[ABC transporters and drug resistance in epilepsy: biological plausibility, pharmacogenetics and precision medicine]. / Transportadores ABC y resistencia a fármacos en la epilepsia: plausibilidad biológica, farmacogenética y medicina de precisión.

INTRODUCTION: A plausible mechanism that may contribute to drug resistance in epilepsy is the failure of drugs to reach the brain tissue, caused by changes in the activity of ABC transporters. The main argument in favour of this hypothesis is that resistance occurs against a wide variety of antiepileptic drugs with different mechanisms of action, suggesting a non-specific underlying phenomenon that limits the effectiveness of drug treatments. DEVELOPMENT: A review of the literature on ABC transporters, their role in the normal physiology of the blood-brain barrier and drug resistance in epilepsy, both in human studies and in animal models, is conducted. Studies of genetic variants in the ABCB1 and ABCC2 genes, which code for these transporters, and recent genomic studies in epilepsy and related pathologies are also reviewed, followed by a discussion of their scope and limitations. CONCLUSIONS: To date, the association of genetic variants of ABC transporters with resistance to anticonvulsant drugs remains a matter of debate. The increasingly widespread use and accessibility of modern sequencing technologies is expected to allow the establishment of genetic markers that provide a precision medicine based approach to the treatment of epilepsy.

TITLE: Transportadores ABC y resistencia a fármacos en la epilepsia: plausibilidad biológica, farmacogenética y medicina de precisión.Introducción. Un mecanismo plausible que puede contribuir a la resistencia a fármacos en la epilepsia es la falta de llegada de los fármacos al tejido encefálico, causado por cambios en la actividad de los transportadores ABC. El principal argumento a favor de esta hipótesis es que la resistencia ocurre frente a una gran variedad de fármacos antiepilépticos con distintos mecanismos de acción, lo que sugiere un fenómeno subyacente no específico que limita la efectividad de los tratamientos farmacológicos. Desarrollo. Se realiza una revisión bibliográfica de los transportadores ABC, su papel en la fisiología normal de la barrera hematoencefálica y en la resistencia a fármacos en la epilepsia, tanto en estudios en humanos como en modelos animales. Se revisan además los estudios de variantes genéticas en los genes ABCB1 y ABCC2, que codifican para estos transportadores, y los recientes estudios genómicos en la epilepsia y patologías afines, discutiendo sus alcances y limitaciones. Conclusiones. Hasta ahora, la asociación de variantes genéticas de transportadores ABC con la resistencia a fármacos anticonvulsivantes sigue siendo materia de debate. Se espera que la creciente masificación y accesibilidad a tecnologías de secuenciación modernas permitan establecer marcadores genéticos que otorguen una aproximación de medicina de precisión para el tratamiento de la epilepsia.

Neonatal exposure to oestradiol increases dopaminergic transmission in nucleus accumbens and morphine-induced conditioned place preference in adult female rats.

Steroid sex hormones produce physiological effects in reproductive tissues and also in nonreproductive tissues, such as the brain, particularly in cortical, limbic and midbrain areas. Dopamine (DA) neurones involved in processes such as prolactin secretion (tuberoinfundibular system), motor circuit regulation (nigrostriatal system) and driving of motivated behaviour (mesocorticolimbic system) are specially regulated by sex hormones. Indeed, sex hormones promote neurochemical and behavioural effects induced by drugs of abuse by tuning midbrain DA neurones in adult animals. However, the long-term effects induced by neonatal exposure to sex hormones on dopaminergic neurotransmission have not been fully studied. The present study aimed to determine whether a single neonatal exposure with oestradiol valerate (EV) results in a programming of dopaminergic neurotransmission in the nucleus accumbens (NAcc) of adult female rats. To answer this question, electrophysiological, neurochemical, cellular, molecular and behavioural techniques were used. The data show that frequency but not amplitude of the spontaneous excitatory postsynaptic current is significantly increased in NAcc medium spiny neurones of EV-treated rats. In addition, DA content and release are both increased in the NAcc of EV-treated rats, caused by an increased synthesis of this neurotransmitter. These results are functionally associated with a higher percentage of EV-treated rats conditioned to morphine, a drug of abuse, compared to controls. In conclusion, neonatal programming with oestradiol increases NAcc dopaminergic neurotransmission in adulthood, which may be associated with increased reinforcing effects of drugs of abuse.

