CNS & Neurological Disorders - Drug Targets - Volume 16, Issue 9, 2017

Background and Objective: Stroke is one of the leading causes of death. There has been compelling evidence that stroke has a genetic component. Genetic variants not only influence susceptibility to stroke but have also been found to alter the response to pharmacological agents and influence the clinical outcome of the disease. Stroke patients are treated with antiplatelet drugs like aspirin and clopidogrel to prevent a secondary stroke. In spite of the fact that many new antiplatelet drugs have been developed, aspirin is still considered as a golden standard for the antiplatelet therapy. Aspirin achieves its action by inhibiting platelet cyclooxygenase (COX) system involved in the formation of thromboxane A2 (TXA2). TXA2 triggers reactions leading to platelet activation and aggregation. This Non-steroidal anti-inflammatory drug (NSAID) acts by inhibiting this mediator. Despite the demonstrated benefits of aspirin, many patients develop secondary stroke or other vascular events, an observation that has led to the concept of aspirin resistance. Studies have demonstrated that adequate antiplatelet effects are not achieved in 5-45% patients suggesting that many individuals are aspirin resistant. Aspirin resistance is multifactorial in origin. A genetic component has also been suggested, and variants in more than a dozen genes involved in absorption, distribution, metabolism, excretion (ADME) and pharmacodynamics of aspirin have been shown to be responsible for aspirin resistance. In addition, the patients on aspirin treatment also face adverse drug reactions on account of genetic variation. Conclusion: The present review has been compiled with an aim to revisit all the studies related to genetic variation contributing to aspirin resistance as well as adverse drug reactions. The output of high throughput genomic technology like genome wide association studies and others has also been discussed.

Background and Objective: In this mini-review, we have compiled the most recent and comparable information to shed light on the action of PEGylation in the biodistribution of carbon nanotubes (CNT) in the central nervous system (CNS). It is well known that due to the complexity of the CNS and the severity of the outcome following changes in this system, this is one of the areas where there are more investments in research to develop new technologies and approaches for more effective and less invasive treatments. The CNS is highly protected against toxic and invasive microorganisms thanks to the blood brain barrier (BBB), but this protection also prevents the passage of potentially beneficial molecules for the treatment of neurological disorders. Nanotechnology attempts to develop nanocompounds that are biocompatible and non-immunogenic, and that are able to cross the BBB in therapeutic amounts without causing damage and to diffuse through nerve tissue. These compounds should also be cleared and biodistributed properly, being capable of performing drug delivery exclusively for CNS pathologies, such as neurodegenerative diseases (Parkinson's and Alzheimer's) and brain tumors. Conclusion: In this way, this review focuses on CNT PEGylation, aiming to help in the development of viable and effective nanomedicines for neuroscience applications.

Background & Objective: The 18-kDa translocator protein (TSPO) is located in the outer mitochondrial membrane where it is thought to co-regulate steroidogenesis, cellular bioenergetics as well as several other cellular processes. Originally discovered as a binding site for diazepam outside the CNS, notably in steroidogenic tissue and mononuclear phagocytes, the TSPO's historical designation was peripheral benzodiazepine receptor. Much of the recent interest in TSPO is due to the observation that its regulation in the brain is associated with microglial activation. Importantly, this activation can be visualized in vivo by positron emission tomography (PET) using TSPO ligands. TSPO levels in normal brain tissue are close to current detection limits, being restricted to blood vessels and possibly areas of natural cell turnover. However, any progressive tissue damage is associated with a marked increase in TSPO expression, most prominently in activated microglia. Therefore, the inducible TSPO expression can serve as an exquisitely responsive sensor in a range of active brain pathologies, which are often conflated under the term ‘neuroinflammation’. However, what occurs histologically in ‘neuroinflammation’ is different from classical brain tissue inflammation in the vast majority of cases. The resulting conceptual confusion poses potentially significant risks for patients who receive misguided anti-inflammatory treatment. It also obscures the fact that microglia may have other important roles, notably at synapses. ‘Neuroinflammation’ is at the current level of our understanding primarily the observation of dynamic tissue changes in the brain, the relevance of which for disease progression or brain plasticity phenomena is likely to be context dependent and remains to be worked out in detail. Here, we discuss the potential of TSPO as a therapeutic drug target for CNS disorders. Conclusion: In this review, we focus on psychiatric and neurodegenerative disorders, elaborate the role of TSPO and the effects of TSPO ligands on common disease phenotypes reviewing evidence from both animal models and patient cohorts and discuss future directions. As a modulator of pivotal cell processes, TSPO may serve as a drug target in well defined translational applications.

Background and Objective: Alzheimer's disease (AD) is arguably the largest healthcare issue of our time. AD is thought to be principally the result of an inter-play between the β-amyloid peptide and Tau, and it is driven by several genetic and environmental risk factors. Recent studies have shown that small non-protein-coding microRNA (miRNA) and the associated post-transcriptional gene regulation are important regulators of many neurodegenerative diseases, including AD. We reviewed recent studies identifying various miRNA dysregulated in AD. These miRNAs could play a significant role in the pathophysiology of AD, in both β-amyloid peptide and Tau toxicity. Conclusion: The identification of dysregulated miRNAs pattern can serve as specific AD biomarkers which may provide the basis for new and effective diagnostic approach. In addition, these miRNAs may represent new targets for pharmaceutical development.

