Vitamin D Receptor Polymorphisms in a Spanish Cohort of Parkinson's Disease Patients.

Background: Vitamin D receptor (VDR) is a nuclear hormone receptor widely expressed in the substantia nigra. Its association with an increased risk of Parkinson's disease (PD) is based on vitamin D deficiency and/or different polymorphisms in its gene receptor. This fact has been demonstrated by several case-control studies. Materials and Methods: Consequently, we investigated the association between VDR ApaI, BsmI, FokI, and TaqI gene polymorphisms and PD in a Spanish cohort that included 54 cases and 17 healthy controls. The detection of single nucleotide polymorphisms (SNPs) was performed using a polymerase chain reaction-restriction fragment length polymorphism. Results: Our data indicate that the SNPs were not associated with the age of onset of PD, nor with the occurrence of motor symptoms. However, only BsmI polymorphism was significantly associated with PD in this Spanish cohort. In fact, BsmI genotype was five times higher among PD patients than among controls, and the A allele was considered as a genetic risk for PD. Additionally, the combination of FokI and BsmI polymorphisms was significantly associated with PD and could represent a risk factor. Conclusion: We conclude that ApaI, TaqI, and FokI polymorphisms were not associated with PD, but BsmI could be a risk factor for PD in this randomized population.

Comparative Genetic Analysis of the Promoters of the ATG16L1 and ATG5 Genes Associated with Sporadic Parkinson's Disease.

Sporadic Parkinson's disease, characterised by a decline in dopamine, usually manifests in people over 65 years of age. Although 10% of cases have a genetic (familial) basis, most PD is sporadic. Genome sequencing studies have associated several genetic variants with sporadic PD. Our aim was to analyse the promoter region of the ATG16L1 and ATG5 genes in sporadic PD patients and ethnically matched controls. Genotypes were obtained by using the Sanger method with primers designed by us. The number of haplotypes was estimated with DnaSP software, phylogeny was reconstructed in Network, and genetic divergence was explored with Fst. Seven and two haplotypes were obtained for ATG16L1 and ATG5, respectively. However, only ATG16L1 showed a significant contribution to PD and a significant excess of accumulated mutations that could influence sporadic PD disease. Of a total of seven haplotypes found, only four were unique to patients sharing the T allele (rs77820970). Recent studies using MAPT genes support the notion that the architecture of haplotypes is worthy of being considered genetically risky, as shown in our study, confirming that large-scale assessment in different populations could be relevant to understanding the role of population-specific heterogeneity. Finally, our data suggest that the architecture of certain haplotypes and ethnicity determine the risk of PD, linking haplotype variation and neurodegenerative processes.

The senescence-accelerated mouse prone-8 (SAM-P8) oxidative stress is associated with upregulation of renal NADPH oxidase system

Herein, we investigate whether the NADPH oxidase might be playing a key role in the degree of oxidative stress in the senescence-accelerated mouse prone-8 (SAM-P8). To this end, the activity and expression of the NADPH oxidase, the ratio of glutathione and glutathione disulfides (GSH/GSSG), and the levels of malonyl dialdehyde (MDA) and nitrotyrosine (NT) were determined in renal tissue from SAM-P8 mice at the age of 1 and 6 months. The senescence-accelerated-resistant mouse (SAM-R1) was used as control. At the age of 1 month, NADPH oxidase activity and Nox2 protein expression were higher in SAM-P8 than in SAM-R1 mice. However, we found no differences in the GSH/GSSG ratio, MDA, NT, and Nox4 levels between both groups of animals. At the age of 6 months, SAM-R1 mice in comparison to SAM-P8 mice showed an increase in NADPH oxidase activity, which is associated with higher levels of NT and increased Nox4 and Nox2 expression levels. Furthermore, we found oxidative stress hallmarks including depletion in GSH/GSSG ratio and increase in MDA levels in the kidney of SAM-P8 mice. Finally, NADPH oxidase activity positively correlated with Nox2 expression in all the animals (r = 0.382, P < 0.05). Taken together, our data allow us to suggest that an increase in NADPH oxidase activity might be an early hallmark to predict future oxidative stress in renal tissue during the aging process that takes place in SAM-P8 mice (AU)

Respuesta inflamatoria durante los procesos de isquemia: moléculas de adhesión e inmunomodulación / Inflammatory response during ischaemic processes: adhesion molecules and immunomodulation

Introducción. Tras la isquemia cerebral se produce la muerte necrótica de las células afectadas por la ausencia de oxígeno y glucosa, especialmente de las neuronas. Esta necrosis desencadena la activación del sistema inmune y el inicio de la respuesta inflamatoria. El sistema nervioso central cuenta con células inflamatorias innatas como la microglía y los macrófagos, que poseen una función importante en la recepción y propagación de señales inflamatorias. Desarrollo. La respuesta inflamatoria se caracteriza por la expresión de mediadores inflamatorios y la invasión de células inflamatorias circulantes. El paso de los leucocitos a través del endotelio implica dos etapas coordinadas en el tiempo: la adhesión y la subsiguiente migración transendotelial. Por ello, las moléculas de adhesión en leucocitos y células endoteliales, como son las selectinas, las sialomucinas, la superfamilia de las inmunoglobulinas y las integrinas, constituyen moléculas clave que contribuyen al daño cerebral. Sin embargo, dicha respuesta precisa eliminar los restos celulares tanto necróticos como apoptóticos para iniciar los posibles procesos de reparación y plasticidad cerebral. Por tanto, la respuesta inflamatoria es una respuesta coordinada, y tras la activación de la inflamación se desencadena también una respuesta inmunosupresora y antiinflamatoria. Conclusiones. La inflamación se ha asociado a un aumento en el daño cerebral en pacientes con infarto cerebral, aunque es necesaria para activar los mecanismos de reparación. Por ello resulta preciso un estricto control de la respuesta inflamatoria después del infarto cerebral para reducir el daño del tejido afectado sin la inhibición de los mecanismos de reparación (AU)