Amphetamine treatment affects the extra-hypothalamic vasopressinergic system in a sex- and nucleus-dependent manner.

The lateral septum (LS), a brain structure implicated in addictive behaviours, regulates the activation of dopaminergic neurones in the ventral tegmental area. Vasopressinergic projections from the extended amygdala to the LS, which are sexually dimorphic, could be responsible for the vulnerability to addiction in a sex-dependent manner. The present study aimed to investigate the modulatory effects of amphetamine (AMPH) on the expression of vasopressin (AVP) in the vasopressinergic extra-hypothalamic system in sensitised male and female rats. Adult male and female Sprague-Dawley rats underwent an AMPH-locomotor sensitisation protocol. Acute AMPH increased AVP mRNA expression in the medial amygdala (MeA), whereas AMPH-induced sensitisation increased AVP mRNA expression in the bed nucleus of the stria terminalis (BNST) only in females. Interestingly, the increase in AVP expression in BNST was higher in oestrus females compared to dioestrus females and acute AMPH resulted in a decrease in AVP levels in the LS, only in males. Thus, there are complex and region-specific interactions between AMPH and the extra-hypothalamic vasopressinergic system in the brain, underlying possible alterations in different behaviours caused by acute and chronic AMPH exposure.

Meta-analysis of association between obsessive-compulsive disorder and the 3' region of neuronal glutamate transporter gene SLC1A1.

The neuronal glutamate transporter gene SLC1A1 is a candidate gene for obsessive-compulsive disorder (OCD) based on linkage studies and convergent evidence implicating glutamate in OCD etiology. The 3' end of SLC1A1 is the only genomic region with consistently demonstrated OCD association, especially when analyzing male-only probands. However, specific allele associations have not been consistently replicated, and recent OCD genome-wide association and meta-analysis studies have not incorporated all previously associated SLC1A1 SNPs. To clarify the nature of association between SLC1A1 and OCD, pooled analysis was performed on all available relevant raw study data, comprising a final sample of 815 trios, 306 cases and 634 controls. This revealed weak association between OCD and one of nine tested SLC1A1 polymorphisms (rs301443; uncorrected P = 0.046; non-significant corrected P). Secondary analyses of male-affecteds only (N = 358 trios and 133 cases) demonstrated modest association between OCD and a different SNP (rs12682807; uncorrected P = 0.012; non-significant corrected P). Findings of this meta-analysis are consistent with the trend of previous candidate gene studies in psychiatry and do not clarify the putative role of SLC1A1 in OCD pathophysiology. Nonetheless, it may be important to further examine the potential associations demonstrated in this amalgamated sample, especially since the SNPs with modest associations were not included in the more highly powered recent GWAS or in a past meta-analysis including five SLC1A1 polymorphisms. This study underscores the need for much larger sample sizes in future genetic association studies and suggests that next-generation sequencing may be beneficial in examining the potential role of rare variants in OCD.

Mutations in monoamine oxidase (MAO) genes in mice lead to hypersensitivity to serotonin-enhancing drugs: implications for drug side effects in humans.

