CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 17, Issue 8, 2018

Background & Objective: Over the last two decades, Alzheimer disease (AD) associated research has accomplished an overwhelming momentum, as it is one of the major current healthcare issues in the developed world. AD is characterized by the presence of Aβ mediated extracellular amyloid fibrils and tau-mediated intracellular neurofibrillar tangles and reports have highlighted their subsequent effects on neuronal synaptic activity, antioxidant response and recently explored mitochondrial dysfunction. Additionally, recent reports have demonstrated the mitochondrial dysfunction and associated physiological as well as cellular alterations triggered by fibrillar structures inside the brain tissue. Accumulated evidence indicated that mitochondrial dysfunction also plays a detrimental role in AD pathogenesis and reduction in mitochondrial dysfunction may provide an additional beneficial effect in AD patients. Currently available drugs are ineffective in disease progression and more symptomatic while mechanism oriented drug explorations have been intensively investigated. Therefore, search for effective therapeutic approaches in Alzheimer disease has directed the ongoing research more towards specific biomarker selection, physicochemical properties of drugs and its subsequent interaction with target molecules. Conclusion: In present review, we have comprised an overview of the therapeutic advancement in Alzheimer disease with a prevalent hypothesis and current ongoing putative therapeutic approaches to provide recent insights in AD pathogenesis.

Background & Objective: Autism is a developmental disorder that manifests itself in early childhood. Autism is characterized by inability to acquire social skills, repetitive behaviors and failure of speech and nonverbal communication development. Recent studies have shown that genetic mutations occur in majority of individuals with autism. These mutations cause a variety of disorders that ultimately lead to brain disorders. It is noteworthy that all mutations do not follow the same pattern. They encompass various kinds of mutations. Autism needs to be treated during childhood as untreated patients usually do not progress to the later stages of development. In this regard, many studies have been performed and numerous treatments have been proposed to improve the outcome of this disease. Conclusion: In this review, we have discussed new advancements made in understanding the pathophysiology of autism. Furthermore, we have also discussed new treatments which have been proposed and have successfully translated affected children. Overall, it is concluded that new advances have largely helped these patients.

Background & Objective: Metabolic syndrome (MetS) is an interconnected group of physiological, biochemical, clinical and metabolic factors that directly increase the risk of cardiovascular disease, type 2 diabetes mellitus (T2DM) and mortality. Rising evidence suggests that MetS plays a significant role in the progression of Alzheimer's disease and other neurodegenerative diseases. Nonetheless, the factors linking this association has not yet been elucidated. As we are facing an increasing incidence of obesity and T2DM in all stages of life, understanding the association of MetS and neurodegenerative diseases is crucial to lessen the burden of the disease. Conclusion: In this review, we will discuss the possible mechanisms which may relate the association between MetS and cognitive decline which include vascular damages, elevation of reactive oxygen species (ROS), insulin resistance and low-grade inflammation.

Background: It was previously shown that inactivation of gamma-synuclein which is a small soluble neuronal protein affects psycho-emotional status and cognitive abilities in knock-out mice. Objective: Determine the role of gamma-synuclein inactivation on memory performance in aging animals. Method: We used the passive avoidance test and acute amphetamine administration in aging gammasynuclein knock-out mice. Results: As a result, we found moderate aging-unlinked deficit of dopaminergic neurotransmitter system of gamma-synuclein knock-out mice. At the same time, the evidence of progressive synaptic vesicle trafficking machinery impairment was obtained. Conclusion: Therefore most likely these dysfunctions are associated with a reduction in the highefficient learning performance in tests that require intact working memory.

Background: Epilepsy and Alzheimer's disease are common neuropathies with a complex pathogenesis. Both of them have some correlations in etiology, pathogenesis, pathological changes, clinical manifestations and treatment. Objective: This study investigated the key genes and molecular genetic mechanism in epilepsy and Alzheimer's disease by bioinformatics analysis. Method: Two gene expression profiles were used to screen differentially expressed genes by GEO2R tool. The Gene Ontology (GO) and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway enrichment analysis was performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID). Then the protein-protein interaction (PPI) network was constructed by Search Tool for the Retrieval of Interacting Genes (STRING) and Cytoscape software which can be used to analyze modules with MCODE. Results: A total of 199 differentially expressed genes (DEGs) in the two groups. According to GO_BP analysis and KEGG pathway enrichment by DAVID, we found DEGs referring to several pathways significantly down-regulated in endocytosis, such as endocytosis, synaptic vesicle cycle, lysosome, cAMP signaling pathway, circadian entrainment, LTP, glutamatergic synapse and GABAergic synapse pathway. The regulator genes of the upstream pathway of circadian rhythms were obviously downgraded. Conclusion: Our research demonstrated that the regulatory genes of the upstream pathway of circadian rhythms were obviously downgraded. These biological pathways and DEGs or hub genes may contribute to revealing the molecular relationship between Alzheimer's disease and epilepsy.

Background & Objective: Major depressive disorder (MDD) has been associated with inflammatory processes, including increased cytokine levels, even in individuals who are otherwise physically healthy, while some MDD patients may show insulin resistance (IR). Method: However, correlations between cytokines and IR parameters have not been studied extensively in MDD. In the present study, we measured IL-1β, IL-4, IFN-γ, TGF-β1, insulin and glucose in 63 MDD patients and 27 healthy controls. The associations between cytokine levels and IR were examined. Results: The results revealed a significant increase (p<0.05) in serum levels of IL-1β, IL-4, IFN-γ, TGF-β1, insulin, insulin/glucose ratio, and insulin resistance (HOMA2IR) in MDD patients as compared with controls. There was a significant correlation between HOMA2IR with both IFN-γ (ρ=0.289, p<0.05) and TGF-β1 (ρ=0.364, p<0.05). Conclusion: The present study further confirms that MDD is accompanied by activation of the immune system with significant elevations in the levels of four cytokines. These results indicate stimulation of the immune system and increased IR and modulation of IR by increased cytokine levels in MDD. These findings show that immune activation and associated IR are a new drug target in depression.

Background: There is evidence that changes in neuro-immune responses coupled with dysfunctions in serotonin metabolism underpin the pathophysiology of autism spectrum disorders (ASD). Objective: This study aimed to delineate whether ASD subgroups or characteristics show aberrations in tryptophan and brain-derived neurotrophic factor (BDNF) metabolism. Methods: 65 individuals with ASD (diagnosed according to ICD criteria) and 30 healthy control patients were included. Measured were serum levels of tryptophan, kynurenine (KYN), kynurenic acid (KA), quinolinic acid (QA), BDNF and PRO-BDNF and total blood 5-HT and 5-OH-tryptophan (5-HTP). Results: Elevated BDNF levels and lower tryptophan and KA levels were characteristics of both childhood autism and intellectual disability disorder, whilst elevated tryptophan and lower 5-HT synthesis were hallmarks of Asperger syndrome. A pathological MRI was associated with elevated tryptophan and lowered KA. Abnormal EEG results and dysmorphology were both associated with an elevated BDNF/ PRO-BDNF ratio. Any brain pathology and gastro-intestinal symptoms were accompanied by lowered KA. Conclusions: Increased BDNF production and changes in the metabolism of tryptophan are associated with many ASD characteristics, showing particularly strong associations with childhood autism and Intellectual and Developmental Disabilities. Peripheral BDNF and tryptophan metabolism appear to take part in the pathophysiology of autism spectrum disorders and their phenotypes.