Brain-Targeting Delivery of Two Peptidylic Inhibitors for Their Combination Therapy in Transgenic Polyglutamine Disease Mice via Intranasal Administration.

Polyglutamine diseases are a set of progressive neurodegenerative disorders caused by misfolding and aggregation of mutant CAG RNA and polyglutamin protein. To date, there is a lack of effective therapeutics that can counteract the polyglutamine neurotoxicity. Two peptidylic inhibitors, QBP1 and P3, targeting the protein and RNA toxicities, respectively, have been previously demonstrated by us with combinational therapeutic effects on the Drosophila polyglutamine disease model. However, their therapeutic efficacy has never been investigated in vivo in mammals. The current study aims to (a) develop a brain-targeting delivery system for both QBP1 and L1P3V8 (a lipidated variant of P3 with improved stability) and (b) evaluate their therapeutic effects on the R6/2 transgenic mouse model of polyglutamine disease. Compared with intravenous administration, intranasal administration of QBP1 significantly increased its brain-to-plasma ratio. In addition, employment of a chitosan-containing in situ gel for the intranasal administration of QBP1 notably improved its brain concentration for up to 10-fold. Further study on intranasal cotreatment with the optimized formulation of QBP1 and L1P3V8 in mice found no interference on the brain uptake of each other. Subsequent efficacy evaluation of 4-week daily QBP1 (16 µmol/kg) and L1P3V8 (6 µmol/kg) intranasal cotreatment in the R6/2 mice demonstrated a significant improvement on the motor coordination and explorative behavior of the disease mice, together with a full suppression on the RNA- and protein-toxicity markers in their brains. In summary, the current study developed an efficient intranasal cotreatment of the two peptidylic inhibitors, QBP1 and L1P3V8, for their brain-targeting, and such a novel therapeutic strategy was found to be effective on a transgenic polyglutamine disease mouse model.

Acetyl-4'-phosphopantetheine is stable in serum and prevents phenotypes induced by pantothenate kinase deficiency.

Coenzyme A is an essential metabolite known for its central role in over one hundred cellular metabolic reactions. In cells, Coenzyme A is synthesized de novo in five enzymatic steps with vitamin B5 as the starting metabolite, phosphorylated by pantothenate kinase. Mutations in the pantothenate kinase 2 gene cause a severe form of neurodegeneration for which no treatment is available. One therapeutic strategy is to generate Coenzyme A precursors downstream of the defective step in the pathway. Here we describe the synthesis, characteristics and in vivo rescue potential of the acetyl-Coenzyme A precursor S-acetyl-4'-phosphopantetheine as a possible treatment for neurodegeneration associated with pantothenate kinase deficiency.

Skipped BSCL2 Transcript in Celia's Encephalopathy (PELD): New Insights on Fatty Acids Involvement, Senescence and Adipogenesis.

OBJECTIVE: PELD (Progressive Encephalopathy with or without Lipodystrophy or Celia's Encephalopathy) is a fatal and rare neurodegenerative syndrome associated with the BSCL2 mutation c.985C>T, that results in an aberrant transcript without the exon 7 (Celia seipin). The aim of this study was to evaluate both the process of cellular senescence and the effect of unsaturated fatty acids on preadipocytes from a homozygous c.985C>T patient. Also, the role of aberrant seipin isoform on adipogenesis was studied in adipose-derived human mesenchymal stem cells. MATERIAL AND METHODS: Cellular senescence was evaluated using ß-galactosidase staining of preadipocytes obtained from a homozygous c.985C>T patient. Moreover, these cells were cultured during 24 hours with Intralipid, a soybean oil-based commercial lipid emulsion. The expression of the different BSCL2 transcripts was measured by qPCR. Adipose-derived human mesenchymal stem cells were differentiated to a fat lineage using StemPRO adipogenesis kit, and the expression of BSCL2 transcripts and several adipogenesis-related genes was measured by qPCR. RESULTS: the treatment of preadipocytes with unsaturated fatty acids significantly reduced the expression of the BSCL2 transcript without exon 7 by 34 to 63%. On the other hand, at least in preadipocytes, this mutation does not disturb cellular senescence rate. Finally, during adipocyte differentiation of adipose-derived human mesenchymal stem cells, the expression of adipogenic genes (PPARG, LPIN1, and LPL) increased significantly over 14 days, and noteworthy is that the BSCL2 transcript without exon 7 was differentially expressed by 332 to 723% when compared to day 0, suggesting an underlying role in adipogenesis. CONCLUSIONS: our results suggest that Celia seipin is probably playing an underestimated role in adipocyte maturation, but not in senescence, and its expression can be modified by exogenous factors as fatty acids.

Kaleidoscopic protein-protein interactions in the life and death of ataxin-1: new strategies against protein aggregation.