A possible side effect of serotonin-enhancing drugs is the serotonin syndrome, which can be lethal. Here we examined possible hypersensitivity to two such drugs, the serotonin precursor 5-hydroxy-L-tryptophan (5-HTP) and the atypical opioid tramadol, in mice lacking the genes for both monoamine oxidase A (MAOA) and MAOB. MAOA/B-knockout (KO) mice displayed baseline serotonin syndrome behaviors, and these behavioral responses were highly exaggerated following 5-HTP or tramadol versus baseline and wild-type (WT) littermates. Compared with MAOA/B-WT mice, baseline tissue serotonin levels were increased ∼2.6-3.9-fold in MAOA/B-KO mice. Following 5-HTP, serotonin levels were further increased ∼4.5-6.2-fold in MAOA/B-KO mice. These exaggerated responses are in line with the exaggerated responses following serotonin-enhancing drugs that we previously observed in mice lacking the serotonin transporter (SERT). These findings provide a second genetic mouse model suggestive of possible human vulnerability to the serotonin syndrome in individuals with lesser-expressing MAO or SERT polymorphisms that confer serotonergic system changes.

Differential responsiveness to alcohol odor in human neonates: effects of maternal consumption during gestation.

Previous human and animal studies have shown that specific memories arise during prenatal life as a function of fetal processing of chemosensory stimuli present in the amniotic fluid. Furthermore, the animal literature indicates that fetal exposure to alcohol modifies subsequent neonatal and infantile responsiveness toward the sensory attributes of the drug. The main goal of the present study was to analyze whether differential maternal alcohol consumption during pregnancy affects neonatal reactivity to ethanol odor. To achieve this goal, an initial experiment examined how healthy human neonates respond to olfactory stimuli. In this first experiment, newborns (postpartum age: 24-48 h) were evaluated in terms of motor responsiveness elicited by repetitive stimulation with either alcohol or lemon odors. Infants exhibited a marked increase in duration of overall body and head and facial activity when the odorants were first presented. In four successive trials, behavioral responsiveness progressively declined until reaching baseline values. The introduction of a novel odorant served to dishabituate the motor responses under analysis. In the second experiment newborn's reactivity to the mentioned odorants was evaluated as a function of maternal self-reported patterns of consumption of alcohol during gestation. Mothers were classified as frequent or infrequent drinkers. Babies born to frequent drinkers exhibited heightened reactivity toward ethanol odor when compared to newborns delivered by infrequent drinkers. No differences emerged when comparing the responses of both groups of infants elicited by a non-ethanol stimulus such as lemon. The results coupled with prior human and animal research suggest the possibility of intrauterine experience with alcohol odor that yields a sensory memory likely to be retrieved immediately after birth.

Enfermedad de Chagas: efecto clastogénico de nifurtimox y benznidazol en niños / Chagas' disease: clastogenic effect of nifurtimox and benznidazole in children

Se realizaron estudios citogenéticos en 10 pacientes que padecieron enfermedad de Chagas aguda, para evaluar el daño cromosómico antes, durantre y posterior al tratamiento con Nifurtimox o Benznidazol. Se demostró el efecto clastogénico de ambos farmacos durante el tratamiento al observarse que producen un elelvado porcentaje de micronúcleos y una frecuencia aumentada de expresión de Sitios Frágiles (SF) localizados con técnica de bandeo G en: 1p31, 2p24, 314, 5q34, 6q25, 7q32, 8q24, 14q24, 16q23, Xp22 todos ellos ubicados en áreas cromosómicas lindantes con proto-oncogenes o con puntos de rotura específicos en cáncer. Estas observaciones indican que existe un riesgo potencial para la población tratada con nifurtimox o Benznidazol

Tratamiento de la enfermedad de chagas con nifurtimox durante los primeros meses de vida / Treatment of chagas disease with nifurtimox during the first months of life

