Central Nervous System Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Central Nervous System Agents) - Volume 18, Issue 1, 2018

Introduction: Neuromyelitis optica (NMO) and Multiple Sclerosis (MS) have been reported in different populations. NMO is more frequent in non-Caucasians, and clinical phenotype differences between populations are likely influenced by genetic susceptibility. In Brazil, it has been reported that NMO patients have a mainly European ancestry background. Like other autoimmune diseases, NMO has a multifactorial origin (i.e., genetics, environmental and infectious factors). Regarding the genetics of NMO, epidemiological findings suggest that a polygenic background has an important role in the development of this type of disease. In this context, various genes have been studied, such as those involved in the synthesis of the T cell beta chain receptor, the VH2-5 gene, myelin basic protein, the CTLA-4 gene, and the interleukin-1 gene. Materials and Methods: We performed a study with the main objective of identifying candidate genes involved in the susceptibility to develop NMO in a Mexican population. Result: We included 35 patients with an NMO diagnosis according to the Wingerchuk 2006 criteria. The mean age of the patients was 43.3 years old (20-67), and 80 percent of the patients were women. The presence of HLA-DRB1*03 and HLA-DRB1*10 alleles were more frequent in NMO patients than in controls (n=198; p=0.03 and 0.005, respectively). Conclusion: There were no differences in the other alleles that have been described in MS subjects, such as HLA-DRB1*04, HLA-DRB1*08 and HLA-DRB1*13. These findings may support the hypothesis that implicated immune-genetics as a key factor in development of this type of disease.

Introduction: Multiple Sclerosis (MS) is a chronic, inflammatory, neurodegenerative demyelinating disease of the central nervous system (CNS). Unfortunately, MS causes important disability in young adults and its prevalence is increasing. While the etiology of MS etiology is not completely understood, it seems to be a multifactorial entity that is influenced by both genetic and epigenetic modifications. Epigenetic mechanisms add or remove different chemical groups for the activation or inhibition of gene expression to block the production of proinflammatory proteins. It is truly important to identify the factors that can trigger epigenetic changes in MS to complement the therapeutic approach, prevent disability and improve patients quality of life. Here, we have conducted a review of external factors that influence in MS and their epigenetic mechanisms. For example, hypomethylation can promote changes in the myelin and subsequent autoimmune reactions. Therapeutic tools can be used, including the histone deacetylase inhibitor Trichostatin A, which ameliorates demyelinating diseases in rodents. However, drugs are not only the therapeutic option: recent studies have also evaluated the therapeutic potential of several bioactive dietary components in neurodegeneration and axonal dysfunction. Numerous food-derived molecules exert important metabolic actions. These molecules include plant polyphenols such as catechins and isoflavones, Ω-3 and Ω-6 polyunsaturated fatty acids, short-chain fatty acids, sulfur-containing compounds such as dally sulfide and other compounds. Antioxidant and anti-inflammatory components in the diet involve transcription factors as well. However, many external factors have shown to influence MS, although no specific epigenetic mechanisms are known. Conclusion: In this review, we gather both established and new evidences about the genetic, epigenetic and environmental factors influencing MS and the dietary components that could modulate MS relapse and progression.

Background: Chronic demyelinating diseases of the central nervous system (CNS) are autoimmune conditions that, although rarely fatal, may lead to severe disability. Among these diseases, Multiple Sclerosis (MS) and neuromyelitis optica (NMO) are particularly important and subject of worldwide research. MS and NMO are chronic types of CNS disease, with recurrent episodes of demyelination. For many years, these two conditions were considered to be only one, but lately it is known that they have different epidemiological, physiopathological and prognostic characteristics. The present study aims at reviewing the specificities of MS and NMO affecting patients before they complete 18 years of age. Methods: Literature review on data about MS and NMO in patients below the age of 18 years. Results: There are no clinical trials for any drug used to treat MS and NMO in children or adolescents. Data are mainly on anedoctal cases, case series and recommendations from experts. At present, there is no evidence-based treatment to be recommended for patients with MS and NMO before the age of 18 years. Conclusion: Despite being a particularly vulnerable population for severe disability in the future, there are no evidence-based guidelines for the treatment of MS and NMO in children and adolescents.

