CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 18, Issue 1, 2019

Alzheimer's disease is the most common form of dementia. It is characterized by betaamyloid peptide fibrils which are extracellular deposition of a specific protein, accompanied by extensive neuroinflammation. Various studies show the presence of a number of inflammation markers in the AD brain: elevated inflammatory cytokines and chemokines, and an accumulation of activated microglia in the damaged regions. NF-ΚB is a family of redox sensitive transcriptional factors, and it is known that NF-ΚB has binding sites in the promoter region of the genes involved in amyloidogenesis and inflammation. Long-term use of non-steroidal anti-inflammatory drugs prevents progression of AD and delays its onset, suggesting that there is a close correlation between NF-ΚB and AD pathogenesis. This study aims to (1) assess the association between NF-ΚB activity and AD through discussion of a variety of experimental and clinical studies on AD and (2) review treatment strategies designed to treat or prevent AD with NF-ΚB inhibitors.

Background & Objective: Imbalance in histone acetylation levels and consequently the dysfunction in transcription are associated with a wide variety of neurodegenerative diseases. Histone proteins acetylation and deacetylation is carried out by two opposite acting enzymes, histone acetyltransferases and histone deacetylases (HDACs), respectively. In-vitro and in-vivo animal models of neurodegenerative diseases and post mortem brains of patients have been reported overexpressed level of HDACs. In recent past numerous studies have indicated that HDAC inhibitors (HDACIs) might be a promising class of therapeutic agents for treating these devastating diseases. HDACs being a part of repressive complexes, the outcome of their inhibition has been attributed to enhanced gene expression due to heightened histone acetylation. Beneficial effects of HDACIs has been explored both in preclinical and clinical studies of these diseases. Thus, their screening as future therapeutics for neurodegenerative diseases has been widely explored. Conclusion: In this review, we focus on the putative role of HDACs in neurodegeneration and further discuss their potential as a new therapeutic avenue for treating neurodegenerative diseases.

Background: Bipolar Disorder (BD) is a psychiatric disorder characterized by mood disturbances. The pathophysiology of BD is still poorly understood. In the last years, research studies focused on the role of inflammation in BD. Objective: Performed a systematic review and meta-analysis to evaluate the potential effect of the cyclo- oxygenases (Cox)-2 inhibitor Celecoxib adjunct treatment in BD through randomized controlled trials (RCT). Methods: A search on the electronic databases was proceeded, on MEDLINE, EMBASE, Scopus, Cochrane Central Register of Controlled Trials (CENTRAL), Biomed Central, Web of Science, IBECS, LILACS, PsycINFO, Congress Abstracts, and Grey literature (Google Scholar and the British Library) for studies published from January 1990 to February 2018. A search strategy was developed using the terms: “Bipolar disorder” or “Bipolar mania” or “Bipolar depression” or “Bipolar mixed” or “Bipolar euthymic” and “Celecoxib” or “Cyclooxygenase-2 inhibitors” or “Cox-2 inhibitors” as text words and Medical Subject Headings (i.e., MeSH and EMTREE) and searched. The therapeutic effects of adjunctive treatment with Celecoxib were analyzed. The meta-analysis was performed including the results of the Young Mania Rating Scale (YMRS) at the end of RCT. Results: Three primary studies were included in the systematic review, with a total of 121 patients. The meta-analysis showed a significant effect on the YMRS scores from patients with BD who used Celecoxib adjuvant treatment in comparison to placebo. Conclusion: The systematic review suggests that adjuvant treatment with Celecoxib improves the response of major treatments in patients with BD when compared with adjuvant placebo treatment. Systematic Review Registration Number: The review protocol was registered at PROSPERO (registration number: CRD42017067635); in June 06 2017.

