CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 17, Issue 9, 2018

Background & Objective: Diabetes and neurodegenerative diseases (ND) are progressive morbidities and represent a major public health burden. A growing body of evidence points towards the comorbidity of diabetes and NDs with a possible exacerbation of latter by former. Considering the high prevalence of both morbidities in aging world population, even a modest impact of diabetes on NDs could lead to significant public health implications. Several hypotheses and mechanistic evidence were proposed linking altered glucose metabolism to the risk of progressive dementia. Unregulated production of reactive oxygen species (ROS) and resultant oxidative stress (OS) are the common features of diabetes as well as NDs. Conclusion: This review explores the concept of altered glucose metabolic pathways leading to ROS increase and its possible link to NDs, with a special emphasis on Alzheimer's diseases (AD). We also discuss the detailed mechanistic link between hyperglycemia, ROS generation, and neurodegeneration to highlight potential therapeutic avenues for better prevention and treatment.

Background & Objective: Hydrogen sulfide [H2S] has been widely known as a toxic gas for more than 300 years in the scientific community. However, the understanding about this small molecule has changed after the discovery of involvement of H2S in physiological and pathological mechanisms in brain. H2S is a third gasotransmitter and neuromodulator after carbon monoxide [CO] and nitric oxide [NO]. H2S plays an important role in memory and cognition by regulating long-term potentiation [LTP] and calcium homeostasis in neuronal cells. The disturbances in endogenous H2S levels and trans-sulfuration pathway have been implicated in neurodegenerative disorders like Alzheimer's disease, Parkinson disease, stroke and traumatic brain injury. According to the results obtained from various studies, H2S not only behaves as neuromodulator but also is a potent antioxidant, anti-inflammatory and anti-apoptotic molecule suggesting its neuroprotective potential. Conclusion: Recently, there is an increased interest in developing H2S releasing pharmaceuticals to target various neurological disorders. This review covers the information about the involvement of H2S in neurodegenerative diseases, its molecular targets and its role as potential therapeutic molecule.

Background & Objective: Protein misfolding and aggregation have been considered the common pathological hallmarks for a number of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). These abnormal proteins aggregates damage mitochondria and induce oxidative stress, resulting in neuronal cell death. Prolonged neuronal damage activates microglia and astrocytes, development of inflammation reaction and further promotes neurodegeneration. Thus, elimination of abnormal protein aggregates without eliciting any adverse effects are the main treatment strategies. To overcome this, recent studies have deployed single- chain fragment variable antibodies (scFvs) to target the pathological protein aggregates, such as amyloid-beta (Aβ) peptides, α-synuclein (α-syn) and Huntingtin (Htt). To date scFv has been effective at inhibiting abnormal protein aggregates formation in both in vitro and in vivo model system of AD, PD and HD. Conclusion: Currently active research is still ongoing to improve the scFv gene delivery technology, to further enhance brain penetration, intracellular stability, solubility and efficacy of scFv intrabody.

Background and Objective: A steep rise in the incidences of neurodegenerative disorders could be the combined effect of several non-genetic factors such as increased life expectancy, environmental pollutants, lifestyle, and dietary habits, as population-level genetic change require multiple generations. Emerging evidence suggests that chronic over-nutrition induces brain metabolic stress and neuroinflammation, and are individually known to promote neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). Although the association of metabolic disorders such as diabetes, hypertension, dyslipidemia, and atherosclerosis with the dietary habits is well known, neuronal implications of diet and nutritional factors is still in its infancy. Transcriptomics and proteomics-based studies support the view that nutraceuticals target multiple neuroprotective pathways in a slow but effective manner without causing severe adverse effects, and may represent the future of tackling neurodegenerative disorders. Conclusion: In this article we i) review the diet/dietary supplement connection with brain metabolic stress and neuroinflammation and ii) summarize current knowledge of the effects of nutraceuticals on neurodegenerative disorders.

Background & Objective: Traumatic Brain Injury (TBI) is one of the major causes of mortality and morbidity worldwide. It represents mild, moderate and severe effects of physical assault to brain which may cause sequential, primary or secondary ramifications. Primary injury can be due to the first physical hit, blow or jolt to one of the brain compartments. The primary injury is then followed by secondary injury which leads to biochemical, cellular, and physiological changes like blood brain barrier disruption, inflammation, excitotoxicity, necrosis, apoptosis, mitochondrial dysfunction and generation of oxidative stress. Apart from this, there is also an immediate increase in glutamate at the synapses following severe TBI. Excessive glutamate at synapses in turn activates corresponding NMDA and AMPA receptors that facilitate excessive calcium influx into the neuronal cells. This leads to the generation of oxidative stress which further leads to mitochondrial dysfunction, lipid peroxidation and oxidation of proteins and DNA. As a consequence, neuronal cell death takes place and ultimately people start facing some serious disabilies. Conclusion: In the present review we provide extensive overview of the role of reactive oxygen species (ROS)-induced oxidative stress and its fatal effects on brain after TBI.