Introduction: This overview is aimed at reevaluating fundamental approaches of current MS therapies with focus being placed on their targeted underlying immune, molecular and cellular mechanisms. Currently used therapies are discussed in regard to their mechanisms of action, clinical accomplishments and unwanted side effects and complications. Special emphasis is given to the current first generation Disease Modifying Therapies (DMT) and their actions at immune mechanisms of disease. Effects of DMT on CD4+Th1 cells and their associated cytokines and signaling pathways are discussed in more detail. Conclusion: Attention is paid to emerging role of a CD4 T cell chemotactic cytokine, IL-16 in regulation of relapsing MS and its model, experimental autoimmune encephalomyelitis (EAE). Immune mechanisms mediated by IL-16 are critically evaluated in the context of mechanisms of DMT and its potential as prospective MS therapy. In relation to clinical assessment of therapy, existing and prospective molecular biomarkers are highlighted and discussed where applicable.

Background: The transport of CNS acting drugs across blood-brain barrier (BBB) is complex and guided by the molecular weight, pH, physicochemical and pathological state of the BBB among others. Methods: In view of this, literatures were assessed for possible conversion of Non-CNS to CNS acting drugs, whose ability to penetrate CNS can be improved using polymers for biomedical applications. Results: The findings have shown that compounds with pyridine, pyrrole, carboxamide, pyridone among others can be converted to CNS acting drugs that can be loaded in specialized carrier polymers for transportation across BBB. Such carriers are polymers, co-polymers, nanopolymers and polymeric miscelles that have amine around and pyridine as their hydrophobic site and carboxylic acid as their hydrophilic site. But balanced hydrophilic/hydrophobic site (amphiphilic) may not increase the transport rate of the carrier molecule. Conclusion: Polymeric nanoparticles and copolymers can be used. Examples of such polymers are poly (lactic-co-glycolic acid), polylactic and poly (propyleneglycol, poly (DI)-lactide, polycaprolactone, and polyethylene glycol (hydrophilic). They are non-soluble, biodegradable, release the entrapped drug as they degrade via passive diffusion from polymeric core. Some of their degradation products can be converted to glycolic acid and lactic acid which are converted to carbon dioxide and water through the Kreb's cycle and finally eliminated via urination, perspiration, defecation and expiration.

Background: Adequate function of the nervous system depends on the balance of glianeuron complex interactions. Astrocytes, in particular, are key elements in this process due to the significant participation of these cells in essential properties of the nervous system such as neuroinflammation, regulation of neurotransmitters, release of gliotransmitters and control of synaptic plasticity, among others. Astrocytes express the receptor for advanced glycation end products (RAGE) which is very important in the recognition of endogenous molecules released in the context of infection, physiological stress or chronic inflammation. RAGE can bind several advanced glycation end products, S100 proteins, HMGB1, amyloid-β and other additional DAMP molecules. The nuclear factorkappa B (NF-ΚB) transcription pathway is the main intracellular signaling pathway activated by the RAGE receptor, inducing an increase in the expression and release of proinflammatory cytokines. Due to its numerous interactions, RAGE is suspected to be involved in various physiological and pathological processes. Conclusion: It is plausible that a prolonged exposure to RAGE ligands or abnormally increased concentrations of some ligands may induce lengthy periods of intracellular proinflammatory activation, which may induce the appearance of reactive astrocytes involved in the development and/or progression of neurodegenerative disorders. Blocking or reducing the duration of activation of RAGE/NF-ΚB signaling in astrocytes may become an important therapeutic alternative for the treatment of neurodegenerative disorders in the future.

Background: A complete neurological exam contributes in establishing spinal cord injury severity and its extent by identifying the damage to the sensory and motor pathways involved in order to address a more case-specific and precise pharmacological therapy. However, assessment of neurologic function in spinal cord injury models is usually reported by using sensory or motor tests independently. Methods: A reliable integral method is needed to precisely evaluate location and severity of the injury at baseline and, in further assessments, to establish the degree of spontaneous recovery. A combination of sensation-based tests and motor-based tests was used to evaluate impaired neurologic function after spinal cord injury and the degree of spontaneous recovery, in different stages, on an in vivo model. Results: Combined neurologic evaluation was useful to establish location and severity of the injury in all animals and also to detect degrees of spontaneous recovery at different stages after the injury. Comparisons of neurological function were assessed in time-days and groups between BBB motor score, latency maintenance of posture, locomotion and latency presentation of grooming before and after the injury. Our results suggest that a combined assessment strategy, including sensory and motor tests, can lead to better evaluation of spinal cord injury severity and location, and documentation of the extent of spontaneous recovery following SCI and identify specific motor and sensory pathway integrity. Conclusion: In conclusion, a combined assessment strategy provides a concise method for evaluating the impact of interventions in experimental models of SCI.

