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Aggregation of mutant huntingtin, because of an expanded polyglutamine track, underlies the cause of neurodegeneration in Huntington disease (HD). However, it remains unclear how some alterations at the cellular level lead to specific structural changes in HD brains. In this context, the neuroprotective effect of the activation of AMP-activated protein kinase (AMPK) appears to be a determinant factor in several neurodegenerative diseases, including HD. In the present work, we describe a series of indole-derived compounds able to activate AMPK at the cellular level. By using animal models of HD (both worms and mice), we demonstrate the in vivo efficacy of one of these compounds (IND1316), confirming that it can reduce the neuropathological symptoms of this disease. Taken together, in vivo results and in silico studies of druggability, allow us to suggest that IND1316 could be considered as a promising new lead compound for the treatment of HD and other central nervous system diseases in which the activation of AMPK results in neuroprotection

The discovery and application of antibiotics in the common clinical practice has undeniably been one of the major medical advances in our times. Their use meant a drastic drop in infectious diseases-related mortality and contributed to prolonging human life expectancy worldwide. Nevertheless, antibiotics are considered by many a double-edged sword. Their extensive use in the past few years has given rise to a global problem: antibiotic resistance. This factor and the increasing evidence that a wide range of antibiotics can damage mammalian mitochondria, have driven a significant sector of the medical and scientific communities to advise against the use of antibiotics for purposes other to treating severe infections. Notwithstanding, a notorious number of recent studies support the use of these drugs to treat very diverse conditions, ranging from cancer to neurodegenerative or mitochondrial diseases. In this context, there is great controversy on whether the risks associated to antibiotics outweigh their promising beneficial features. The aim of this review is to provide insight in the topic, purpose for which the most relevant findings regarding antibiotic therapies have been discussed.

[EN]: Thyroid hormones (TH) play an essential role both in the developing and the adult central nervous system (CNS). The concentrations of the genomically active hormone T3 in the brain depend on TH transport across the brain barriers, the local generation of T3 in astrocytes by type 2 deiodinase (D2), and TH degradation by type 3 deiodinase (D3). In addition, during foetal development, circulating TH concentrations derive partly from the mother. How all these factors interact during mice foetal development to ensure “brain euthyroidism” is not well known. This work has explored the sources of T3 that ensure brain euthyroidism during mice foetal development by treating euthyroid pregnant dams with T4 or T3 from embryonic day 12 (E12) to E18. The outcome of the treatment revealed that a large amount of foetal T4 during late gestation is of maternal origin and that maternal-foetal T3 transfer is tightly regulated, most probably at the placental level. Also, that T4 transport across the choroid plexus along with D2 activity at the blood-cerebrospinal fluid barrier might be key events in TH action in brain during foetal development, as conversion of T4 into T3 by D2 activity might be the only source of T3 during mouse brain development. Mutations in the gene expressing the TH monocarboxylate transporter 8 (MCT8), in humans, lead to altered circulating TH levels and a severe neurodevelopmental disorder. Due to the crucial role of this transporter, the interaction between Mct8-dependent transport and D2 activity was studied. D2 activity was found to be required to generate the brain hyperthyroidism characteristic of Mct8 deficient (Mct8KO) animals during perinatal stages of development. Besides, Mct8KO mice were used to test novel therapeutic approaches as possible treatments for MCT8 deficiency. The use of the TH analogue triiodothyroacetic acid (TRIAC) restored plasma T3 levels but severely decreased T4 levels leading to a state of brain hypothyroidism with reduced T3, [ES]: Las hormonas tiroideas (HT) juegan un papel esencial en el desarrollo y función del sistema nervioso central. En el cerebro, las concentraciones de la hormona activa a nivel genómico, T3, dependen del transporte de HT a través de las barrera cerebrales, de la generación local de T3 en los astrocitos mediante la desyodasa tipo 2 (D2) y de la degradación de HT por la desyodasa tipo 3 (D3). Además, durante el desarrollo fetal las concentraciones de HT circulantes provienen en parte de la madre. Cómo interactúan todos estos factores durante el desarrollo fetal en ratón para asegurar un “eutiroidismo cerebral” no se conoce suficientemente. En este trabajo se han explorado las fuentes de T3 que posibilitan un eutiroidismo cerebral durante el desarrollo fetal del ratón mediante el tratamiento de madres gestantes con T4 o T3 desde el día embrionario 12 (E12) hasta E18. El resultado del tratamiento reveló que una gran parte de la T4 fetal durante las fases finales de la gestación es de origen materno y que la transferencia materno-fetal de T3 está estrictamente regulada, probablemente a nivel placentario. También, que el transporte de T4 a través del plexo coroideo junto con la actividad de D2 en la barrera sangre-líquido cefalorraquídeo podrían ser eventos claves en la acción de las HT en el cerebro durante el desarrollo fetal, ya que la conversión de T4 a T3 mediante la actividad de D2 podría ser la única fuente de T3 durante el desarrollo cerebral del ratón. Mutaciones en el gen que expresa el transportador de HT, transportador de monocarboxilatos 8 (MCT8), provocan alteraciones en los niveles circulantes de HT y discapacidades graves del neurodesarrollo en humanos. Debido al papel fundamental de este transportador, se estudió la interacción entre el transporte dependiente de Mct8 y la actividad de D2. Los resultados indican que la actividad de D2 es necesaria para generar el hipertiroidismo cerebral característico de los ratones deficientes de Mct8 durante etapas p

