Novel pathogenic variant of DICER1 in an adolescent with multinodular goiter, ovarian Sertoli-Leydig cell tumor and pineal parenchymal tumor of intermediate differentiation.

OBJECTIVES: To present a case of a new pathogenic variant of DICER1. CASE PRESENTATION: 13-year-old female with non-toxic multinodular goiter and ovarian Sertoli-Leydig cell tumor, in whom a pineal parenchymal tumor of intermediate differentiation was diagnosed. Next-generation sequencing revealed a new germline mutation in the DICER1 gene (exon 16, c2488del [pGlu830Serfs*2] in heterozygosis), establishing the diagnosis of DICER1 syndrome. CONCLUSIONS: Mutations in the DICER1 gene cause genetic predisposition to a wide spectrum of benign or malignant tumors from childhood to adulthood.

Expression of nuclear factor-erythroid 2-related factor 2 in rat brain following the administration of kainic acid and pentylenetetrazole.

Epilepsy is a neurological disorder of the central nervous system characterized by hypersynchronized neuronal activity and has been associated with oxidative stress. Oxidative stress interferes with the expression of genes as well as transcriptional factors such as nuclear factor-erythroid 2-related factor 2 (Nrf2). We evaluated the expression of Nrf2 in the rat brain in treated with kainic acid (KA) and pentylenetetrazole (PTZ). Nrf2 immunoreactivity was observed in astrocytes of the hippocampal region in rats exposed at KA. Nrf2 expression was increased significantly in rats with KA and PTZ. These results provide evidence that the increased expression of Nrf2 is part of the mechanism against KA and PTZ toxicity.

Metallothionein expression in the rat brain following KA and PTZ treatment.

Epilepsy is a neurological disorder that has been associated with oxidative stress therefore epilepsy models have been develop such as kainic acid and pentylenetetrazol are usually used to understanding of the molecular mechanisms of this disease. We examined the metallothionein expression in rat brains of treated with kainic acid and pentylenetetrazol. Increase in metallothionein and nitrotirosyne immunoreactivity of both seizures epilepsy models was observed. Moreover, we show a significant increase on levels of MT expression. These results suggest that the increase of metallothionein expression is related with kainic acid and pentylenetetrazol treatments as response to damage mediated by oxidative stress.

Chronic deep brain stimulation of the hypothalamic nucleus in wistar rats alters circulatory levels of corticosterone and proinflammatory cytokines.

Deep brain stimulation (DBS) is a therapeutic option for several diseases, but its effects on HPA axis activity and systemic inflammation are unknown. This study aimed to detect circulatory variations of corticosterone and cytokines levels in Wistar rats, after 21 days of DBS-at the ventrolateral part of the ventromedial hypothalamic nucleus (VMHvl), unilateral cervical vagotomy (UCVgX), or UCVgX plus DBS. We included the respective control (C) and sham (S) groups (n = 6 rats per group). DBS treated rats had higher levels of TNF-α (120%; P < 0.01) and IFN-γ (305%; P < 0.001) but lower corticosterone concentration (48%; P < 0.001) than C and S. UCVgX animals showed increased corticosterone levels (154%; P < 0.001) versus C and S. UCVgX plus DBS increased IL-1ß (402%; P < 0.001), IL-6 (160%; P < 0.001), and corsticosterone (178%; P < 0.001 versus 48%; P < 0.001) compared with the C and S groups. Chronic DBS at VMHvl induced a systemic inflammatory response accompanied by a decrease of HPA axis function. UCVgX rats experienced HPA axis hyperactivity as result of vagus nerve injury; however, DBS was unable to block the HPA axis hyperactivity induced by unilateral cervical vagotomy. Further studies are necessary to explore these findings and their clinical implication.

Antioxidant, anticonvulsive and neuroprotective effects of dapsone and phenobarbital against kainic acid-induced damage in rats.

Excitotoxicity due to glutamate receptors (GluRs) overactivation is a leading mechanism of oxidative damage and neuronal death in various diseases. We have shown that dapsone (DDS) was able to reduce both neurotoxicity and seizures associated to the administration of kainic acid (KA), an agonist acting on AMPA/KA receptors (GluK1-GluK5). Recently, it has been shown that phenobarbital (PB) is also able to reduce epileptic activity evoked by that receptor. In the present study, we tested the antioxidative, anticonvulsive and neuroprotective effects of DDS and PB administered alone or in combination upon KA toxicity to rats. Results showed that KA increased lipid peroxidation and diminished reduced glutathione (GSH), 24 h after KA administration and both drugs in combination or individually inhibited these events. Likewise, KA promotes mortality and this event was antagonized by effect of both treatments. Additionally, the behavioral evaluation showed that DDS and PB administered alone or in combination decreased the number of limbic seizures and reduced the percentage of animals showing tonic-clonic seizures versus the control group, which was administered only with KA. Finally, our study demonstrated that all of the treatments prevented the neuronal death of the pyramidal cell layer of hippocampal CA-3. In conclusion, the treatment with DDS and PB administrated alone or in combination exerted antioxidant, anticonvulsive and neuroprotective effects against the neurotoxicity induced by KA in rats, but their effects were not additive. Thus, it may be good options of treatment in diseases such as epilepsy and status epilepicus, administered separately.