Background and Objective: Epilepsy is etiologically and genetically complex neurological disorder affecting millions of people worldwide. Juvenile myoclonic epilepsy (JME) is the most common epilepsy syndrome that starts in the teen age group commonly between ages 12, 18, and lasts till adulthood. One out of fourteen people with epilepsy suffers with JME. Myoclonic seizures and muscle twitching or uncontrolled jerking are the most common type of seizures in the people suffering with JME. Method: To observe the novel CNVs involved in JME, we investigated a Saudi family with nine siblings including one male and one female affected members. In this study we used high density whole genome Agilent sure print G3 Hmn CGH 2x 400K array-CGH chips. Our results showed CNVs including the amplifications and deletions in different chromosomal regions in the patients as compared to the normal members of the family. Amplifications were observed in the chromosome 22 cytoband 22q11.23 with LDL receptor related protein 5 like (LRP5L), Immunoglobulin Lambda-Like Polypeptide 3 (IGLL3) and crystallin beta B2 pseudogene (CRYBB2P) genes respectively whereas the deletions were observed in the chromosomal regions 4q22.2 with Glutamate receptor, ionotropic, delta 2 (GRID2) as potential gene cytoband 1p31.1 with potential Neuronal Growth Regulator 1 gene (NEGR1) gene in this region and NME/NM23 family member (NME7) gene cytoband 1q24. Moreover, the array CGH resulting in deletions and duplication were also validated by using primer for simple PCR or also by using quantitative real time PCR analysis. We found deletions and duplication in JME patients in our study for the first time in Saudi population. Results & Conclusion: The findings in this study suggest that the array-CGH may be considered as a first line of genetic testing for diagnosis of epilepsy unless strong evidence is presented for a monogenic syndrome. The use of high throughput technique in this study will help to identify novel mechanisms underlying epileptic disorder in order to lower the burden of epilepsy in Saudi Arabia.

Introduction: Natalizumab (NAT) is an effective treatment for relapsing remitting multiple sclerosis (RRMS), as it makes the blood-brain-barrier impenetrable by binding to the α4integrin subunit. The objectives of our study were to find new peripheral mechanisms of action of NAT and new biomarkers of treatment response. Material and Methods: We prospectively assessed the serum levels of 15 cytokines from the Th17 Cytokine Panel using Bio-plex Pro Human in a group of 29 RRMS patients treated with NAT and 29 healthy subjects (HS) at inclusion and after 8 months of NAT treatment. For each patient, demographic data, number of relapses and Expanded Disability Status Scale (EDSS) were collected and compared with the initial and final values of each cytokine. Moreover, the Th17/Treg shift was assessed using the interleukine (IL)-17F/IL-10 ratio and the cytokine signature (the sum of all the cytokines). Advanced statistical analysis was used. Results: RRMS patients had significantly lower serum levels of IL-23, IL-17F, IL-1β and IL-31 compared to HS. Serum sCD40L, IL-17F, IL-31 and cytokine signature levels significantly decreased after 8 months of NAT treatment. Positively correlations were found between the relapse number and IL- 17F, IL-1β, IL-31 serum levels and between EDSS and tumor necrotic factor-α, IL-1β and IL-17/IL-10 serum levels. IL-10 serum levels correlated negatively with the EDSS score. Conclusion: In evaluating the mode of action of NAT, it is important to determine the value of each cytokine, the Th17/Treg shift and the cytokine signature. NAT significantly decreased peripheral serum levels of some pro-inflammatory cytokines as a novel mechanism of action. IL-17F, sCD40L and IL-31 were the best biomarkers to assess the effectiveness of NAT.

Background & Objective: Involvement of amyloid beta and tau proteins in pathogenesis of Alzheimer's disease (AD) has been studied extensively. However, electrophysiological activity, and cellular processes like membrane transport are mostly unstudied. Electrophysiological processes provide a bridge between brain activity and cognition, and show promise as translatable biomarkers in preclinical and clinical applications. Biochemical imbalance leads to change in glutamate-based neurotransmission, antioxidant capacity, and in membrane polarization-repolarization events, eventually, resulting in AD. We hypothesize that in AD, these processes are unified at a single metabolic hub and we carried out a holistic system-biology approach. Method: In the present study, we integrated and analyzed multiple AD expression datasets from the GEO database to identify significant genes associated with electrophysiological pathways and attempted determination of interconnected canonical molecular pathways. Partek Genomic suite based expression analysis identified 200 significantly expressed genes using cut-off value of ≤ 0.05 and 2 fold change. Transducer of ERBB2, 2 (TOB2); lactotransferrin (LFT) and RAS-like, family 12 (RASL12) were most up-regulated genes, while neurofilament light polypeptide (NEFL); collagen, type V, alpha 2 (COL5A2); visinin-like 1 (VSNL1); cannabinoid receptor 1 (brain) (CNR1); neurofilament, medium polypeptide (NEFM); regulator of G-protein signaling 4 (RGS4), and synaptosomalassociated protein, 25kDa (SNAP25) were most down-regulated ones. Conclusion: Interestingly, we found majority of transporter genes identified in dataset as downregulated. Ingenuity pathways analysis revealed glutamate receptor signaling, CREB signaling, dopamine- DARPP32 feedback in cAMP signaling, fMLP signaling in neutrophils, and synaptic long term potentiation pathway playing critical role in AD pathophysiology and having correlation with electrophysiological dysfunction.