N,N-dimethyltryptamine compound found in the hallucinogenic tea ayahuasca, regulates adult neurogenesis in vitro and in vivo.

N,N-dimethyltryptamine (DMT) is a component of the ayahuasca brew traditionally used for ritual and therapeutic purposes across several South American countries. Here, we have examined, in vitro and vivo, the potential neurogenic effect of DMT. Our results demonstrate that DMT administration activates the main adult neurogenic niche, the subgranular zone of the dentate gyrus of the hippocampus, promoting newly generated neurons in the granular zone. Moreover, these mice performed better, compared to control non-treated animals, in memory tests, which suggest a functional relevance for the DMT-induced new production of neurons in the hippocampus. Interestingly, the neurogenic effect of DMT appears to involve signaling via sigma-1 receptor (S1R) activation since S1R antagonist blocked the neurogenic effect. Taken together, our results demonstrate that DMT treatment activates the subgranular neurogenic niche regulating the proliferation of neural stem cells, the migration of neuroblasts, and promoting the generation of new neurons in the hippocampus, therefore enhancing adult neurogenesis and improving spatial learning and memory tasks.

Subtly Modulating Glycogen Synthase Kinase 3 ß: Allosteric Inhibitor Development and Their Potential for the Treatment of Chronic Diseases.

Glycogen synthase kinase 3 ß (GSK-3ß) is a central target in several unmet diseases. To increase the specificity of GSK-3ß inhibitors in chronic treatments, we developed small molecules allowing subtle modulation of GSK-3ß activity. Design synthesis, structure-activity relationships, and binding mode of quinoline-3-carbohydrazide derivatives as allosteric modulators of GSK-3ß are presented here. Furthermore, we show how allosteric binders may overcome the ß-catenin side effects associated with strong GSK-3ß inhibition. The therapeutic potential of some of these modulators has been tested in human samples from patients with congenital myotonic dystrophy type 1 (CDM1) and spinal muscular atrophy (SMA) patients. We found that compound 53 improves delayed myogenesis in CDM1 myoblasts, while compounds 1 and 53 have neuroprotective properties in SMA-derived cells. These findings suggest that the allosteric modulators of GSK-3ß may be used for future development of drugs for DM1, SMA, and other chronic diseases where GSK-3ß inhibition exhibits therapeutic effects.

Multitarget drug discovery for Alzheimer's disease: triazinones as BACE-1 and GSK-3ß inhibitors.

Cumulative evidence strongly supports that the amyloid and tau hypotheses are not mutually exclusive, but concomitantly contribute to neurodegeneration in Alzheimer's disease (AD). Thus, the development of multitarget drugs which are involved in both pathways might represent a promising therapeutic strategy. Accordingly, reported here in is the discovery of 6-amino-4-phenyl-3,4-dihydro-1,3,5-triazin-2(1H)-ones as the first class of molecules able to simultaneously modulate BACE-1 and GSK-3ß. Notably, one triazinone showed well-balanced in vitro potencies against the two enzymes (IC50 of (18.03±0.01) µM and (14.67±0.78) µM for BACE-1 and GSK-3ß, respectively). In cell-based assays, it displayed effective neuroprotective and neurogenic activities and no neurotoxicity. It also showed good brain permeability in a preliminary pharmacokinetic assessment in mice. Overall, triazinones might represent a promising starting point towards high quality lead compounds with an AD-modifying potential.

Modulation of cAMP-specific PDE without emetogenic activity: new sulfide-like PDE7 inhibitors.

A forward chemical genetic approach was followed to discover new targets and lead compounds for Parkinson's disease (PD) treatment. By analysis of the cell protection produced by some small molecules, a diphenyl sulfide compound was revealed to be a new phosphodiesterase 7 (PDE7) inhibitor and identified as a new hit. This result allows us to confirm the utility of PDE7 inhibitors as a potential pharmacological treatment of PD. On the basis of these data, a diverse family of diphenyl sulfides has been developed and pharmacologically evaluated in the present work. Moreover, to gain insight into the safety of PDE7 inhibitors for human chronic treatment, we evaluated the new compounds in a surrogate emesis model, showing nonemetic effects.

