Ibuprofen and Lipoic Acid Diamide as Co-Drug with Neuroprotective Activity: Pharmacological Properties and Effects in β-Amyloid (1–40) Infused Alzheimer's Disease Rat Model

Both oxidative stress and inflammation are elevated in brains of Alzheimer's disease patients, but their pathogenic significance still remains unclear. Current evidence support the hypothesis that non-steroidal anti-inflammatory drugs (NSAIDs) and antioxidant therapy might protect against the development of Alzheimer's disease, and ibuprofen has the strongest epidemiological support. In the present work our attention was focused on (R)-α-lipoic acid considered as a potential neuroprotective agent in Alzheimer's disease therapy. In particular, we investigated a new co-drug (1) obtained by joining (R)-α-lipoic acid and ibuprofen via a diamide bond, for evaluating its potential to antagonize the deleterious structural and cognitive effects of β-amyloid (1–40) in an infused Alzheimer's disease rat model. Our results indicated that infusion of β-amyloid (1–40) impairs memory performance through a progressive cognitive deterioration; however, ibuprofen and co-drug 1 seemed to protect against behavioural detriment induced by simultaneous administration of β-amyloid (1–40) protein. The obtained data were supported by the histochemical findings of the present study: β-amyloid protein was less expressed in 1-treated than in ibuprofen and (R)-α-lipoic acid alone-treated cerebral cortex. Taken together, the present findings suggest that co-drug 1 treatment may protect against the cognitive dysfunction induced by intracerebroventricular infusion of β-amyloid (1–40) in rats. Thus, co-drug 1 could prove useful as a tool for controlling Alzheimer's disease-induced cerebral amyloid deposits and behavioural deterioration

MAO A VNTR polymorphism and amygdala volume in healthy subjects

The X-linked Monoamine Oxidase A (MAO A) gene presents a well known functional polymorphism consisting of a variable number of tandem repeats (VNTR) (long and short variants) previously associated with altered neural function of the amygdala. Using automatic subcortical segmentation (Freesurfer), we investigated whether amygdala volume could be influenced by this genotype. We studied 109 healthy subjects (age range 18-80 years; 59 male and 50 female), 74 carrying the MAO A High-activity allele and 35 the MAO A Low-activity allele. No significant effect of the MAO A polymorphism or interaction effect between polymorphism × gender was found on amygdalar volume. Thus, our findings suggest that the reported impact of the MAO A polymorphism on amygdala function is not coupled with consistent volumetric changes in healthy subjects. Future studies are needed to investigate whether the association between volume of the amygdala and the MAO A VNTR polymorphism is influenced by social/psychological variables, such as impulsivity, trauma history and cigarette smoking behaviour, not taken into account in this work

Neurofunctional correlates of attention rehabilitation in Parkinson's disease: an explorative study

The effectiveness of cognitive rehabilitation (CR) in Parkinson's disease (PD) is in its relative infancy, and nowadays there is insufficient information to support evidence-based clinical protocols. This study is aimed at testing a validated therapeutic strategy characterized by intensive computer-based attention-training program tailored to attention deficits. We further investigated the presence of synaptic plasticity by means of functional magnetic resonance imaging (fMRI). Using a randomized controlled study, we enrolled eight PD patients who underwent a CR program (Experimental group) and seven clinically/demographically-matched PD patients who underwent a placebo intervention (Control group). Brain activity was assessed using an 8-min resting state (RS) fMRI acquisition. Independent component analysis and statistical parametric mapping were used to assess the effect of CR on brain function. Significant effects were detected both at a phenotypic and at an intermediate phenotypic level. After CR, the Experimental group, in comparison with the Control group, showed a specific enhanced performance in cognitive performance as assessed by the SDMT and digit span forward. RS fMRI analysis for all networks revealed two significant groups (Experimental vs Control) × time (T0 vs T1) interaction effects on the analysis of the attention (superior parietal cortex) and central executive neural networks (dorsolateral prefrontal cortex). We demonstrated that intensive CR tailored for the impaired abilities impacts neural plasticity and improves some aspects of cognitive deficits of PD patients. The reported neurophysiological and behavioural effects corroborate the benefits of our therapeutic approach, which might have a reliable application in clinical management of cognitive defici

Pain and agitation treatment in severe dementia patients: The need for Italian Mobilization-Observation-Behavior-Intensity-Dementia (I-MOBID2) pain scale translation, adaptation and validation with psychometric testing

The 97% of dementia patients develops fluctuant neuropsychiatric symptoms often related to under-diagnosed and unrelieved pain. Up to 80% severe demented nursing home residents experiences chronic pain due to age-related comorbidities. Patients lacking self-report skills risk not to be appropriately treated for pain. Mobilization-Observation-Behavior-Intensity-Dementia (MOBID2) is the sole pain scale to consider the frequent co-occurrence of musculoskeletal and visceral pain and to unravel concealed pain through active guided movements. Accordingly, the Italian real-world setting can benefit from its translation and validation. This clinical study provides a translated, adapted and validated version of the MOBID2, the Italian I-MOBID2. The translation, adaptation and validation of the scale for non-verbal, severe demented patients was conducted according to current guidelines in a cohort of 11 patients over 65 with mini-mental state examination ≤ 12. The I-MOBID2 proves: good face and scale content validity index (0.89); reliable internal consistency (Cronbach's α = 0.751); good to excellent inter-rater (Intraclass correlation coefficient, and test-retest (ICC = 0.902) reliability. The construct validity is high (Rho = 0.748 p < 0.05 for 11 patients, Spearman rank order correlation of the overall pain intensity score with the maximum item score of I-MOBID2 Part 1; rho=0.895 p < 0.01 for 11 patients, for the overall pain intensity score with the maximum item score of I-MOBID2 Part 2) and a good rate of inter-rater and test-retest agreement was demonstrated by Cohen's K = 0.744. The average execution time is of 5.8 min, thus making I-MOBID2 a useful tool suitable also for future development in community setting with administration by caregivers

