CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 18, Issue 3, 2019

Background & Objective: Type 3 diabetes (T3D) is chronic insulin resistant state of brain which shares pathology with sporadic Alzheimer’s disease (sAD). Insulin signaling is a highly conserved pathway in the living systems that orchestrate cell growth, repair, maintenance, energy homeostasis and reproduction. Although insulin is primarily studied as a key molecule in diabetes mellitus, its role has recently been implicated in the development of Alzheimer’s disease (AD). Severe complications in brain of diabetic patients and metabolically compromised status is evident in brain of AD patients. Underlying shared pathology of two disorders draws a trajectory from peripheral insulin resistance to insulin unresponsiveness in the central nervous system (CNS). As insulin has a pivotal role in AD, it is not an overreach to address diabetic condition in AD brain as T3D. Insulin signaling is indispensable to nervous system and it is vital for neuronal growth, repair, and maintenance of chemical milieu at synapses. Downstream mediators of insulin signaling pathway work as a regulatory hub for aggregation and clearance of unfolded proteins like Aβ and tau. Conclusion: In this review, we discuss the regulatory roles of insulin as a pivotal molecule in brain with the understanding of defective insulin signaling as a key pathological mechanism in sAD. This article also highlights ongoing trials of targeting insulin signaling as a therapeutic manifestation to treat diabetic condition in brain.

Background: Currently, a large number of people throughout the world are affected by neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease which appear with a lapse in recall, attention and altered cognitive functions. Learning and memory, the fundamental indices defining cognitive functions, are the complex psychological processes governing acquisition, consolidation, and retrieval of stored information. These processes are synchronized by the coordination of various parts of the brain including hippocampus, striatum and amygdala. Objective: The present review is centered on different behavioral paradigms in rodents interpreting learning and memory both explicitly and implicitly. Furthermore, it is also emphasizing on the interaction of various brain structures during different stages of associative, spatial and non-spatial memory. Methods: We embarked on an objective review of literature relevant to screening methods for evaluation of drug’s influence on a wide range of cognitive functions (learning and memory) as well as the underlying mechanism responsible for modulation of these functions. Results: Our review highlighted the behavioral paradigms based on associative, spatial/nonspatial and working memory. The cited research acknowledged the hippocampal and striatal control on learning and memory. Conclusion: Since the neurodegenerative disorders and dementia have continuously been increasing, a wide range of therapeutic targets have been developed at the cellular and molecular level. This arises the necessity of screening of these targets in different cognitive behavioral paradigms which reflect their memory enhancing potential. The understanding of behavioral models and the involvement of brain structures in cognitive functions highlighted in the present review might be helpful to advance therapeutic interventions.

Background & Objective: Intracerebral hemorrhage (ICH) is the most devastating subtype of stroke, for which there are few effective interventions. Computed tomography is accepted as the gold standard for diagnosis, whereas surgical evacuation is the main treatment for ICH. However, in emergency rooms, time is limited and information regarding a patient’s clinical status or tolerance is typically not available. Many studies over the last decade have investigated the fundamental mechanisms of ICH and especially hematoma, which not only cause physical damage but also release toxins that have detrimental effects. However, there remain many gaps in our understanding of ICH. Compared to ischemic stroke, there is little known about the ICH pathogenesis and treatment options, and few specific biomarkers are available for monitoring disease progression, which include hematoma enlargement and perihematoma edema. Noncoding RNAs (ncRNAs) are involved in various biological processes and are potential biomarkers and therapeutic tools in central nervous system diseases. Recent studies have examined the role of ncRNAs including microRNAs, long noncoding RNAs, and circular RNAs—the three main subgroups associated with stroke—in ICH models. A deeper understanding of the functions of ncRNAs in different biological processes can provide a basis for developing more effective therapeutic strategies to prevent neuronal damage following ICH. In clinical settings, ncRNAs can serve as biomarkers for predicting the degree of injury resulting from ICH. Conclusion: In this review, we discuss the current state of knowledge of the role of ncRNAs in ICH.

