Ion Channels and Transporters as Therapeutic Agents: From Biomolecules to Supramolecular Medicinal Chemistry

Ion channels and transporters typically consist of biomolecules that play key roles in a large variety of physiological and pathological processes. Traditional therapies include many ionchannel blockers, and some activators, although the exact biochemical pathways and mechanisms that regulate ion homeostasis are yet to be fully elucidated. An emerging area of research with great innovative potential in biomedicine pertains the design and development of synthetic ion channels and transporters, which may provide unexplored therapeutic opportunities. However, most studies in this challenging and multidisciplinary area are still at a fundamental level. In this review, we discuss the progress that has been made over the last five years on ion channels and transporters, touching upon biomolecules and synthetic supramolecules that are relevant to biological use. We conclude with the identification of therapeutic opportunities for future exploratio

Role of the anterior temporal lobes in semantic representations: paradoxical results of a cTBS study

According to the 'Semantic Hub' model, which was developed from data gathered in the moderate to advanced stages of semantic dementia (SD), a unitary amodal mechanism, located in the anterior parts of both temporal lobes (ATLs), should support the interactive activation of semantic representations in all modalities and for all semantic categories. This model has been challenged by clinical findings, which show that in the early stages of SD, when important asymmetries can be observed at the level of the right and left ATLs, the semantic impairment can be modality-specific, mainly affecting lexical-semantic knowledge when the left temporal lobe is more atrophic and pictorial representations when atrophy prevails on the right side. On the other hand, findings of experiments conducted in normal subjects with repetitive transcranial magnetic stimulations (rTMS), support the unitary model. In the most compelling of these studies, rTMS was used to investigate the role of right and left ATLs directly, by comparing semantic processing of the same concepts, presented as written words or pictures. The efficiency of semantic processing for words and pictures was reduced to the same degree by rTMS applied to the left and right ATLs. However, to consider more in depth some methodological inconsistencies of these studies and with the aim of discussing the effects of rTMS on high-level cognitive functions, we decided to repeat that experimental paradigm, using the continuous theta burst stimulation (cTBS) protocol over the right ATL, left ATL and vertex (as control site). A significant interaction was found between side of cTBS application and type of stimulus, but, contrary to our predictions, we observed significantly faster (rather than slower) responses to pictures after application of cTBS to the right ATL and no difference between responses to written words after application of cTBS to the left ATL in comparison with the vertex. These unexpected results are discussed with respect to the nature of the semantic representations supported by the right and left ATLs and to re-appraisal of the 'virtual lesion' account to explain results obtained with rTMS experiments on high-level cognitive functions

Overground walking training with the i-Walker, a robotic servo-assistive device, enhances balance in patients with subacute stroke: a randomized controlled trial

Background: Patients affected by mild stroke benefit more from physiological overground walking training than walking-like training performed in place using specific devices. The aim of the study was to evaluate the effects of overground robotic walking training performed with the servo-assistive robotic rollator (i-Walker) on walking, balance, gait stability and falls in a community setting in patients with mild subacute stroke. Methods: Forty-four patients were randomly assigned to two different groups that received the same therapy in two daily 40-min sessions 5 days a week for 4 weeks. Twenty sessions of standard therapy were performed by both groups. In the other 20 sessions the subjects enrolled in the i-Walker-Group (iWG) performed with the i-Walker and the Control-Group patients (CG) performed the same amount of conventional walking oriented therapy. Clinical and instrumented gait assessments were made pre- and post-treatment. The follow-up observation consisted of recording the number of fallers in the community setting after 6 months. Results: Treatment effectiveness was higher in the iWG group in terms of balance improvement (Tinetti: 68.4 +/- 27.6 % vs. 48.1 +/- 33.9 %, p = 0.033) and 10-m and 6-min timed walking tests (significant interaction between group and time: F(1,40) = 14.252, p = 0.001; and F(1,40) = 7.883, p = 0.008, respectively). When measured, latero-lateral upper body accelerations were reduced in iWG (F = 4.727, p = 0.036), suggesting increased gait stability, which was supported by a reduced number of falls at home. Conclusions: A robotic servo-assisted i-Walker improved walking performance and balance in patients affected by mild/moderate stroke, leading to increased gait stability and reduced falls in the community

Movements execution in amnestic mild cognitive impairment and Alzheimer's disease.