Introduction. After cerebral ischemia, necrotic cell death occurs specially for neurons, mainly due to the privation of oxygen and glucose. Cell necrosis triggers the activation of the immune system followed by an inflammatory response. This reaction is characterized by the activation of astrocytes and microglia together with the infiltration of peripheral immune cells. Development. Both, microglia and inflammatory cells, including circulating peripheral inflammatory cells, get activated and release a plethora of inflammatory mediators, cytokines, chemokines, etc. Such released factors induce the overexpression of adhesion molecules, increasing the blood brain barrier permeability, thus favoring even more inflammatory cell infiltration. In the end, this contributes to increase brain damage. Inflammatory response is nevertheless necessary in order to eliminate cellular debris from both apoptotic and necrotic cells. It seems to be also implicated in the initiation of certain mechanisms responsible for brain repair and plasticity. As a result, the inflammatory response is a coordinated effort. Activation of inflammation triggers an immunosuppressant and anti-inflammatory response. A high rate of infections in patients suffering from stroke, together with increased serum levels of anti-inflammatory molecules in these patients, support this statement. The anti-inflammatory response could be interpreted as the organism attempting to control the heightened inflammatory response that occurs after cerebral ischemia. On the other hand, following an ischemic event, there are several new cerebral epitopes that get exposed to the immune system, which would never have been exposed under normal physiological conditions. Conclusion. Therefore immunosuppression after an ischemic accident hinders the development of auto-immune responses (AU)

La inflamación como agente terapéutico en el infarto cerebral: respuesta inflamatoria celular y mediadores inflamatorios / Inflammation as a therapeutic agent in cerebral infarction: cellular inflammatory response and inflammatory mediators

Introducción. El sistema nervioso central (SNC) posee células inflamatorias innatas como la microglía y los macrófagos, los cuales tienen una función importante en la recepción y propagación de señales inflamatorias. Recientemente se ha postulado que el sistema inmune y el proceso inflamatorio participan de forma activa en la pérdida neuronal descrita en enfermedades del SNC agudas (infarto cerebral) y crónicas (esclerosis múltiple, enfermedad de Alzheimer). Desarrollo. Se revisan los procesos que conducen a la activación del sistema inmune y el inicio de la respuesta inflamatoria tras la isquemia cerebral, donde se produce la muerte necrótica de las células afectadas, especialmente de las neuronas. Así se profundiza en el papel de las células inflamatorias innatas de las que dispone el SNC, como la microglía y los macrófagos, las cuales poseen una función importante en la recepción y propagación de señales inflamatorias. Además, la respuesta inflamatoria se caracteriza por un incremento en los niveles de expresión de mediadores inflamatorios, que sobrerregulan las moléculas de adhesión y aumentan la permeabilidad de la barrera hematoencefálica. Se ha descrito también que la inflamación promueve la rápida sobreexpresión y activación de una variedad de genes, habiéndose postulado a los factores de transcripción como posibles dianas sobre las que actuar en la reparación y la terapéutica. Sin embargo, la activación transcripcional puede verse como una espada de doble filo porque la transcripción individual de factores puede inducir tanto a genes neuroprotectores como neurotóxicos. Conclusión. Un mayor conocimiento de las distintas moléculas involucradas en la respuesta inflamatoria permitiría el diseño de nuevas aproximaciones farmacológicas que contribuirían a la mejora en el tratamiento de la isquemia cerebral (AU)

Introduction. The immune central nervous system (CNS) innate immune cells including microglia and macrophages play integral roles in receiving and propagating inflammatory signals. Inflammation is generally a beneficial response of an organism to infection but, when prolonged or inappropriate, it can be detrimental. Neuronal loss in acute (e.g. stroke and head injury) and chronic (e.g. multiple sclerosis and Alzheimer’s disease) CNS diseases has been associated with inflammatory processes systemically and in the brain. Development. Herein we review the processes that participate in the activation of the immune system and the starting of inflammatory response after stroke, where neuronal necrotic cell death has been described. We addressed the relevance of the innate inflammatory cells that are on the CNS, as microglia and macrophages, which have an important role inreceiving and spreading inflammatory signals. In addition, the inflammatory response is characterized by an increase in the levels of expression of inflammatory mediators, which regulate adhesion molecules, and increase the permeability of the blood-brain barrier. It has also been described that inflammation promotes the rapid over-expression and activation of a variety of genes, and it has been postulated that transcription factors should be studied for their potential use in therapeutics and repair. Transcriptional activation can be a double-edged sword since depending on the individual transcription factor it can induce the expression of either neuroprotective or neurotoxic genes. Conclusion. In summary, a better understanding of the different molecules mediating the immune response will allow the design of new pharmacological tools that could improve stroke treatment (AU)