[Background]: Monocarboxylate transporter 8 (MCT8) is a thyroid hormone-specific cell membrane transporter. Mutations in the MCT8 gene lead to profound psychomotor retardation and abnormal thyroid hormone serum levels with low thyroxine (T4) and high triiodothyronine (T3). Currently, therapeutic options for patients are limited. Triiodothyroacetic acid (TRIAC) has potential therapeutic value. The aim of this study was to evaluate the effects and efficacy of therapeutic doses of TRIAC on Mct8-deficient mice (Mct8KO)., [Methods]: Wild-type (Wt) and Mct8KO mice were treated with 30 ng TRIAC/g BW/day, given in drinking water, from postnatal day 21 to 30. TRIAC, T4 and T3 levels in plasma, as well as T3 and TRIAC content in the cerebral cortex and striatum were measured by specific radioimmunoassays. The activities of deiodinases 1 and 2 were measured in liver and cortex. The effect of TRIAC treatment in the expression of T3-dependent genes was measured in the heart, cerebral cortex and striatum., [Results]: Plasma TRIAC concentration were the same in Wt and Mct8KO animals after treatment. TRIAC treatment greatly decreased plasma T4 in Wt and Mct8KO mice, and reduced T3 to normal levels in the Mct8KO. Deiodinase 1 activity and gene expression in the liver increased while it did not have any effect on the expression of Serca2a in the heart. TRIAC treatment did not induce the expression of T3-dependent genes in the cerebral cortex or striatum but further decreased expression of Flywch2 in the cortex and Aldh1a1 and Flywch2 in the striatum. Direct measurements of TRIAC and T3 content in the cortex and striatum revealed a decrease in T3 after treatment with no significant increase in the level of endogenous TRIAC., [Conclusions]: Therapeutic doses of TRIAC in Mct8KO mice restored plasma T3 levels but severely decreased T4 levels. TRIAC has a direct effect on deiodinase 1 in the liver and does not have an effect on gene expression in the heart. The increase in the plasma TRIAC levels after treatment is not sufficient to increase TRIAC levels in the brain and to promote the expression of T3-dependent genes in brain cells. Instead, it leads to a state of brain hypothyroidism with reduced T3 content.

A fission-yeast bioassay guided screening on several plant extracts is carried out to search for anticancer agents, and an extract from leaves of Corema album (L.) D. Don (Ericaceae) is found to have antiproliferative activity. Further fractionation afforded 2′,4′-dihydroxychalcone (DHC) as the main cytotoxic compound present in the extract. Our detailed biological analysis shows that antiproliferative activity of this flavonoid is likely due to its ability to induce DNA damage which blocks cell cycle progression.