Plasma polypyrrole implants recover motor function in rats after spinal cord transection.

We studied the use of three biocompatible materials obtained by plasma polymerization of pyrrole (PPy), pyrrole doped with iodine (PPy/I) and a copolymer formed with pyrrole and polyethylene glycol (PPy/PEG), implanted, separately, after a complete spinal cord transection in rats. Motor function assessed with the BBB scale and somatosensory evoked potentials (SEPs) in the implanted rats were studied. Results showed that the highest motor recovery was obtained in rats with PPy/I implants. They also showed a significant reduction in the latency of SEPs. Histological analyses showed no signs of implant rejection; on the contrary, implants based on PPy improved the SEPs conduction and motor function after lesion.

Copper blocks quinolinic acid neurotoxicity in rats: contribution of antioxidant systems.

Reactive oxygen species and oxidative stress are involved in quinolinic acid (QUIN)-induced neurotoxicity. QUIN, a N-methyl-D-aspartate receptor (NMDAr) agonist and prooxidant molecule, produces NMDAr overactivation, excitotoxic events, and direct reactive oxygen species formation. Copper is an essential metal exhibiting both modulatory effects on neuronal excitatory activity and antioxidant properties. To investigate whether this metal is able to counteract the neurotoxic and oxidative actions of QUIN, we administered copper (as CuSO(4)) intraperitoneally to rats (2.5, 5.0, 7.5, and 10.0 mg/kg) 30 min before the striatal infusion of 1 microliter of QUIN (240 nmol). A 5.0 mg/kg CuSO(4) dose significantly increased the copper content in the striatum, reduced the neurotoxicity measured both as circling behavior and striatal gamma-aminobutyric acid (GABA) depletion, and blocked the oxidative injury evaluated as striatal lipid peroxidation (LP). In addition, copper reduced the QUIN-induced decreased striatal activity of Cu,Zn-dependent superoxide dismutase, and increased the ferroxidase activity of ceruloplasmin in cerebrospinal fluid from QUIN-treated rats. However, copper also produced significant increases of plasma lactate dehydrogenase activity and mortality at the highest doses employed (7.5 and 10.0 mg/kg). These results show that at low doses, copper exerts a protective effect on in vivo QUIN neurotoxicity.

Influence of the pontomencephalic region upon PGO activity regulation at the aducens nucleus in cats

Se ha propuesto que en el tegmento pontomesencefálico, específicamente en la región denominada "área X" (AX) y en el núcleo parabraquial lateral (Pbl), se localizan las células generadoras de la actividad ponto-geniculo-occipital (PGO) que ocurre durante el sueño paradójico. Las evidencias se basan en el análisis de la actividad PGO registrada a nivel tálamico (en el núcleo geniculado lateral; NGL). Sin embargo, la actividad PGO también puede ser registrada en el núcleo abducens (VI par). Con el fin de determinar si la región pontomesencefálica también participa en la regulación de la actividad PGO que se registra a nivel pontino, realizamos pequeñas lesiones electroliticas en el Pbl en el AX, registrado simultáneamente la actividad PGO en el NGL y en el VI par. Se utilizaron gatos anestesiados, curarizados y pretratados con reserpina. La lesión del AX suprimió la actividad PGO registrada en el NGL pero no afectó las espigas registradas a nivel pontino. La lesión del Pbl no modificó la actividad PGO registrada en el NGL ni en el VI par. Estos datos no apoyan la influencia del AX del Pbl sobre la actividad PGO registrada a nivel pontino y sugieren que la región pontomesencefálica sólo juega un papel en la transmisión de las espigas PGO desde el puente al NGL.

Repetitive electrical stimulation of X area and parabrachial lateral nucleus: effects upon ponto-geniculo-occipital activity in the reserpinezed cat

La actividad ponto-geniculo-occipital (PGO) es un potencial de campo característico del sueño paradójico, que puede ser inducido por la administración de reserpina. Se ha postulado que el área X y el núcleo parabraquial lateral contienen las células que generan la actividad PGO. En el presente estudio, se analizan los efectos de la estimulación eléctrica repetida, tipo Kindling, aplicada en el área X y en el núcleo parabraquial lateral, con la finalidad de inducir cambios plásticos progresivos en la actividad PGO. Se utilizaron gatos reserpinizados, curarizados y con respiración articial. La actividad PGO se registró en el núcleo geniculado lateral y se analizó la frecuencia de estas espigas al minuto, a los 5 minutos y a la hora de aplicada la estimulación repetida (pulsos cuadrados del ms de duración con una frecuencia de 60Hz y una intensidad de 150 uA aplicados durante un segundo). La estimulación del área X no provoca modificaciones en la frecuencia de espigas PGO, mientras que en el núcleo parabraquial lateral se observa un incremento progresivo relativamente pobre en la frecuencia de este potencial. Los hallazgos obtenidos con la estimulación del área X descartan la posibilidad de inducir cambios funcionales plásticos de esta región. En cambio, la respuesta a la estimulación del parabraquial lateral indica una activación del sistema generador de espigas PGO. Estas diferencias sugerirían que ambos núcleos tienen distinta influencia sobre la actividad PGO, aunque es posible que las respuestas encontradas en el parabraquial lateral sean efectos indirectos, debido a sus relaciones anatómicas