Se analiza la respuesta terapéutica al nifurtimox (15mg/kg/día) en 48 de 51 niños con infección chagásica, todos menos uno hijos de madres con serología positiva. Los resultados obtenidos parecen indicar que los mismos no dependen del tiempo de ingestión de la droga (3 y 2 o menos meses) sino que están realcionados con la edad al iniciar el tratamiento. Los 43 pacientes tratados precozmente ( menores de 16 meses de edad) negativizaron su parasitemia y su serología en forma persistente, salvo un caso de reinfección. En los 5 pacientes restantes mayores de 17 meses de edad al inicar nifurtimox, las respuestas fueron variables: negativización serológica luego de 3 años de controles positivos y positividad serológica luego de controles negativos (la reinfección no pudo descartarse). En 3 pacientes que no realizaron tratamiento los estudios parasitológicos y serológicos fueron positivos a los 7, 10 y 7 años. Las reacciones adversas a la droga en 31 niños estudiados fueron: anorexia (58,5%), irritabilidad (46,3%) y vómitos (21,9%). Un 19,5% de los niños no presentaron ninguna manifestación. En aquellos en que se estudió la evolución ponderal durante el tratamiento, se observó una marcada disminución de la curva de peso en el grupo comprendido entre los 6 y 9 meses de edad, siendo menos marcada entre los 3 y 6 meses e imperceptible antes de los 3 meses. La experiencia obtenida resalta la necesidad de un diagnóstico precoz sobre todo en aquellos cuyas madres sean serológicamente positivas o habiten en zonas endémicas

Sindrome de hipoplasia femoral-facies / Femoral hypoplasia-facies syndrome

Es presentada una paciente con el sindrome de hipoplasia femoral-facies rara (SHF-FR) Dentro del patron de malformaciones descripto para este sindrome, las caracteristicas faciales que presento esta nina corresponderian a los casos intermedios, siendo una contribucion mas a favor de la hipotesis de que el SHF-FR representa el final del espectro de un complejo malformativo de expresividad variable y no existiria como entidad sindromica especifica

Asociacion VATER y seudohermafroditismo femenino. / VATER association and female pseudohermaphroditism

Presentamos una paciente con asociacion VATER y seudohermafroditismo femenino (SHF) probablemente "no adrenal". Se describen 6 pacientes con estas caracteristicas referidas en la literatura (tabla 1).Sobre la base del clasico concepto en Embiologia de Campo Complejo de Desarrollo, estos casos podrian ser considerados dentro de un complejo malformativo de amplio espectro y expresividad variable. El descubrimiento de los defectos integrantes de la asociacion VATER deberia conducir a la investigacion de la posible presencia de SHF

Enfermedad de Chagas congénita / Congenital Chagas'disease

Refiere estudios realizados por investigadores argentinos sobre Chagas congénito en modelos experimentales animales (sobre pasaje transplacentario del Trypanosoma cruzi, lesiones placentarias, actividad enzimática), y en humanos (en embarazadas y sus hijos): estudios enzimáticos e inmunológicos (infección por endocitosis, procesos de inestabilización inducidos por T. cruzi en su interacción con membranas placentarias). Menciona que los métodos de diagnóstico parasitológico certifican el diagnóstico, pero no detectan todos los casos, así como también, que el inmunodiagnóstico presenta margen de error, siendo las reacciones serológicas de anticuerpo IgG una alternativa para la identificación de infección asintomática dentro del primer año de vida -demostrando tener un valor real a partir de los seis meses de edad. Reulta necesaria la búsqueda de un marcador inmunológico de la infección que pueda ser usado en el momento del nacimiento. Se estudian diferentes manifestaciones clínicas de la infección congénita, en distintas regiones geográficas, desde niños prematuros con relevante sintomatología y elevada mortalidad, hasta niños nacidos a término gestacional oligosintómaticos o asintomáticos con escasa o nula mortalidad; recomendándose que estos estudios sean protocolizados uniformemente para lograr una informaci1>n comparable. Se estudia la respuesta terapéutica al Nifurtimox en niños con diagnóstico de infección congénita,d emostrándose la efectividad de los derivados pitrofuránicos. Finalmente, menciona estudios de seguimento y de incidencia de la enfermedad de Chagas congénita