Phosphodiesterase 7 inhibition preserves dopaminergic neurons in cellular and rodent models of Parkinson disease.

BACKGROUND: Phosphodiesterase 7 plays a major role in down-regulation of protein kinase A activity by hydrolyzing cAMP in many cell types. This cyclic nucleotide plays a key role in signal transduction in a wide variety of cellular responses. In the brain, cAMP has been implicated in learning, memory processes and other brain functions. METHODOLOGY/PRINCIPAL FINDINGS: Here we show a novel function of phosphodiesterase 7 inhibition on nigrostriatal dopaminergic neuronal death. We found that S14, a heterocyclic small molecule inhibitor of phosphodiesterase 7, conferred significant neuronal protection against different insults both in the human dopaminergic cell line SH-SY5Y and in primary rat mesencephalic cultures. S14 treatment also reduced microglial activation, protected dopaminergic neurons and improved motor function in the lipopolysaccharide rat model of Parkinson disease. Finally, S14 neuroprotective effects were reversed by blocking the cAMP signaling pathways that operate through cAMP-dependent protein kinase A. CONCLUSIONS/SIGNIFICANCE: Our findings demonstrate that phosphodiesterase 7 inhibition can protect dopaminergic neurons against different insults, and they provide support for the therapeutic potential of phosphodiesterase 7 inhibitors in the treatment of neurodegenerative disorders, particularly Parkinson disease.

Indice fisicoquímico de la calidad de agua para el manejo de lagunas tropicales de inundación

Physicochemical water quality index, a management tool for tropical-flooding lagoons. We propose ICA-L, a wetland physicochemical water quality index (WWQI), to be used as a management tool for seasonal-flooding lagoons in Palo verde National Park, Guanacaste, Costa Rica. The goal is to preserve their natural role for native plants as well as migrants and local animal species. The index was developed in four steps: parameter selection, assignment of parameter weight, transformation of data to their corresponding sub indices and selection of an appropriate aggregation function. In this process, the following criteria were used as a reference: WQI from the National Sanitation Foundation, WQI for the Des Moines River, Escribano and De Frutos WQI, the international legislation on maximum acceptable concentration for different water quality variables, and the authors’ personal criteria. The index includes the following parameters: dissolved oxygen percent saturation, pH, nitrate concentration, total phosphorus concentration, chemical oxygen demand, concentration of suspended solids, electrical conductivity and temperature. The index sets itself to zero if the concentration of some toxic substance exceeds the maximum allowed limit. The adjustment values were based on "weights" defined in the National Sanitation Foundation Water quality Index (ICA-NSF). In this study, the weight of fecal coliforms count was excluded, the values of turbidity and the one for total solids were integrated into one (suspended solids) and a factor of 0.08 was assigned to the conductivity parameter. The sub indices associated to suspended solids were obtained from the quality of Kahler-Royer variation graph; the values for pH and the nitrate concentration from the graphs constructed for ICA-NSF. The percentage of dissolved oxygen saturation, in sites like irrigation channels, was evaluated directly from the quality variation graph constructed for ICANSF, whereas the same parameter for the flooding lagoons required an adjustment based on the optimal value for similar non contaminated ecosystems. The conductivity was evaluated from adjustments in the qualification functions commented by Escribano & De Frutos. Chemical oxygen demand, total phosphorus and temperature, were qualified based on the functions developed for the ICA-L. Rev. Biol. Trop. 56 (4): 1905-1918. Epub 2008 December 12.

