Targeting autotaxin impacts disease advance in the SOD1-G93A mouse model of amyotrophic lateral sclerosis.

A preclinical strategy to broaden the search of potentially effective treatments in amyotrophic lateral sclerosis (ALS) relies on identifying factors controlling motor neuron (MN) excitability. These partners might be part of still unknown pathogenic pathways and/or useful for the design of new interventions to affect disease progression. In this framework, the bioactive membrane-derived phospholipid lysophosphatidic acid (LPA) affects MN excitability through LPA receptor 1 (LPA1 ). Furthermore, LPA1  knockdown is neuroprotective in transgenic ALS SOD1-G93A mice. On this basis, we raised the hypothesis that the major LPA-synthesizing ectoenzyme, autotaxin (ATX), regulates MN excitability and is a potential target to modulate disease development in ALS mice. We show here that PF-8380, a specific ATX inhibitor, reduced intrinsic membrane excitability (IME) of hypoglossal MNs in brainstem slices, supporting that baseline ATX activity regulates MN IME. PF-8380-induced alterations were prevented by a small-interfering RNA directed against mRNA for lpa1 . These outcomes support that impact of ATX-originated lysophospholipids on MN IME engages, at least, the G-protein-coupled receptor LPA1 . Interestingly, mRNAatx levels increased in the spinal cord of pre-symptomatic (1-2 months old) SOD1-G93A mice, thus preceding MN loss. The rise in transcripts levels also occurred in cultured spinal cord MNs from SOD1-G93A embryos, suggesting that mRNAatx upregulation in MNs is an etiopathogenic event in the ALS cell model. Remarkably, chronic administration in the drinking water of the orally bioavailable ATX inhibitor PF-8380 delayed MN loss, motor deterioration and prolonged life span in ALS mice. Treatment also led to a reduction in LPA1 -immunoreactive patches in transgenic animals mostly in MNs. These outcomes support that neuroprotective effects of interfering with ATX in SOD1-G93A mice rely, at least in part, on LPA1  knockdown in MNs. Therefore, we propose ATX as a potential target and/or a biomarker in ALS and highlight ATX inhibitors as reasonable tools with therapeutic usefulness for this lethal pathology.

Lysophosphatidic Acid and Several Neurotransmitters Converge on Rho-Kinase 2 Signaling to Manage Motoneuron Excitability.

Intrinsic membrane excitability (IME) sets up neuronal responsiveness to synaptic drive. Several neurotransmitters and neuromodulators, acting through G-protein-coupled receptors (GPCRs), fine-tune motoneuron (MN) IME by modulating background K+ channels TASK1. However, intracellular partners linking GPCRs to TASK1 modulation are not yet well-known. We hypothesized that isoform 2 of rho-kinase (ROCK2), acting as downstream GPCRs, mediates adjustment of MN IME via TASK1. Electrophysiological recordings were performed in hypoglossal MNs (HMNs) obtained from adult and neonatal rats, neonatal knockout mice for TASK1 (task1 -/-) and TASK3 (task3 -/-, the another highly expressed TASK subunit in MNs), and primary cultures of embryonic spinal cord MNs (SMNs). Small-interfering RNA (siRNA) technology was also used to knockdown either ROCK1 or ROCK2. Furthermore, ROCK activity assays were performed to evaluate the ability of various physiological GPCR ligands to stimulate ROCK. Microiontophoretically applied H1152, a ROCK inhibitor, and siRNA-induced ROCK2 knockdown both depressed AMPAergic, inspiratory-related discharge activity of adult HMNs in vivo, which mainly express the ROCK2 isoform. In brainstem slices, intracellular constitutively active ROCK2 (aROCK2) led to H1152-sensitive HMN hyper-excitability. The aROCK2 inhibited pH-sensitive and TASK1-mediated currents in SMNs. Conclusively, aROCK2 increased IME in task3 -/-, but not in task1 -/- HMNs. MN IME was also augmented by the physiological neuromodulator lysophosphatidic acid (LPA) through a mechanism entailing Gαi/o-protein stimulation, ROCK2, but not ROCK1, activity and TASK1 inhibition. Finally, two neurotransmitters, TRH, and 5-HT, which are both known to increase MN IME by TASK1 inhibition, stimulated ROCK2, and depressed background resting currents via Gαq/ROCK2 signaling. These outcomes suggest that LPA and several neurotransmitters impact MN IME via Gαi/o/Gαq-protein-coupled receptors, downstream ROCK2 activation, and subsequent inhibition of TASK1 channels.

