Small molecules to perform big roles: The search for Parkinson's and Huntington's disease therapeutics.

Neurological motor disorders (NMDs) such as Parkinson's disease and Huntington's disease are characterized by the accumulation and aggregation of misfolded proteins that trigger cell death of specific neuronal populations in the central nervous system. Differential neuronal loss initiates the impaired motor control and cognitive function in the affected patients. Although major advances have been carried out to understand the molecular basis of these diseases, to date there are no treatments that can prevent, cure, or significantly delay the progression of the disease. In this context, strategies such as gene editing, cellular therapy, among others, have gained attention as they effectively reduce the load of toxic protein aggregates in different models of neurodegeneration. Nevertheless, these strategies are expensive and difficult to deliver into the patients' nervous system. Thus, small molecules and natural products that reduce protein aggregation levels are highly sought after. Numerous drug discovery efforts have analyzed large libraries of synthetic compounds for the treatment of different NMDs, with a few candidates reaching clinical trials. Moreover, the recognition of new druggable targets for NMDs has allowed the discovery of new small molecules that have demonstrated their efficacy in pre-clinical studies. It is also important to recognize the contribution of natural products to the discovery of new candidates that can prevent or cure NMDs. Additionally, the repurposing of drugs for the treatment of NMDs has gained huge attention as they have already been through clinical trials confirming their safety in humans, which can accelerate the development of new treatment. In this review, we will focus on the new advances in the discovery of small molecules for the treatment of Parkinson's and Huntington's disease. We will begin by discussing the available pharmacological treatments to modulate the progression of neurodegeneration and to alleviate the motor symptoms in these diseases. Then, we will analyze those small molecules that have reached or are currently under clinical trials, including natural products and repurposed drugs.

A phenolic-rich extract from Ugni molinae berries reduces abnormal protein aggregation in a cellular model of Huntington's disease.

Accumulation of misfolded proteins in the brain is a common hallmark of most age-related neurodegenerative diseases. Previous studies from our group identified the presence of anti-inflammatory and antioxidant compounds in leaves derived from the Chilean berry Ugni molinae (murtilla), in addition to show a potent anti-aggregation activity in models of Alzheimer´s disease. However, possible beneficial effects of berry extracts of murtilla was not investigated. Here we evaluated the efficacy of fruit extracts from different genotypes of Chilean-native U. molinae on reducing protein aggregation using cellular models of Huntington´s disease and assess the correlation with their chemical composition. Berry extraction was performed by exhaustive maceration with increasing-polarity solvents. An unbiased automatic microscopy platform was used for cytotoxicity and protein aggregation studies in HEK293 cells using polyglutamine-EGFP fusion proteins, followed by secondary validation using biochemical assays. Phenolic-rich extracts from murtilla berries of the 19-1 genotype (ETE 19-1) significantly reduced polyglutamine peptide aggregation levels, correlating with the modulation in the expression levels of autophagy-related proteins. Using LC-MS and molecular network analysis we correlated the presence of flavonoids, phenolic acids, and ellagitannins with the protective effects of ETE 19-1 effects on protein aggregation. Overall, our results indicate the presence of bioactive components in ethanolic extracts from U. molinae berries that reduce the load of protein aggregates in living cells.

On the Right Track to Treat Movement Disorders: Promising Therapeutic Approaches for Parkinson's and Huntington's Disease.

Movement disorders are neurological conditions in which patients manifest a diverse range of movement impairments. Distinct structures within the basal ganglia of the brain, an area involved in movement regulation, are differentially affected for every disease. Among the most studied movement disorder conditions are Parkinson's (PD) and Huntington's disease (HD), in which the deregulation of the movement circuitry due to the loss of specific neuronal populations in basal ganglia is the underlying cause of motor symptoms. These symptoms are due to the loss principally of dopaminergic neurons of the substantia nigra (SN) par compacta and the GABAergic neurons of the striatum in PD and HD, respectively. Although these diseases were described in the 19th century, no effective treatment can slow down, reverse, or stop disease progression. Available pharmacological therapies have been focused on preventing or alleviating motor symptoms to improve the quality of life of patients, but these drugs are not able to mitigate the progressive neurodegeneration. Currently, considerable therapeutic advances have been achieved seeking a more efficacious and durable therapeutic effect. Here, we will focus on the new advances of several therapeutic approaches for PD and HD, starting with the available pharmacological treatments to alleviate the motor symptoms in both diseases. Then, we describe therapeutic strategies that aim to restore specific neuronal populations or their activity. Among the discussed strategies, the use of Neurotrophic factors (NTFs) and genetic approaches to prevent the neuronal loss in these diseases will be described. We will highlight strategies that have been evaluated in both Parkinson's and Huntington's patients, and also the ones with strong preclinical evidence. These current therapeutic techniques represent the most promising tools for the safe treatment of both diseases, specifically those aimed to avoid neuronal loss during disease progression.

