studies are costly, labor-intense and time-consuming, the evaluation of carotenoid liberation and micellization at the laboratory scale using simulated in vitro digestion models has proven to be an important tool for obtaining preliminary results prior to conducting human studies. In particular, the liberation from the food matrix and the intestinal micellization can be mimicked by simulated digestion, yielding an estimate of the so-called bioaccessibility of a carotenoid. In the present review, we provide an overview of the carotenoid digestion process in vivo, the currently used in vitro digestion models and the outcomes of previous bioaccessibility studies, with a special focus on correlations with concomitantly conducted human studies. Furthermore, we advocate for the on-going requirement of better standardized digestion protocols and, in addition, we provide suggestions for the complementation of the acquired knowledge and current nutritional recommendations. © 2018 Society of Chemical Industry.

Infección por morganella morganii en paciente postransplantado de riñón: reporte de caso y revisión de literatura / Morganella morganii infection in post-transplant kidney patient: Case Report and literature review

Las infecciones humanas por Morganella morganii es poco frecuente hasta el 3% de las infecciones del tracto urinario, puede producir diversos tipos de infecciones, su papel etiológico es dudoso. Hay pocos reportes a nivel mundial en la literatura sobre infecciones causadas por este patógeno y ninguna en Honduras. Descripción de Caso. Masculino 46 años con antecedentes de trasplante renal hace 4 años por IRC, manejado con prednisona, micofelonato y sirulimus, diabético e hipertensión arterial crónica tratado con Insulina NPH 20 u. cada día y Carvedilol 12.5 mg, referido por el servicio de Nefrología a la Emergencia del HEU por iebre de una semana, continua, sugestivamente alta, no cuantiicada, diaforesis con escalofrío, con disuria de un día de evolución y un episodio de vomito. Con signos vitales P/A 90/60 mmHg, FC 88 x ́, FR 22 x ́, afebril, examen físico normal. Cuatro horas posteriores al ingreso; comenzó con iebre de 38.9 °C agregando antipiréticos al manejo establecido, con hiponatremia, falla renal aguda, uroanálisis patológico. Ecografía renal: Riñón trasplantado de corteza engrosada correspondiendo a pielonefritis aguda, sin masas, colecciones, litos e hidronefrosis, midiendo 12.7x5.8x4.9 cm. Urocultivo: crecimiento de Morganella morganii, resistente a fosfosil, nitrofurantoina, sensible a ciproloxacino y ceftazidime. Paciente se mantuvo afebril, mejorando al manejo establecido con ciproloxacino IV se da alta al quinto día posterior a su ingreso con seguimiento estricto por servicio de nefrología. Conclusiones. Reportamos una patología vista con frecuencia, pero en un paciente especial como es un post trasplante renal que pudo traer múltiples complicaciones para el paciente sumado al que el patógeno es conocida como agente infección de la vía urinaria pero rara vez causa infecciones en personas inmunocompetentes, pero si puedes llegar a ser causa de infección nosocomiales en personas inmunocomprometidas. Debemos de tener seguimiento estricto de este tipo de pacientes desde el más mínimo síntoma para evitar secuelas y/o complicaciones severas

Alterations of Growth Factors in Autism and Attention-Deficit/Hyperactivity Disorder.

Growth factors (GFs) are cytokines that regulate the neural development. Recent evidence indicates that alterations in the expression level of GFs during embryogenesis are linked to the pathophysiology and clinical manifestations of attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorders (ASD). In this concise review, we summarize the current evidence that supports the role of brain-derived neurotrophic factor, insulin-like growth factor 2, hepatocyte growth factor (HGF), glial-derived neurotrophic factor, nerve growth factor, neurotrophins 3 and 4, and epidermal growth factor in the pathogenesis of ADHD and ASD. We also highlight the potential use of these GFs as clinical markers for diagnosis and prognosis of these neurodevelopmental disorders.

Carotenoids and carotenoid esters of orange- and yellow-fleshed mamey sapote (Pouteria sapota (Jacq.) H.E. Moore & Stearn) fruit and their post-prandial absorption in humans.

Although different genotypes of mamey sapote with distinct pulp colors are consumed in countries from Central to South America, in-depth knowledge on genotype-related differences of their carotenoid profile is lacking. Since the fruit was found to contain the potentially vitamin A-active keto-carotenoids sapotexanthin and cryptocapsin, we sought to qualitatively and quantitatively describe the carotenoid profile of different genotypes by HPLC-DAD-MSn. Sapotexanthin and cryptocapsin were present in all genotypes. Keto-carotenoids such as cryptocapsin, capsoneoxanthin, and their esters were most abundant in orange-fleshed fruit, whereas several carotenoid epoxides prevailed in yellow-fleshed fruit. Differing carotenoid profiles were associated with different color hues of the fruit pulp, while the widely variable carotenoid content (3.7-8.0mg/100gFW) was mainly reflected by differences in color intensity (chroma C∗). Furthermore, the post-prandial absorption of sapotexanthin to human plasma was proven for the first time. Besides sapotexanthin, cryptocapsin was found to be resorbed.