Codrugs linking L-Dopa and sulfur-containing antioxidants: new pharmacological tools against Parkinson’s Disease

A series of multifunctional codrugs (1-6) were synthesized to overcome the pro-oxidant effect associated with L-dopa (LD) therapy. Target compounds release LD and dopamine (DA) in human plasma after enzymatic hydrolysis, displaying an antioxidant effect superior to that of N-acetylcysteine (NAC). After intracerebroventricular injection of codrug 4, the levels of DA in the striatum were higher than those in LD-treated groups, indicating that this compound has a longer half-life in brain than LD

Design, synthesis and preliminary pharmacological evaluation of new imidazolinonesas L-DOPA prodrugs

L-DOPA, the immediate biological precursor of dopamine, is still considered the drug of choice in the treatment of Parkinson's disease. However, therapy with L-DOPA is associated with a number of acute problems. With the aim to increase the bioavailability after oral administration, we designed a multi-protected L-DOPA prodrugs able to release the drug by both spontaneous chemical or enzyme catalyzed hydrolysis. The new compounds have been synthesized and preliminarily evaluated for their water solubility, log P, chemical stability, and enzymatic stability. The results indicate that the incorporation of the amino acidic moiety of L-DOPA into an imidazoline-4-one ring provides prodrugs sufficiently stable to potentially cross unchanged the acidic environment of the stomach, and to be absorbed from the intestine. They also might be able to release L-DOPA in human plasma after enzymatic hydrolysis. The ability of prodrugs 6a-b to increase basal levels of striatal DA, and influence brain neurochemistry associated with dopaminergic activity following oral administration, as well as the radical-scavenging activity against DPPH for compounds 6a-b and 15a are also reported

Mindfulness-Based Interventions for Physical and Psychological Wellbeing in Cardiovascular Diseases: A Systematic Review and Meta-Analysis

Background: Recently, there has been an increased interest in the efficacy of mindfulness-based interventions (MBI) for people with cardiovascular diseases (CVD), although the exact beneficial effects remain unclear. Methods: This review aims to establish the role of MBI in the management of wellbeing for patients with CVD. Seventeen articles have been included in this systematic synthesis of the literature and eleven in the meta-analysis. Results: Considering physical (i.e., heart rate, blood pressure) and psychological outcomes (i.e., depression, anxiety, stress, styles of coping), the vast majority of studies confirmed that MBI has a positive influence on coping with psychological risk factors, also improving physiological fitness. Random-effects meta-analysis models suggested a moderate-to-large effect size in reducing anxiety, depression, stress, and systolic blood pressure. Conclusions: Although a high heterogeneity was observed in the methodological approaches, scientific literature confirmed that MBI can now be translated into a first-line intervention tool for improving physical and psychological wellbeing in CVD patients

High serum levels of transforming growth factor β1 are associated with increased cortical thickness in cingulate and right frontal areas in healthy subjects

ABSTRACT

Neurobehavioral Mechanisms of Temporal Processing Deficits in Parkinson's Disease

Parkinson's disease (PD) disrupts temporal processing, but the neuronal sources of deficits and their response to dopamine (DA) therapy are not understood. Though the striatum and DA transmission are thought to be essential for timekeeping, potential working memory (WM) and executive problems could also disrupt timing.The present study addressed these issues by testing controls and PD volunteers 'on' and 'off' DA therapy as they underwent fMRI while performing a time-perception task. To distinguish systems associated with abnormalities in temporal and non-temporal processes, we separated brain activity during encoding and decision-making phases of a trial. Whereas both phases involved timekeeping, the encoding and decision phases emphasized WM and executive processes, respectively. The methods enabled exploration of both the amplitude and temporal dynamics of neural activity. First, we found that time-perception deficits were associated with striatal, cortical, and cerebellar dysfunction. Unlike studies of timed movement, our results could not be attributed to traditional roles of the striatum and cerebellum in movement. Second, for the first time we identified temporal and non-temporal sources of impaired time perception. Striatal dysfunction was found during both phases consistent with its role in timekeeping. Activation was also abnormal in a WM network (middle-frontal and parietal cortex, lateral cerebellum) during encoding and a network that modulates executive and memory functions (parahippocampus, posterior cingulate) during decision making. Third, hypoactivation typified neuronal dysfunction in PD, but was sometimes characterized by abnormal temporal dynamics (e.g., lagged, prolonged) that were not due to longer response times. Finally, DA therapy did not alleviate timing deficits.Our findings indicate that impaired timing in PD arises from nigrostriatal and mesocortical dysfunction in systems that mediate temporal and non-temporal control-processes. However, time perception impairments were not improved by DA treatment, likely due to inadequate restoration of neuronal activity and perhaps corticostriatal effective-connectivity