Sustained Increase of PKA Activity in the Postcommissural Putamen of Dyskinetic Monkeys

Levodopa-induced dyskinesias (LID) are a frequent complication of Parkinson’s disease pharmacotherapy that causes significant disability and narrows the therapeutic window. Pharmacological management of LID is challenging partly because the precise molecular mechanisms are not completely understood. Here, our aim was to determine molecular changes that could unveil targetable mechanisms underlying this drug complication. We examined the expression and downstream activity of dopamine receptors (DR) in the striatum of 1-methyl-4-phenyl-1,2,3,6 tetrahydropiridine (MPTP)-lesioned monkeys with and without l-DOPA treatment. Four monkeys were made dyskinetic and other four received a shorter course of l-DOPA and did not develop LID. Our results show that l-DOPA treatment induces an increase in DRD2 and DRD3 expression in the postcommissural putamen, but only DRD3 is correlated with the severity of LID. Dyskinetic monkeys show a hyperactivation of the canonical DRD1-signaling pathway, measured by an increased phosphorylation of protein kinase A (PKA) and its substrates, particularly DARPP32. In contrast, activation of the DRD2-signaling pathway, visible in the levels of Akt phosphorylated on Thr308 and GSK3β on Ser9, is associated with l-DOPA treatment, independently of the presence of dyskinesias. Our data clearly demonstrate that dyskinetic monkeys present a dysregulation of the DRD3 receptor and the DRD1 pathway with a sustained increase of PKA activity in the postcommissural putamen. Importantly, we found that all signaling changes related to long-term l-DOPA administration are exquisitely restricted to the postcommissural putamen, which may be related to the recurrent failure of pharmacological approaches.     

Reversible dehydration process in a novel three-dimensional covalent network based on pyrimidine-4,6-dionato bridging ligand

The novel metal-organic polymer [Zn(μ-pmdt)(H₂O)]_n (1) (pmdt = pyrimidine-4,6-dionate) exhibits an extended three-dimensional network with two crystallographically independent pmdt bridging ligands, one zinc(II) atom and a coordinated water molecule. The Zn(II) atoms are located at the centre of a distorted ZnN₂OOw tetrahedral chromophore. One of the pmdt ligands acts as tetradentate bridge linking four metal centers, while the other pmdt ligand shows a bidentate coordination mode bridging two metal centers. The compound shows a reversible dehydration process, involving a coordinated water molecule, to lead an amorphous anhydrous phase. This transition has been characterized by thermogravimetric and variable-temperature X-ray powder diffraction techniques.     

In vivo effects of APP are not exacerbated by BACE2 co-overexpression: behavioural characterization of a double transgenic mouse model

Down syndrome, the most common genetic disorder leading to mental retardation, is caused by the presence of all or part of an extra copy of chromosome 21. At relatively early ages, Down syndrome patients develop progressive formation and extracellular aggregation of amyloid-β peptide, considered as one of the causal factors for the pathogenesis of Alzheimer’s disease. This neuropathological hallmark has been attributed to the overexpression of APP but could also be contributed by other HSA21 genes. BACE2 maps to HSA21 and is homologous to BACE1, a β-secretase involved in the amyloidogenic pathway of APP proteolysis, and thus it has been hypothesized that the co-overexpression of both genes could contribute to Alzheimer’s like neuropathology present in Down syndrome. The aim of the present study has been to analyse the impact of the co-overexpression of BACE2 and APP, using a double transgenic mouse model. Double transgenic mice did not present any neurological or sensorimotor alterations, nor genotype-dependent anxiety-like behaviour or age-associated cognitive dysfunction. Interestingly, TgBACE2-APP mice showed deregulation of BACE2 expression levels that were significantly increased with respect to single TgBACE2 mice. Co-overexpression of BACE2 and APP did not increase amyloid-β peptide concentration in brain. Our results suggest that the in vivo effects of APP are not exacerbated by BACE2 co-overexpression but may have some protective effects in specific behavioural and cognitive domains in transgenic mice.     

Epidemiología infecciosa en centros gerontológicos

Introduction

Infection processes in gerontology centres (GC) are one of the main causes of mortality and aggravation of concomitant chronic diseases. An epidemiological surveillance system was set up to find out their magnitude and distribution.

Material and methods

A prevalence study was conducted during the years 2006-2009 in 4 GCs of the Matia Foundation. Prevalence was measured by making an annual cut-off, recording: infection type, demographic data, risk factors and antibiotic use. The incidence was measured for two years in one GC as a pilot centre, recording: infection type and antibiotic use.

Results

The prevalence in the GCs varied between 4.8% and 6.44%. The infection incidence density in the pilot study was between 3.45-5.77 infections per 1,000 resident days. The most common infection location and in this order were, respiratory, urinary and cutaneous. The incidence of respiratory infection is more statistically significant in the presence of dysphagia, malnutrition and COPD. However, no significant relationship was seen in the incidence of urinary infection with the different risk factors analysed.

Conclusions

The frequency and repercussions of nosocomial infections in GCs demonstrate the need for intervention plans and the development of adequate prevention measures.     

The Role of the Subthalamic Nucleus in L-DOPA Induced Dyskinesia in 6-Hydroxydopamine Lesioned Rats

L-DOPA is the most effective treatment for Parkinson's disease (PD), but prolonged use leads to disabling motor complications including dyskinesia. Strong evidence supports a role of the subthalamic nucleus (STN) in the pathophysiology of PD whereas its role in dyskinesia is a matter of controversy. Here, we investigated the involvement of STN in dyskinesia, using single-unit extracellular recording, behavioural and molecular approaches in hemi-parkinsonian rats rendered dyskinetic by chronic L-DOPA administration. Our results show that chronic L-DOPA treatment does not modify the abnormal STN activity induced by the 6-hydroxydopamine lesion of the nigrostriatal pathway in this model. Likewise, we observed a loss of STN responsiveness to a single L-DOPA dose both in lesioned and sham animals that received daily L-DOPA treatment. We did not find any correlation between the abnormal involuntary movement (AIM) scores and the electrophysiological parameters of STN neurons recorded 24 h or 20-120 min after the last L-DOPA injection, except for the axial subscores. Nonetheless, unilateral chemical ablation of the STN with ibotenic acid resulted in a reduction in global AIM scores and peak-severity of dyskinesia. In addition, STN lesion decreased the anti-dyskinetogenic effect of buspirone in a reciprocal manner. Striatal protein expression was altered in dyskinetic animals with increases in ΔFosB, phosphoDARPP-32, dopamine receptor (DR) D3 and DRD2/DRD1 ratio. The STN lesion attenuated the striatal molecular changes and normalized the DRD2/DRD1 ratio. Taken together, our results show that the STN plays a role, if modest, in the physiopathology of dyskinesias.