Understanding how proteins protect themselves from aberrant aggregation is of primary interest for understanding basic biology, protein biochemistry, and human disease. We discuss the paradigmatic example of ataxin-1 (Atx1), the protein responsible for neurodegenerative spinocerebellar ataxia type 1 (SCA1). This disease is part of the increasing family of pathologies caused by protein aggregation and misfolding. We discuss the importance of protein-protein interactions not only in the nonpathological function of Atx1 but also in protecting the protein from aggregation and misfolding. The lessons learned from Atx1 may lead to a more general understanding of the cell's protective strategies against aggregation. The obtained knowledge may suggest a new perspective for designing specific therapeutic strategies for the cure of misfolding diseases.

Rasagilina en monoterapia en pacientes en fases tempranas de la enfermedad de Parkinson y en terapia combinada y coadyuvante a levodopa en fases moderada y avanzada / Rasagiline in monotherapy in patients with early stages of Parkinson’s disease and in combined and adjunct therapy to levodopa with moderate and advanced stages

La rasagilina ha sido efectiva en las fases iniciales de la enfermedad de Parkinson y en dosis de 1 mg ha mostrado un posible efecto modificador de la progresión de la enfermedad. El correcto manejo de los fármacos dopaminérgicos ha demostrado retrasar la aparición de las fluctuaciones motoras y las discinesias en la enfermedad de Parkinson. El uso combinado de fármacos con una estimulación dopaminérgica más prolongada (rasagilina, agonistas dopaminérgicos) no sólo ejerce un beneficio al disminuir la estimulación dopaminérgica pulsátil de los receptores dopaminérgicos estriatales, sino que permite disminuir los requerimientos totales de levodopa diarios. Su adición al resto de fármacos dopaminérgicos ha demostrado ser tan eficaz como la entacapona para disminuir la frecuencia y gravedad de las fluctuaciones motoras. Asimismo, se ha observado que iniciar de manera más precoz el tratamiento con rasagilina se asocia a un retraso en la necesidad de utilizar otros fármacos dopaminérgicos, lo que indica que el efecto motor sintomático de la rasagilina se mantiene en el tiempo y no se limita a las fases iniciales de la enfermedad (AU)

Rasagiline is effective in the early stages of the disease and has shown a possible effect of modifying disease progression at a dose of 1 mg. The accurate management of dopaminergic drugs in Parkinson’s disease is able to delay the appearance of motor fluctuations and dyskinesias. The combination of different drugs that provide a more continuous dopaminergic stimulation (rasagiline, dopamine agonists) not only exerts a benefit through diminishing the impact of pulsatile stimulation on post-synaptic dopamine receptors, but allows to decrease total daily levodopa requirements. The combination of rasagiline with other dopaminergic drugs has demonstrated to be as efficacious as entacapone for improving both the frequency and severity of motor fluctuations. Likewise, new evidences have shown that the earlier introduction of rasagiline is associated with a delay in introducing other dopaminergic drugs, thus indicating that the symptomatic benefit of rasagiline on daily motor function is not only present in the early Parkinson’s disease stages, but is maintained over time (AU)

Neuroprotección mediada por diterpenos aislados de Sideritis spp. frente al estrés oxidativo en astrocitos / Results from the application of a quality management system in the community pharmacy

El estrés oxidativo es un proceso de oxidación no controlado de las estructuras biológicas, desencadenado por radicales libres, que produce daño y muerte celular. Numerosas evidencias implican al estrés oxidativo en la patogénesis de enfermedades neurodegenerativas como Alzheimer o Parkinson. Compuestos con capacidad antioxidante pueden prevenir el daño oxidativo al inhibir la producción de radicales libres. Más de 160 diterpenos han sido identificados y aislados de las partes aéreas de Sideritis spp. A ellos se atribuyen en gran medida actividades antiinflamatorias, antioxidantes y digestivas por las cuales se utilizan estas especies en la medicina tradicional mediterránea. El objetivo de este estudio es evaluar el efecto neuroprotector de los diterpenosandalusol, conchitriol y lagascatriol, aislados de las partes aéreas de Sideritis spp. frente al estrés oxidativo inducido por peróxido de hidrógeno en la línea celular U373MG de astrocitoma humano. El posible efecto protector de los diterpenos frente al daño provocado por peróxido de hidrógeno ha sido evaluado mediante el ensayo de MTT. La capacidad de captación de radicales libres de los compuestos se ha estudiado mediante la técnica del DPPH. Los resultados del presente estudio demuestran que los diterpenos andalusol, conchitriol y lagascatriol (5 y 10 μM) protegen a las células U373 MG de la toxicidad del peróxido de hidrógeno, lo que se atribuye en parte a la capacidad antioxidante de dichos compuestos. Se sugiere que estos diterpenos podrían ejercer un efecto beneficioso en la prevención de enfermedades neurodegenerativas asociadas al estrés oxidativo. Estudios futuros irán encaminados a una profundización de su mecanismo de acción(AU)