Background and Objective: Bacterial meningitis is a serious disease with high rate of mortality and morbidity in children. Invasion of pathogens causes brain and meningeal inflammation, which leads to the release of biomarkers into cerebrospinal fluid (CSF). Identification of these biomarkers can help the physicians to differentiate between bacterial and aseptic meningitis. In the current study, some of these biomarkers such as Procalcitonin, C reactive protein (CRP), and Ferritin, were compared in cerebrospinal fluid (CSF) of patients with bacterial and aseptic meningitis. Methods: In a prospective cross sectional study in a referral children hospital in Tehran during 2011- 2013, the CSF levels of Procalcitonin, Ferritin, and CRP were measured in 57 children with clinically suspected meningitis. The Mann-Whitney u test and the chi-square test were used to compare two groups, children with bacterial and aseptic meningitis. The cut-offs of biomarker levels for differentiation between the 2 groups were constructed by receiver-operating - characteristic curve (ROC). Results: 57 subjects (30 bacterial and 27 aseptic meningitis), were enrolled in this survey. In comparing the two groups, the CSF levels of Ferritin, CRP, and procalcitonin in bacterial meningitis were significantly higher than in aseptic meningitis (P values=#130;0.001, 0.001, #130;0.001respectively), with sensitivity/ specificity being 92.9% / 68%, 92.9% / 84%, and 96.4% / 80%, respectively. Positive Predictive Values (PPV) were, correspondingly, 96.4%, 92.8%, and 92.8% for procalcitonin, Ferritin, and CRP. Corresponding Negative Predictive Values (NPV) were, respectively equal to 95.4%, 70%, and 88%. Conclusion: CSF of children with bacterial meningitis contains higher levels of inflammatory mediators including Procalcitonin, Ferritin, and CRP, compared to aseptic meningitis The biomarkers provided high sensitivity (especially PCT) and specificity (especially CRP). Using these complementary biomarkers would be useful for early diagnosis of bacterial meningitis and selection of appropriate treatment.

Background: According to the WHO, around 50 million people worldwide are suffering from epilepsy. It is due to the repeated occurring of seizures. These seizures are caused by sudden which may vary from a brief lapse of attention or muscle jerks, to severe and prolonged convulsions. Objectives: The aim of the present work was to synthesize 2-phenyl substituted quinazolinone derivatives and to evaluate them for anticonvulsant and neurotoxic activity. Methods: A series of novel 3-{4-[2-amino-4-(substitutedphenyl)-2H-[1.3] oxazin/thiazin-6-yl} 2- phenyl-3H-quinazolin-4-one derivatives were synthesized and evaluated for their anticonvulsant activity. The structures of the compound have been confirmed by spectral analysis. The molecular docking was performed for all the synthesized compounds to assess their binding mode to Gamma- aminobutyric acid type A (GABAA) receptor in order to rationalize their anticonvulsant activities in a qualitative way. Anticonvulsant activities of compounds were screened by using (Maximal electroshock) MES induced seizures and subcutaneous pentylenetetrazole (scPTZ) induced seizure models in Wistar rats of either sex. None of the compounds demonstrated any sign of neurotoxicity. Result: Compounds 3-{4-[2-amino-4-(4-nitro-phenyl)-2H-[1, 3] oxazin-6-yl} 2-phenyl-3H-quinazolin- 4-one (5a) have shown significant activity against tonic seizure by the MES model and 3-{4-[2-amino- 4-(4-nitro-phenyl)-2H-[1, 3] thiazin-6-yl} 2-phenyl-3H-quinazolin-4-one (5d) against clonic seizure by scPTZ induced seizure model. Conclusion: All the newly synthesized compounds had significant anticonvulsant activity. The same two compounds 5a and 5d showed promising activity, while the other compounds have moderate activity. The proposed work is to effort towards the development and identification of novel molecules as anticonvulsant agents by the synthesis of some novel quinazolinone derivatives with improved biological activity.