Background: It has been described that doxazosin, an antihypertensive drug, also promotes glioblastoma cells death by inhibiting cell proliferation, arresting cell cycle and inducing apoptosis. Doxazosin has also demonstrated several modulator effects on renin-angiotensin system (RAS)- regulating aminopeptidase activities, which are highly involved in tumor growth in experimental glioma. Therefore, it remains to elucidate if the anti-tumoral effects of doxazosin could also be mediated by the proteolytic regulatory components of the RAS. Objective: To analyze the effects of doxazosin on cell growth and on RAS-regulating proteolytic regulatory aspartyl aminopeptidase (ASAP), aminopeptidase A (APA), aminopeptidase N (APN), aminopeptidase B (APB) and insulin-regulated aminopeptidase (IRAP) specific activities in the human neuroblastoma NB69 and astroglioma U373-MG tumoral cell lines. Methods: Human neuroblastoma NB69 and astroglioma U373-MG cell lines were treated with doxazosin 50-500 μM for 24h or 48h. The effects on cell growth and on RAS-regulating aminopeptidase specific activities were analyzed. Results: Doxazosin treatments promote a concentration-dependent inhibition on cell growth in both NB69 and U373-MG cells, being NB69 cells more sensitive to the drug than U373-MG cells. However, its effects on RAS-regulating aminopeptidase specific activities depend on the concentration used, the duration of the treatment and the cell type. These data confirm the existence of a different dynamic progression of RAS cascade in each tumoral cell line as a consequence of the treatment with doxazosin and time of action, which also implies a very dynamic metabolism of the peptides which participate in each step of RAS cascade. Conclusion: Our results indicate that doxazosin modifies the proteolytic regulatory enzymes of RAS cascade, modulating the bioactive efficacy of the different angiotensin peptides, and therefore, of their functional roles as initiators/promoters of cell proliferation as autocrine/paracrine mediators.

Objective: Botulinum toxin has many applications in the treatment of central diseases, as biological macromolecules, it is difficult to pass through the blood-brain barrier which greatly limits their application. In this paper, we verified whether the botulinum toxin heavy chain HCS has a specific neural guidance function. Methods: We have constructed a fusion protein with botulinum toxin heavy chain and a membrane penetrating peptide TAT (TAT-EGFP-HCS). Recombinant plasmid of botulinum toxin light chain (LC) and TAT were also constructed. The biological activity of HCS, LC, TAT-EGFP-HCS and TAT-EGFP-LC were measured by its ability to cleave protein SNAP-25. The intracellular expression efficiency was evaluated by detecting the fluorescence intensity of EGFP in the cells by fluorescence microscopy and FACS. In addition, we also determined the effect of the above plasmid expression on the apoptosis of PC12 cells. Finally, the tissue specificity of TAT-EGFP-HCS in vivo experiments was also examined. Results: In the present study, we have constructed a fusion protein with botulinum toxin heavy chain and a membrane penetrating peptide TAT which can lead the entire molecule through the blood-brain barrier and reach the central nervous system. Moreover, we also examined the biological activities of this recombinant biological macromolecule and its physiological effects on nerve cells in vitro and in vivo. Conclusion: TAT-EGFP-HSC expressed in vitro has neural guidance function and can carry large proteins across the cell membrane without influencing the biological activity.

Background: Alzheimer's disease (AD) is a neurodegenerative disease characterized by the progressive and incapacitating decay of cognitive, neuropsychiatric, and behavioral manifestations. L-tryptophan is the precursor amino acid of serotonin, which is a neurotransmitter responsible for mood balance and the sense of well-being and can be administered in the form of nanoparticles. Objective: This study analyzed the effectiveness of L-tryptophan nanoparticles and L-tryptophan on behavioral physiological alterations resulting from AD in animal models. Methods: The sample consisted of 50 Rattus norvegicus rats, divided in 10 groups with 5 animals each: one negative control (NC), three positive control groups (C3, C7, and C21), three groups treated with L-tryptophan nanoparticles (T3N, T7N, and T21N) at the concentration of 1.5 mg, and three groups treated with L-tryptophan (T3L, T7L, and T21L) at the concentration of 1.5 mg. The rats underwent stereotactic surgery to induce AD through the injection of amyloid beta-amyloid peptide1-42 in the intracerebroventricular region. All rats were submitted to pre- and post-surgery and post-treatment motor behavior evaluation through the Later Water Maze (LWM) and elevated cross-labyrinth (ECL). Histological analysis was performed to verify the presence of senile plaques, and the statistical analysis used the unpaired T-test. Results: Significant intergroup differences were observed in some of the evaluated parameters between treated and untreated groups. Conclusion: It was concluded that the treatment with L-tryptophan nanoparticles was beneficial to improve behavioral reactions in the Alzheimer's model.