Oxidative stress is an uncontrolled oxidation process of biological structures, triggering by free radicals, which cause damage and death cell. Many evidences implicate oxidative stress in the pathogenesis of neurodegenerative diseases such as Alzheimer and Parkinson. Compounds with antioxidant capacity may prevent from oxidative damage because of the inhibition of free radical production. More than 160 diterpenes have been identified and isolated from aerial parts of Sideriti sspp. These compounds are largely responsible for the anti-inflammatory, antioxidant and digestive activities, reason why these species are used in traditional Mediterranean medicine. To evaluate the neuroprotective effect of the diterpenes andalusol, conchitriol and lagascatriol, isolated from Sideriti sspp. aerial parts, against oxidative stress induced by hydrogen peroxide in the human astrocytoma U373 MG cell line. The possible protective effect of the diterpenes against the damage induced by hydrogen peroxide has been evaluated using MTT assay. The free radical scavenging capacity of these compounds has been studied using DPPH method. Results of the present study demonstrated that the diterpenes andalusol, conchitriol y lagascatriol (5 and 10 μM) protect U373 MG cells from hydrogen peroxide toxicity, which is due to in part to the antioxidant capacity of these compounds. Itis suggested that these diterpenes could exert a beneficial effect in the prevention of neurodegenerative diseases associated to oxidative stress. These future studies will be focused on a deepening of action mechanism(AU)

Thrombin-induced oxidative stress contributes to the death of hippocampal neurons: role of neuronal NADPH oxidase.

The present study investigated whether thrombin can induce the production of reactive oxygen species (ROS) through activation of neuronal NADPH oxidase and whether this contributes to oxidative damage and consequently to neurodegeneration. Immunocytochemical and biochemical evidence demonstrated that, in neuron-enriched hippocampal cultures, thrombin induces neurodegeneration in a dose-dependent manner. In parallel, ROS production was evident as assessed by analyzing DCF and hydroethidine. Real-time PCR analysis, at various time points after thrombin treatment, also demonstrated that expression of NADPH oxidase subunits (p47(phox) and p67(phox)) occurs. In addition, Western blot analysis and double-label immunocytochemistry showed an up-regulation in the expression of cytosolic components (Rac 1 and p67(phox)), the translocation of cytosolic proteins (p47(phox) and p67(phox)) to the membrane, and the localization of gp91(phox) or p47(phox) expression in hippocampal neurons of cultures and CA1 layer. The thrombin-induced ROS production, protein oxidation, and loss of cultured hippocampal neurons were partially attenuated by an NADPH oxidase inhibitor and/or by several antioxidants. Collectively, the present study is the first to demonstrate that, in cultured hippocampal neurons, thrombin-induced neurotoxicity is, at least in part, caused by neuronal NADPH oxidase-mediated oxidative stress. This strongly suggests that thrombin can act as an endogenous neurotoxin, and inhibitors of thrombin and/or antioxidants can be useful agents for treating oxidative stress-mediated hippocampal neurodegenerative diseases, such as Alzheimer's disease.

Familial infantile bilateral striatal necrosis: clinical features and response to biotin treatment.

BACKGROUND: Infantile bilateral striatal necrosis (IBSN) encompasses several syndromes of bilateral symmetric, spongy degeneration of the caudate nucleus, putamen, and globus pallidus. The familial form of IBSN is rare, and inheritance is either autosomal recessive or maternal. METHOD: The authors describe an Israeli Bedouin kindred in which 15 children born to consanguineous parents were affected with familial IBSN. They evaluated the clinical and radiologic evolution of the disease in 11 patients and the cerebral pathologic findings in one patient. Three of the children were treated with oral biotin 100 mg/day. RESULTS: Inheritance was apparently autosomal recessive. The untreated children had a similar clinical picture including developmental arrest beginning at the age of 7 to 15 months, choreoathetosis, and dysphagia. Pendular nystagmus appeared at a late stage. MRI, performed at various stages of the disease, showed severe basal ganglia atrophy. Postmortem study in one patient showed severe atrophy of the lenticular nuclei with gliosis and loss of neurons. Biotin, 100 mg/day, administered to the proband over a period of 15 months, may have slowed progression. In two other children treatment was initiated earlier and appeared to arrest or improve disease. CONCLUSIONS: Familial infantile bilateral striatal necrosis was inherited as an autosomal recessive trait. Clinical features included developmental arrest, dysphagia, and choreoathetosis. Imaging and pathology showed atrophy and degeneration of the basal ganglia. Oral biotin may have benefited three children.