Mitochondrial DNA mutations are an important cause of human disease for which there is no effective treatment. Myoclonic epilepsy with ragged-red fibers (MERRF) is a mitochondrial disease usually caused by point mutations in transfer RNA genes encoded by mitochondrial DNA. The most common mutation associated with MERRF syndrome, m.8344A > G in the gene MT-TK, which encodes transfer RNA Lysine, affects the translation of all mitochondrial DNA encoded proteins. This impairs the assembly of the electron transport chain complexes leading to decreased mitochondrial respiratory function. Here we report on how this mutation affects mitochondrial function in primary fibroblast cultures established from patients harboring the A8344G mutation. Coenzyme Q 10 (CoQ) levels, as well as mitochondrial respiratory chain activity, and mitochondrial protein expression levels were significantly decreased in MERRF fibroblasts. Mitotracker staining and imaging analysis of individual mitochondria indicated the presence of small, rounded, depolarized mitochondria in MERRF fibroblasts. Mitochondrial dysfunction was associated with increased oxidative stress and increased degradation of impaired mitochondria by mitophagy. Transmitochondrial cybrids harboring the A8344G mutation also showed CoQ deficiency, mitochondrial dysfunction, and increased mitophagy activity. All these abnormalities in patient-derived fibroblasts and cybrids were partially restored by CoQ supplementation, indicating that these cell culture models may be suitable for screening and validation of novel drug candidates for MERRF disease. © 2012 The American Society for Experimental NeuroTherapeutics, Inc., DYT1 dystonia is a childhood-onset movement disorder with autosomal dominant inheritance. The disease is caused by a 3-bp deletion (ΔGAG) in the TOR1A gene that removes a glutamic acid residue (ΔE) of the encoded protein, torsin A. Interestingly, the ΔGAG mutation shows reduced penetrance of only 30%. Thus, additional genetic and enviromental modifiers affecting the manifestation of DYT1 dystonia symptoms are likely to exist. A recent hypothesis proposed a molecular link between DYT1 and DYT6 dystonia based on the possible regulation of torsin A transcription by THAP1.1, 2 Aiming to expand on prior analysis testing whether THAP1 is a genetic modifier for DYT1 dystonia,3, 4 we performed a genetic screen for sequence variations in the THAP1 gene and also in THAP1-binding sites of the TOR1A promoter in carriers of the ΔGAG DYT1 deletion.

[Backgroun and Purpose]: MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) is a mitochondrial disease most usually caused by point mutations in tRNA genes encoded by mitochondrial DNA (mtDNA). Approximately 80% of cases of MELAS syndrome are associated with a m.3243A > G mutation in the MT-TL1 gene, which encodes the mitochondrial tRNALeu (UUR). Currently, no effective treatments are available for this chronic progressive disorder. Treatment strategies in MELAS and other mitochondrial diseases consist of several drugs that diminish the deleterious effects of the abnormal respiratory chain function, reduce the presence of toxic agents or correct deficiencies in essential cofactors., [Experimental Approach]: We evaluated the effectiveness of some common pharmacological agents that have been utilized in the treatment of MELAS, in yeast, fibroblast and cybrid models of the disease. The yeast model harbouring the A14G mutation in the mitochondrial tRNALeu(UUR) gene, which is equivalent to the A3243G mutation in humans, was used in the initial screening. Next, the most effective drugs that were able to rescue the respiratory deficiency in MELAS yeast mutants were tested in fibroblasts and cybrid models of MELAS disease., [Key Results]: According to our results, supplementation with riboflavin or coenzyme Q10 effectively reversed the respiratory defect in MELAS yeast and improved the pathologic alterations in MELAS fibroblast and cybrid cell models., [Conclusions and Implications]: Our results indicate that cell models have great potential for screening and validating the effects of novel drug candidates for MELAS treatment and presumably also for other diseases with mitochondrial impairment.

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a mitochondrial disease most usually caused by point mutations in tRNA genes encoded by mtDNA. Here, we report on how this mutation affects mitochondrial function in primary fibroblast cultures established from 2 patients with MELAS who harbored the A3243G mutation. Both mitochondrial respiratory chain enzyme activities and coenzyme Q(10) (CoQ) levels were significantly decreased in MELAS fibroblasts. A similar decrease in mitochondrial membrane potential was found in intact MELAS fibroblasts. Mitochondrial dysfunction was associated with increased oxidative stress and the activation of mitochondrial permeability transition (MPT), which triggered the degradation of impaired mitochondria. Furthermore, we found defective autophagosome elimination in MELAS fibroblasts. Electron and fluorescence microscopy studies confirmed a massive degradation of mitochondria and accumulation of autophagosomes, suggesting mitophagy activation and deficient autophagic flux. Transmitochondrial cybrids harboring the A3243G mutation also showed CoQ deficiency and increased autophagy activity. All these abnormalities were partially restored by CoQ supplementation. Autophagy in MELAS fibroblasts was also abolished by treatment with antioxidants or cyclosporine, suggesting that both reactive oxygen species and MPT participate in this process. Furthermore, prevention of autophagy in MELAS fibroblasts resulted in apoptotic cell death, suggesting a protective role of autophagy in MELAS fibroblasts.