Successful malaria elimination in the Ecuador-Peru border region: epidemiology and lessons learned.

BACKGROUND: In recent years, malaria (Plasmodium vivax and Plasmodium falciparum) has been successfully controlled in the Ecuador-Peru coastal border region. The aim of this study was to document this control effort and to identify the best practices and lessons learned that are applicable to malaria control and to other vector-borne diseases. A proximal outcome evaluation was conducted of the robust elimination programme in El Oro Province, Ecuador, and the Tumbes Region, Peru. Data collection efforts included a series of workshops with local public health experts who played central roles in the elimination effort, review of epidemiological records from Ministries of Health, and a review of national policy documents. Key programmatic and external factors are identified that determined the success of this eradication effort. CASE DESCRIPTION: From the mid 1980s until the early 2000s, the region experienced a surge in malaria transmission, which experts attributed to a combination of ineffective anti-malarial treatment, social-ecological factors (e.g., El Niño, increasing rice farming, construction of a reservoir), and political factors (e.g., reduction in resources and changes in management). In response to the malaria crisis, local public health practitioners from El Oro and Tumbes joined together in the mid-1990s to forge an unofficial binational collaboration for malaria control. Over the next 20 years, they effectively eradicated malaria in the region, by strengthening surveillance and treatment strategies, sharing of resources, operational research to inform policy, and novel interventions. DISCUSSION AND EVALUATION: The binational collaboration at the operational level was the fundamental component of the successful malaria elimination programme. This unique relationship created a trusting, open environment that allowed for flexibility, rapid response, innovation and resilience in times of crisis, and ultimately a sustainable control programme. Strong community involvement, an extensive microscopy network and ongoing epidemiologic investigations at the local level were also identified as crucial programmatic strategies. CONCLUSION: The results of this study provide key principles of a successful malaria elimination programme that can inform the next generation of public health professionals in the region, and serve as a guide to ongoing and future control efforts of other emerging vector borne diseases globally.

Growth factors as clinical biomarkers of prognosis and diagnosis in psychiatric disorders.

The psychiatric disorders are one of the most disabling illnesses in the world and represent a major problem for public health. These disorders are characterized by neuroanatomical or biochemical changes and it has been suggested that such changes may be due to inadequate neurodevelopment. Diverse alterations in the gene expression and/or serum level of specific growth factors have been implicated in the etiology, symptoms and progression of some psychiatric disorders. Herein, we summarize the latest information regarding the role of brain-derived neurotrophic factor (BDNF), epidermal growth factor (EGF), fibroblast growth factor (FGF), Insulin-like growth factor (IGF-1), neuroregulin-1 (NGR-1), erythropoietin (EPO), vascular growth factor (VEGF), transforming growth factor beta (TGF-ß), nerve growth factor (NGF) and others cytokines in the pathogenesis of schizophrenia, depression, bipolar and anxiety disorders. Focusing on the role of these growth factors and their relationship with the main impairments (cognitive, emotional and social) of these pathologies. Some of these signaling molecules may be suitable biological markers for diagnosis and prognosis in cognitive, mood and social disabilities across different mental disorders.

Deposition Form and Bioaccessibility of Keto-carotenoids from Mamey Sapote (Pouteria sapota), Red Bell Pepper (Capsicum annuum), and Sockeye Salmon (Oncorhynchus nerka) Filet.

The ultrastructure and carotenoid-bearing structures of mamey sapote (Pouteria sapota) chromoplasts were elucidated using light and transmission electron microscopy and compared to carotenoid deposition forms in red bell pepper (Capsicum annuum) and sockeye salmon (Oncorhynchus nerka). Globular-tubular chromoplasts of sapote contained numerous lipid globules and tubules embodying unique provitamin A keto-carotenoids in a lipid-dissolved and presumably liquid-crystalline form, respectively. Bioaccessibility of sapotexanthin and cryptocapsin was compared to that of structurally related keto-carotenoids from red bell pepper and salmon. Capsanthin from bell pepper was the most bioaccessible pigment, followed by sapotexanthin and cryptocapsin esters from mamey sapote. In contrast, astaxanthin from salmon was the least bioaccessible keto-carotenoid. Thermal treatment and fat addition consistently enhanced bioaccessibility, except for astaxanthin from naturally lipid-rich salmon, which remained unaffected. Although the provitamin A keto-carotenoids from sapote were highly bioaccessible, their qualitative and quantitative in vivo bioavailability and their conversion to vitamin A remains to be confirmed.