Phenolic composition and antioxidant capacity of Ugni molinae Turcz. leaves of different genotypes.

Ugni molinae Turcz. is a native shrub of Chile, known for its edible berries and its leaves, which have been the focus of recent attention, as a good source of phenolic compounds to be used in cosmetics and food products. The aim of this study was to assess the differences in the phenolic composition and antioxidant capacity of the ethanolic extracts from the leaves of 10 genotypes of U. molinae, that were cultivated under the same soil, climate and agronomical management. Antioxidant activity was assessed by complementary methods (ORAC-Fl, FRAP and DPPH assay), phenolic composition of each extract was analyzed by LC-MS. Phenolic and flavonoid total contents were determined by Folin-Ciocalteu and AlCl3 methods. Significative differences were found by these methods, and ellagitannins, gallic acid derivatives and flavonols were identified as responsible for these differences, showing the influence of the genotype on the phenolic composition of U. molinae leaves.

Cuantificación de flavonoides y ácido gálico en hojas de distintos genotipos de Ugni molinae Turcz. y evaluación de su actividad antioxidante / Quantification of flavonoids and gallic acid in leaves of different genotypes of Ugni molinae Turcz. and evaluation of its antioxidant activity

La murtilla es un arbusto silvestre que crece en la zona centro-sur de Chile. Sus hojas han sido utilizadas en la medicina tradicional chilena debido a sus propiedades como antiinflamatoria, analgésica, antimicrobiana y antioxidante. Las propiedades benéficas de la murtilla se deben, en parte, a la presencia de compuestos fenólicos en sus hojas, principalmente compuestos del tipo flavonoides. Diversos estudios previos han demostrado la presencia de quercetina, miricetina, epicatequina y algunos de sus derivados glicosilados en las hojas de murtilla. El objetivo de este estudio fue demostrar que la actividad antioxidante de los extractos etanólicos (EETs) obtenidos desde hojas de diferentes genotipos de murtilla varía según la composición de compuestos fenólicos presentes en dichas hojas. Con este fin, se: a) determinó la capacidad y eficiencia antioxidante (CE50 y EA respectivamente) de los extractos a través del método del radical DPPH, b) cuantificó el porcentaje de flavanonas presentes en los EETs a través del ensayo colorimétrico con 2,4 dinitrofenilhidrazina (2,4 DNP), y c) determinó la presencia de quercetina, rutina, miricitrina y ácido gálico en los EETs a través de cromatografía liquida de alta eficiencia con arreglo de diodos (CLAE-DAD). Los resultados indicaron que existen diferencias significativas (p < 0,05) en las CE50 y la EA de los EETs, siendo el de menos CE50 el EET del genotipo ZF-18 y el EET 14-4 el que obtuvo la mayor EA (2,12 ± 0,03 x10-3). Estas diferencias pueden deberse a las diferencias encontradas en la composición de los EETs, en los cuales se pudo identificar y cuantificar quercetina, rutina y ácido gálico. También existieron diferencias en el %flavanonas, siendo los genotipos 8-2 y 23-2 los que obtuvieron los mayores porcentajes (7,79 ± 0,14% y 7,75 ± 0,4% respectivamente), aunque estas no influyeron en la actividad antioxidante de los EETs. Considerando que los 10 genotipos fueron cultivados en las mismas condiciones, las diferencias encontradas en los EETs se deben a las diferencias en sus genotipos.