Interfering with lysophosphatidic acid receptor edg2/lpa1 signalling slows down disease progression in SOD1-G93A transgenic mice.

AIMS: Alterations in excitability represent an early hallmark in Amyotrophic Lateral Sclerosis (ALS). Therefore, deciphering the factors that impact motor neuron (MN) excitability offers an opportunity to uncover further aetiopathogenic mechanisms, neuroprotective agents, therapeutic targets, and/or biomarkers in ALS. Here, we hypothesised that the lipokine lysophosphatidic acid (lpa) regulates MN excitability via the G-protein-coupled receptor lpa1 . Then, modulating lpa1 -mediated signalling might affect disease progression in the ALS SOD1-G93A mouse model. METHODS: The influence of lpa-lpa1 signalling on the electrical properties, Ca2+ dynamic and survival of MNs was tested in vitro. Expression of lpa1 in cultured MNs and in the spinal cord of SOD1-G93A mice was analysed. ALS mice were chronically treated with a small-interfering RNA against lpa1 (siRNAlpa1 ) or with the lpa1 inhibitor AM095. Motor skills, MN loss, and lifespan were evaluated. RESULTS: AM095 reduced MN excitability. Conversely, exogenous lpa increased MN excitability by modulating task1 'leak' potassium channels downstream of lpa1 . Lpa-lpa1 signalling evoked an excitotoxic response in MNs via voltage-sensitive calcium channels. Cultured SOD1-G93A MNs displayed lpa1 upregulation and heightened vulnerability to lpa. In transgenic mice, lpa1 was upregulated mostly in spinal cord MNs before cell loss. Chronic administration of either siRNAlpa1 or AM095 reduced lpa1 expression at least in MNs, delayed MN death, improved motor skills, and prolonged life expectancy of ALS mice. CONCLUSIONS: These results suggest that stressed lpa-lpa1 signalling contributes to MN degeneration in SOD1-G93A mice. Consequently, disrupting lpa1 slows down disease progression. This highlights LPA1 signalling as a potential target and/or biomarker in ALS.

Sp1-regulated expression of p11 contributes to motor neuron degeneration by membrane insertion of TASK1.

Disruption in membrane excitability contributes to malfunction and differential vulnerability of specific neuronal subpopulations in a number of neurological diseases. The adaptor protein p11, and background potassium channel TASK1, have overlapping distributions in the CNS. Here, we report that the transcription factor Sp1 controls p11 expression, which impacts on excitability by hampering functional expression of TASK1. In the SOD1-G93A mouse model of ALS, Sp1-p11-TASK1 dysregulation contributes to increased excitability and vulnerability of motor neurons. Interference with either Sp1 or p11 is neuroprotective, delaying neuron loss and prolonging lifespan in this model. Nitrosative stress, a potential factor in human neurodegeneration, stimulated Sp1 expression and human p11 promoter activity, at least in part, through a Sp1-binding site. Disruption of Sp1 or p11 also has neuroprotective effects in a traumatic model of motor neuron degeneration. Together our work suggests the Sp1-p11-TASK1 pathway is a potential target for treatment of degeneration of motor neurons.

Consumo de alcohol y factores asociados en estudiantes de instrumentación quirúrgica en una universidad de Bogotá, 2014 / Alcohol drinking and associated factors in surgical instrumentation students at a university in Bogota, 2014

Establecer la frecuencia y los factores asociados al consumo de alcohol en estudiantes de Instrumentación Quirúrgica de una institución universitaria privada de Bogotá en el 2014. Materiales y Métodos: Estudio de corte transversal en una muestra no probabilística por conveniencia de 176 estudiantes del Programa de Instrumentación Quirúrgica. Se obtuvo información sobre características sociodemográficas; sobre la frecuencia de consumo de alcohol alguna vez en la vida, en el último año, en el último mes, en la última semana y sobre la bebida alcohólica más consumida; y también sobre factores de riesgo tales como el nivel de escolaridad de los padres, ingreso familiar mensual, trabajo, consumo de alcohol de los familiares y motivación personal para el consumo. Resultados: El 96% de los estudiantes habían consumido alcohol alguna vez en la vida, el 41,5% lo habían hecho en la última semana y el 33,5% en el último mes. El 81,8% de los encuestados eligieron la cerveza como la bebida que más consumen, el 40,6% dijeron haber ingerido más de cuatro tragos la última vez que consumieron y el lugar más frecuente de consumo fueron los bares y/o discotecas (82,3%). Los factores asociados al consumo del alcohol fueron el consumo por parte de familiares (OR=3,9) y que los amigos los inciten a tomar (OR=2,6), así como el nivel de escolaridad de bachillerato de los padres (OR=0,5). Conclusión: A pesar de ser una muestra constituida principalmente por mujeres, los resultados coinciden con la tendencia que han mostrado otros estudios respecto a la alta frecuencia de consumo de bebidas alcohólicas en estudiantes universitarios...