We evaluated the relationship between motor and neuropsychological deficits in subjects affected by amnestic Mild Cognitive Impairment (aMCI) and {early} Alzheimer's Disease (AD). Kinematics of goal-directed movement of aMCI and AD subjects were compared to those of age-matched control subjects. AD showed a slowing down of motor performance compared to aMCI and controls. No relationships were found between motor and cognitive performances in both AD and aMCI. Our results suggest that the different motor behaviour between AD and aMCI cannot be related to memory deficits, probably reflecting the initial degeneration of parietal-frontal circuits for movement planning. The onset of motor dysfunction in early AD could represent the transition from aMCI to AD

Genetic polymorphisms of glutathione S-transferases GSTM1, GSTT1, GSTP1 and GSTA1 as risk factors for schizophrenia

Oxidative damage is thought to play a role in the predisposition to schizophrenia. We determined if the polymorphisms of the GSTP1, GSTM1, GSTT1 and GSTA1 genes, which affect the activity of these enzymes against oxidative stress, have a role as susceptibility genes for schizophrenia, analyzing 138 schizophrenic patients and 133 healthy controls. We found that the combination of the absence of GSTM1 gene with the of the GSTM1 gene with the polymorphism GSTA1*B/*B, and the presence of the GSTT1 gene, represents a risk factor for schizophrenia, indicating that the combination of different GST polymorphisms has a role in the predisposition to schizophrenia, probably affecting the capacity of the cell to detoxify the oxidized metabolites of catecholamines

Intronic CYP46 polymorphism along with ApoE genotype in sporadic Alzheimer Disease: from risk factors to disease modulators

Increasing biological and clinical findings argue for a link between brain cholesterol turnover and Alzheimer Disease (AD), high cerebral levels of the former increasing Abeta load. Cerebral cholesterol elimination involves two mechanisms dependent on Apolipoprotein E (ApoE) and cholesterol 24-hydroxylase (CYP46). The aim of this study was to evaluate an intronic variation in CYP46 (intron 2, T --> C ) along with ApoE genotype as risk factors for AD and to establish the correlation between CYP46/ApoE polymorphism and disease progression. One-hundred and fifty-seven AD patients, who had been followed periodically through 1-year follow-up after enrollment, and 134 age- and gender-matched controls entered the study. The distribution of CYP46 genotypes was significantly different in AD compared to controls (P<0.004), being CYP*C allele higher in AD patients ( P<0.002). ApoE 4 genotype was more frequent in AD (41.4%) than in controls (15.9%, P<0.0001). The odds ratio (OR) for AD risk in CYP46*C carriers was 2.8, and in ApoE epsilon4 carriers was 4.05; the OR for having both CYP46*C and ApoE epsilon4 was 17.75, demonstrating the their synergic effect on AD risk. In AD patients, CYP46*C along with ApoE epsilon4 genotype were associated with a higher cognitive decline at 1-year follow-up (P<0.02). These findings provide direct evidence that CYP46 and ApoE polymorphisms synergically increase the risk for AD development, and influence on the rate of cognitive decline

Te.M.P.O., an app for using temporal musical mismatch in post-stroke neurorehabilitation: a preliminary randomized controlled study

BACKGROUND: Recently, the potential rehabilitation value of music has been examined and music-based interventions and techniques such as the Negative Mismatch (MMN) have been increasingly investigated in the neurological rehabilitation context. OBJECTIVE: The aim of this study was to investigate the effectiveness of a negative mismatch-based therapy on the disability and quality of life in patients with stroke in sub-acute phase. METHODS: Thirty patients with a stroke diagnosis in sub-acute phase were randomly assigned to one of two groups: Mismatch (Mg) or Control (CTRLg) group. Both groups used an innovative Android application: Temporal Musical Patterns Organisation (Te.M.P.O). The Disability Rating Scale (DRS), the Modified Barthel Index (MBI) and the Stroke Specific Quality of Life scale (SSQoL) were used at the baseline (T0) and after four weeks of training (T1), in order to assess changes over time. RESULTS: Statistical analysis was performed using the data of 24 (Mg = 12, CTRLg = 12) subjects. The results show a major improvement of the Mg with respect to the CTRLg in all clinical scales score. CONCLUSION: The temporal negative mismatch-based therapy performed with the Te.M.P.O. application could be useful in improving the disability and the quality of life in stroke survivors in a sub-acute phase

Polygenic determinants of white matter volume derived from GWAS lack reproducibility in a replicate sample

A recent publication reported an exciting polygenic effect of schizophrenia (SCZ) risk variants, identified by a large genome-wide association study (GWAS), on total brain and white matter volumes in schizophrenic patients and, even more prominently, in healthy subjects. The aim of the present work was to replicate and then potentially extend these findings. According to the original publication, polygenic risk scores using single nucleotide polymorphism (SNP) information of SCZ GWAS (polygenic SCZ risk scores; PSS) were calculated in 122 healthy subjects, enrolled in a structural magnetic resonance imaging (MRI) study. These scores were computed based on P-values and odds ratios available through the Psychiatric GWAS Consortium. In addition, polygenic white matter scores (PWM) were calculated, using the respective SNP subset in the original publication. None of the polygenic scores, either PSS or PWM, were found to be associated with total brain, white matter or gray matter volume in our replicate sample. Minor differences between the original and the present study that might have contributed to lack of reproducibility (but unlikely explain it fully), are number of subjects, ethnicity, age distribution, array technology, SNP imputation quality and MRI scanner type. In contrast to the original publication, our results do not reveal the slightest signal of association of the described sets of GWAS-identified SCZ risk variants with brain volumes in adults. Caution is indicated in interpreting studies building on polygenic risk scores without replication sample