Background & Objective: Cellular physiology and energy metabolism are maintained by the constant supply of energy furnished by the powerhouses of the cell called mitochondria. Cellular homeostasis depends on the timely clearance of damaged cellular organelles and proteins via pathways including autophagy. Mitochondria and mitochondrial autophagy play a vital role in cellular health and failure of these pathways can have a devastating effect on cellular homeostasis. Amongst the various cell types, neuronal cells are more vulnerable to bioenergetic depletion since most of their functions critically depend on the availability of energy derived from mitochondrial metabolism, thus making neurodegenerative disorders an obstinate issue. Research in the past few decades has shown that these neurodegenerative disorders are associated with mitochondrial dysfunction and compromised mitophagy leading to accumulation of protein aggregates which ultimately culminate in neurodegeneration. Conclusion: Thus, targeting mitochondria and autophagy-related proteins and enzymes in neurodegenerative disorders may open the avenues for potential targets for discovering effective therapies. Here, we review the involvement of mitochondrial and autophagy dysfunction in neurodegenerative disorders specifically focusing on Alzheimer's, Parkinson's and Huntington’s disease.

Background: Depression is a mental disorder that affects a large part of the world's population. DHEA is a hormone that has long been attributed to the ability to improve depressive symptoms. However, few studies were conducted with depression individuals not resulting from other medical conditions. Objective: To investigate whether DHEA is more effective than placebo in the treatment of depressive symptoms in subjects with depression not resulting from other psychiatric or medical comorbidities. Methods: An electronic search was carried out using the keywords Dehydroepiandrosterone (Mesh) AND Depression (Mesh) in the following databases: Medical Literature databases Analysis and Retrieval System Online (Medline), Excerpta Medical Database (EMBASE), Latin American and Caribbean Health Sciences (LILACS) and the Cochrane Library through their website for relevant publications until June 2018. Only randomized clinical trials were included. The critical appraisal of the articles was performed using the Risk of Bias Tool from Cochrane Collaboration. Results: The meta-analysis applied in this review pointed to a significant effect in favor of treatment with DHEA compared to placebo. Conclusion: DHEA may be one more effective alternative between the drugs used in the treatment of depression.

Background: Aging is a complex process accompanied with the decline of the different physiological functions. Numerous differentially expressed genes (DEGs) have been found in the aging brain of senescence-accelerated mouse P8 (SAMP8), however, it was challenging to screen out the crucial ones. Objective: This study aimed to explore the crucial genes and pathways in aging brain of SAMP8 mice, which would be beneficial for understanding the pathogenesis of brain aging. Methods: Firstly, 430 genes that are differentially expressed in SAMP8 mice versus SAMR1 mice were obtained from 9 gene expression studies, and gene-gene network was constructed. Clustering analysis and topological analysis were used to single out the hub genes from this network. Secondly, pathway enrichment analysis was utilized to identify the key pathways from the 430 DEGs, and the DEGs in key pathways were considered as functional genes. Thirdly, the inner-network between hub genes and functional genes was constructed, and the key genes were predicted. Parts of the key genes were experimentally verified by quantitative real-time PCR (qRT-PCR), and the associated transcription factors (TFs) were predicted. Results: Our results revealed that 12 crucial genes might affect brain aging, including Trp53, Bcl2, Tnf, Casp9, Fos, Il6, Ptgs2, Il1b, Bdnf, Cdkn1a, Pik3c3, Rps6ka1, among which Casp9, Fos, Ptgs2, Cdkn1a, Pik3c3, and Rps6ka1 had been verified by qRT-PCR in 10-moth-old SAMP8 mice. Five functional groups including mitogen-activated protein kinase (MAPK) signaling pathway, neurotrophin signaling pathway, Hepatitis B, Alzheimer's disease and Oxytocin signaling pathway were significantly changed during aging process in SAMP8 mice. Two key transcription factors of c-Fos and C/EBPbeta were predicted by constructing a TF-target gene network. Conclusion: These putative genes and pathways are closely related to brain senescence and our results would gain new insight into the pathogenesis of brain aging.