Phenytoin enhances the phosphorylation of epidermal growth factor receptor and fibroblast growth factor receptor in the subventricular zone and promotes the proliferation of neural precursor cells and oligodendrocyte differentiation.

Phenytoin is a widely used antiepileptic drug that induces cell proliferation in several tissues, such as heart, bone, skin, oral mucosa and neural precursors. Some of these effects are mediated via fibroblast growth factor receptor (FGFR) and epidermal growth factor receptor (EGFR). These receptors are strongly expressed in the adult ventricular-subventricular zone (V-SVZ), the main neurogenic niche in the adult brain. The aim of this study was to determine the cell lineage and cell fate of V-SVZ neural progenitors expanded by phenytoin, as well as the effects of this drug on EGFR/FGFR phosphorylation. Male BALB/C mice received 10 mg/kg phenytoin by oral cannula for 30 days. We analysed the proliferation of V-SVZ neural progenitors by immunohistochemistry and western blot. Our findings indicate that phenytoin enhanced twofold the phosphorylation of EGFR and FGFR in the V-SVZ, increased the number of bromodeoxyuridine (BrdU)+/Sox2+ and BrdU+/doublecortin+ cells in the V-SVZ, and expanded the population of Olig2-expressing cells around the lateral ventricles. After phenytoin removal, a large number of BrdU+/Receptor interacting protein (RIP)+ cells were observed in the olfactory bulb. In conclusion, phenytoin enhanced the phosphorylation of FGFR and EGFR, and promoted the expression of neural precursor markers in the V-SVZ. In parallel, the number of oligodendrocytes increased significantly after phenytoin removal.

Cyclohexane produces behavioral deficits associated with astrogliosis and microglial reactivity in the adult hippocampus mouse brain.

Cyclohexane is a volatile substance that has been utilized as a safe substitute of several organic solvents in diverse industrial processes, such as adhesives, paints, paint thinners, fingernail polish, lacquers, and rubber industry. A number of these commercial products are ordinarily used as inhaled drugs. However, it is not well known whether cyclohexane has noxious effects in the central nervous system. The aim of this study was to analyze the effects of cyclohexane inhalation on motor behavior, spatial memory, and reactive gliosis in the hippocampus of adult mice. We used a model that mimics recreational drug use in male Balb/C mice (P60), divided into two groups: controls and the cyclohexane group (exposed to 9,000 ppm of cyclohexane for 30 days). Both groups were then evaluated with a functional observational battery (FOB) and the Morris water maze (MWM). Furthermore, the relative expression of AP endonuclease 1 (APE1), and the number of astrocytes (GFAP+ cells) and microglia (Iba1+ cells) were quantified in the hippocampal CA1 and CA3 areas. Our findings indicated that cyclohexane produced severe functional deficits during a recreational exposure as assessed by the FOB. The MWM did not show statistically significant changes in the acquisition and retention of spatial memory. Remarkably, a significant increase in the number of astrocytes and microglia cells, as well as in the cytoplasmic processes of these cells were observed in the hippocampal CA1 and CA3 areas of cyclohexane-exposed mice. This cellular response was associated with an increase in the expression of APE1 in the same brain regions. In summary, cyclohexane exposure produces functional deficits that are associated with an important increase in the APE1 expression as well as the number of astrocytes and microglia cells and their cytoplasmic complexity in the CA1 and CA3 regions of the adult hippocampus.

Cyclohexane, a Potential Drug of Abuse with Pernicious Effects on the Brain.

Cyclohexane is a volatile solvent used as a harmless substitute for dangerous organic solvents in several products, such as paint thinners, gasoline and adhesives. Many of these products are used as drugs of abuse and can severely damage neural tissue and impair neurological functions. However, there is very little information on the effects of cyclohexane on the brain. In humans, cyclohexane produces headaches, sleepiness, dizziness, limb weakness, motor changes, and verbal memory impairment. Recent studies in mice have demonstrated behavioral alterations, reactive gliosis, microglial reactivity, and oxidative stress in the brains of cyclohexane-exposed animals. This indicates that cyclohexane may represent a potential problem for public health. Therefore, studies are needed to clarify the neurobiological effects of this volatile compound, including the cellular and molecular mechanisms of neurotoxicity, and to minimize the human health risk posed by the intentional or accidental inhalation of this potential drug of abuse.