Background: The chronic phase of Spinal Cord (SC) injury is characterized by the presence of a hostile microenvironment that causes low activity and a progressive decline in neurological function; this phase is non-compatible with regeneration. Several treatment strategies have been investigated in chronic SC injury with no satisfactory results. OBJECTIVE- In this proof-of-concept study, we designed a combination therapy (Comb Tx) consisting of surgical glial scar removal plus scar inhibition, accompanied with implantation of mesenchymal stem cells (MSC), and immunization with neural-derived peptides (INDP). Methods: This study was divided into three subsets, all in which Sprague Dawley rats were subjected to a complete SC transection. Sixty days after injury, animals were randomly allocated into two groups for therapeutic intervention: control group and animals receiving the Comb-Tx. Sixty-three days after treatment we carried out experiments analyzing motor recovery, presence of somatosensory evoked potentials, neural regeneration-related genes, and histological evaluation of serotoninergic fibers. Results: Comb-Tx induced a significant locomotor and electrophysiological recovery. An increase in the expression of regeneration-associated genes and the percentage of 5-HT+ fibers was noted at the caudal stump of the SC of animals receiving the Comb-Tx. There was a significant correlation of locomotor recovery with positive electrophysiological activity, expression of GAP43, and percentage of 5-HT+ fibers. Conclusion: Comb-Tx promotes motor and electrophysiological recovery in the chronic phase of SC injury subsequent to a complete transection. Likewise, it is capable of inducing the permissive microenvironment to promote axonal regeneration.

Background: Impulsivity is a complex multi-dimensional combination of behaviors which include: ineffective impulse control, premature decision-making and inability to delay gratification. Objective: The aim of this work was to explore how food odor perception and its emotional value is affected in impulsive children. Methods: Here we compared two cohorts of impulsive and control children with ages between 10 and 16 years. Both groups underwent a functional magnetic resonance imaging experiment, in which foodrelated odor-cues were presented to all of them. Results: Differences in regions of blood oxygen level dependent activation, as well as connectivity, were calculated. Activations were significant for all odors in the impulsive group in the temporal lobe, cerebellum, supplementary motor area, frontal cortex, medial cingulate cortex, insula, precuneus, precentral, para-hippocampal and calcarine cortices. Conclusion: Connectivity results showed that the expected emotional reward, based on odor perceived and processed in temporal lobes, was the main cue driving responses of impulsive children. This was followed by self-consciousness, the sensation of interaction with the surroundings and feelings of comfort and happiness, modulated by the precuneus together with somatosensory cortex and cingulum. Furthermore, reduced connectivity to frontal areas as well as to other sensory integration areas (piriform cortex), combined to show different sensory processing strategies for olfactory emotional cues in impulsive children. Finally, we hypothesize that the cerebellum plays a pivotal role in modulating decision-making for impulsive children.

Background and Objective: Exosomes communicate inter-cellularly and miRNAs play critical roles in this scenario. MiR-214-5p was implicated in multiple tumors with diverse functions uncovered. However, whether miR-214-5p is mechanistically involved in glioblastoma, especially via exosomal pathway, is still elusive. Here we sought to comprehensively address the critical role of exosomal miR-214-5p in glioblastoma (GBM) microenvironment. Methods: The relative expression of miR-214-5p was determined by real-time PCR. Cell viability and migration were measured by MTT and transwell chamber assays, respectively. The secretory cytokines were measured with ELISA kits. The regulatory effect of miR-214-5p on CXCR5 expression was interrogated by luciferase reporter assay. Protein level was analyzed by Western blot. Results: We demonstrated that miR-214-5p was aberrantly overexpressed in GBM and associated with poorer clinical prognosis. High level of miR-214-5p significantly contributed to cell proliferation and migration. GBM-derived exosomal miR-214-5p promoted inflammatory response in primary microglia upon lipopolysaccharide challenge. We further identified CXCR5 as the direct target of miR-214- 5p in this setting. Conclusion: Overexpression of miR-214-5p in GBM modulated the inflammatory response in microglia via exosomal transfer.