To establish the frequency and associated factors with alcohol drinking in Surgical Instrumentation students from a private university in Bogota in 2014. Materials and Methods: Cross-sectional study in a non-probabilistic convenience sample of 176 students of Surgical Instrumentation Program. Sociodemographic information was obtained; and about frequency of alcohol consumption sometime in life, in the last year, in the last month, in the last week and the most consumed alcoholic beverage; and also on risk factors such as level of education of parents, monthly family income, work, family and personal motivation for alcohol consumption Results: 96% of the students had consumed alcohol at some time in life, 41,5% had done so in the past week and 33,5% in the last month; 81,8% of respondents chose beer as the more consumed drink, 40.6% said they had consumed more than four drinks the last time and the most frequent place of consumption were the bars and/or clubs (82,3%). Factors associated with alcohol consumption were consumption by family (OR = 3.9) and the inciting friends to take (OR = 2.6), and the level of education of high school parents (OR = 0.5). Conclusion: Despite being a sample consisting mainly of women, the results are consistent with the trend that other studies have shown respect to the high frequency of drinking in college students...

Caracterización de la compra de antibióticos en droguerías de Bogotá: una mirada desde los usuarios / Characterising the purchase of antibiotics in drugstores in Bogotá: a users' perspective

Objetivo: Caracterizar el proceso de compra de antibióticos con fórmula médica u odontológica o sin esta en la población participante de dieciocho localidades de Bogotá. Método: Diseño transversal aplicado durante el segundo semestre del 2009 mediante 534encuestas a las personas que compraron antibióticos a la salida de droguerías ubicadas en dieciocho localidades de Bogotá. Se indagó sobre variables sociodemográficas, conocimientos y actitudes de los participantes sobre los antibióticos y exploración de las prácticasrelacionadas con el uso de estos medicamentos, características de la compra de antibióticos y autoprescripción. Resultados: El 43,1%de los participantes compraron el antibiótico en las droguerías sin fórmula médica u odontológica y no asistieron a consulta médica.El porcentaje de autoprescripción con antibióticos fue del 13%. Un 30,2% de los antibióticos fue prescrito por un familiar (15,2%), el farmaceuta (11,4 %), un vecino (3%) y un curandero o hierbatero (0,6%). Conclusiones: En el conglomerado de las dieciocho localidadesde Bogotá existe una elevada proporción de personas no facultadas para hacerlo que recomienda antibióticos a la población. Debe enfatizarse que más del 40% de las ventas de antibióticos en las droguerías en las que se hizo la evaluación se hicieron sin la respectivay necesaria fórmula médica. La población participante tiene conocimientos, actitudes y prácticas que afectan el uso adecuado de los antibióticos y no contribuyen a la contención de la resistencia bacteriana en el Distrito Capital.

Objective: Characterising how antibiotics are bought with a doctor’s and/or dentist’s prescription in the participating population from Bogotá’s eighteen local districts. Methods: 534 people buying antibiotics when leaving drugstores in eighteen of Bogotá’s districts were surveyed during the second half of 2009, using a cross-sectional design. The participants’ socio-demographic variables, knowledge and attitudes towards antibiotics were investigated and practice related to using such medicaments, characteristics regarding buying antibiotics and self-medication was also explored. Results: 43.1% of the participants had bought antibiotics in drugstores without a doctor or dentist’s prescription and had not consulted a doctor or dentist; 13% of them were self-medicating themselves withantibiotics. 30.2% of the antibiotics had been prescribed by a family member (15.2%), a pharmacist (11.4%), a neighbour (3%) or an alternative medicine healer or herbalist (0.6%). Conclusions: A high percentage of people who had not been authorised to do sowere recommending antibiotics to the population living in the conglomerate of Bogotá’s eighteen districts. It should be emphasised.