Se creó un índice fisicoquímico de calidad del agua (ICA-L), para lagunas que se desbordan, el cual fue validado en el sector de riego de Tamarindo, y en una sección del sistema de lagunas del Parque Nacional Palo verde (Guanacaste, Costa Rica). El índice incluye las variables: porcentaje de saturación de oxígeno disuelto, pH, concentración de nitratos, concentración de fósforo total, demanda química de oxígeno, concentración de sólidos suspendidos, conductividad eléctrica y temperatura. El índice se fija automáticamente en cero si la concentración de alguna sustancia tóxica excede el máximo permitido. Los factores de ponderación se ajustaron con base en los pesos definidos en el Índice de Calidad de Agua de la National Sanitation Foundation (ICA-NSF), se excluyó el peso del conteo de coliformes fecales, se integró la ponderación de turbiedad y de sólidos totales una sola, de sólidos suspendidos, y se asignó a la conductividad un factor de 0.08. El índice per-mite evaluar la capacidad del agua de las lagunas tropicales de inundación de agua dulce, para lograr el sostenimiento de la biodiversidad y el desarrollo de la vida acuática, cuando surgen peligros por prácticas agropecuarias.

Implication of the endocannabinoid system in the locomotor hyperactivity associated with congenital hypothyroidism.

Alterations in motor functions are well-characterized features observed in humans and experimental animals subjected to thyroid hormone dysfunctions during development. Here we show that congenitally hypothyroid rats display hyperactivity in the adult life. This phenotype was associated with a decreased content of cannabinoid receptor type 1 (CB(1)) mRNA in the striatum and a reduction in the number of binding sites in both striatum and projection areas. These findings suggest that hyperactivity may be the consequence of a thyroid hormone deficiency-induced removal of the endocannabinoid tone, normally acting as a brake for hyperactivity at the basal ganglia. In agreement with the decrease in CB(1) receptor gene expression, a lower cannabinoid response, measured by biochemical, genetic and behavioral parameters, was observed in the hypothyroid animals. Finally, both CB(1) receptor gene expression and the biochemical and behavioral dysfunctions found in the hypothyroid animals were improved after a thyroid hormone replacement treatment. Thus, the present study suggests that impairment in the endocannabinoid system can underlay the hyperactive phenotype associated with hypothyroidism.

[Physicochemical water quality index, a management tool for tropical-flooding lagoons]. / Indice fisicoquímico de la calidad de agua para el manejo de lagunas tropicales de inundación.

We propose ICA-L, a wetland physicochemical water quality index (WWQI), to be used as a management tool for seasonal-flooding lagoons in Palo Verde National Park, Guanacaste, Costa Rica. The goal is to preserve their natural role for native plants as well as migrants and local animal species. The index was developed in four steps: parameter selection, assignment of parameter weight, transformation of data to their corresponding sub indices and selection of an appropriate aggregation function. In this process, the following criteria were used as a reference: WQI from the National Sanitation Foundation, WQI for the Des Moines River, Escribano and De Frutos WQI, the international legislation on maximum acceptable concentration for different water quality variables, and the authors' personal criteria. The index includes the following parameters: dissolved oxygen percent saturation, pH, nitrate concentration, total phosphorus concentration, chemical oxygen demand, concentration of suspended solids, electrical conductivity and temperature. The index sets itself to zero if the concentration of some toxic substance exceeds the maximum allowed limit. The adjustment values were based on "weights" defined in the National Sanitation Foundation Water quality Index (ICA-NSF). In this study, the weight of fecal coliforms count was excluded, the values of turbidity and the one for total solids were integrated into one (suspended solids) and a factor of 0.08 was assigned to the conductivity parameter. The sub indices associated to suspended solids were obtained from the quality of Kahler-Royer variation graph; the values for pH and the nitrate concentration from the graphs constructed for ICA-NSF. The percentage of dissolved oxygen saturation, in sites like irrigation channels, was evaluated directly from the quality variation graph constructed for ICA-NSF, whereas the same parameter for the flooding lagoons required an adjustment based on the optimal value for similar non contaminated ecosystems. The conductivity was evaluated from adjustments in the qualification functions commented by Escribano & De Frutos. Chemical oxygen demand, total phosphorus and temperature, were qualified based on the functions developed for the ICA-L.