Stroke continues to be a major cause of death and disability worldwide. In this respect, the most important mechanisms underlying stroke pathophysiology are inflammatory pathways, oxidative stress, as well as apoptosis. Accordingly, miRNAs are considered as non-coding endogenous RNA molecules interacting with their target mRNAs to inhibit mRNA translation or reduce its transcription. Studies in this domain have similarly shown that miRNAs are strongly associated with coronary artery disease and correspondingly contributed to the brain ischemia molecular processes. To retrieve articles related to the study subject, i.e. the role of miRNAs involved in inflammatory pathways, oxidative stress, and apoptosis in stroke from the databases of Web of Science, PubMed (NLM), Open Access Journals, LISTA (EBSCO), and Google Scholar; keywords including cerebral ischemia, microRNA (miRNA), inflammatory pathway, oxidative stress, along with apoptosis were used. It was consequently inferred that, miRNAs could be employed as potential biomarkers for diagnosis and prognosis, as well as therapeutic goals of cerebral ischemia.

Objectives: The bipolar affective disorder (BAD) pathophysiology is multifactorial and has not been fully clarified. Method: We measured selected mitochondrial parameters in peripheral blood components. The analyses were performed for patients suffering from a manic episode during remission and were compared to those performed for healthy controls. BAD was clinically evaluated using well-established diagnostic scales and questionnaires. Mitochondrial respiration was examined in intact and permeabilized blood platelets using high-resolution respirometry. The citrate synthase (CS) and electron transport system (ETS) complex (complex I, II, and IV) activities were examined in platelets. Results: The CS, complex II and complex IV activities were decreased in the BAD patients, complex I activity was increased, and the ratio of complex I to CS was significantly increased. In the intact platelets, respiration after complex I inhibition and residual oxygen consumption were decreased in the BAD patients compared to the healthy controls. In the permeabilized platelets, a decreased ETS capacity was found in the BAD patients. No significant differences were found between BAD patients in mania and remission. Conclusion: Increased complex I activity can be a compensatory mechanism for decreased CS and complex II and IV activities. We conclude that complex I and its abnormal activity contribute to defects in cellular energy metabolism during a manic episode and that the deficiency in the complex's functioning, but not the availability of oxidative phosphorylation substrates, seems to be responsible for the decreased ETS capacity in BAD patients. The observed parameters can be further evaluated as ‘trait’ markers of BAD.

Background: The cannabinoid system may be involved in the humoral mechanisms at the neuromuscular junction. Ultramicronized-palmitoylethanolamide (μm-PEA) has recently been shown to reduce the desensitization of Acetylcholine (ACh)-evoked currents in denervated patients modifying the stability of ACh receptor (AChR) function. Objective: To analyze the possible beneficial effects of μm-PEA in patients with myasthenia gravis (MG) on muscular fatigue and neurophysiological changes. Method: The duration of this open pilot study, which included an intra-individual control, was three weeks. Each patient was assigned to a 1-week treatment period with μm-PEA 600 mg twice a day. A neurophysiological examination based on repetitive nerve stimulation (RNS) of the masseteric and the axillary nerves was performed, and the quantitative MG (QMG) score was calculated in 22 MG patients every week in a three-week follow-up period. AChR antibody titer was investigated to analyze a possible immunomodulatory effect of PEA in MG patients. Results: PEA had a significant effect on the QMG score (p=0.03418) and on RNS of the masseteric nerve (p=0.01763), thus indicating that PEA reduces the level of disability and decremental muscle response. Antibody titers did not change significantly after treatment. Conclusion: According to our observations, μm-PEA as an add-on therapy could improve muscular response to fatigue in MG. The possible modulation of AChR currents as a means of eliciting a direct effect from PEA on the conformation of ACh receptors should be investigated. The co-role of cytokines also warrants an analysis. Given the rapidity and reversibility of the response, we suppose that PEA acts directly on AChR, though further studies are needed to confirm this hypothesis.

Objective and Method: To investigate trends in the scientific evolution of the journal CNS & Neurological Disorders - Drug Targets in the neuroscience scope, we compared the contribution of publications between this journal and others from different geographical regions of the world. To track research output we conducted a bibliometric analysis of neuroscience research based on the SCimago Journal and Country Rank® from 2003 to 2017. Journal rankings were verified according to the following inclusion criteria: journals publishing the neuroscience scope and sub-areas; geographical location and journal trajectory. Additionally, the total number of original, peer-reviewed and conference articles was analyzed using bibliometric tools. Results: Results showed that Europe, North America and the Middle East have been the greatest contributors of neuroscience publications. Nevertheless, there is a huge discrepancy in the number of journals per region. Until 2017, Europe was on top with 85 journals in the neuroscience field. Moreover, research on neuroscience displayed a swift expanding trend, with significant growth in recent years. Conclusion: In spite of CNS & Neurological Disorders - Drug Targets being a recent journal, it is an international journal emphasizing quality and innovations, and it is a hallmark on the scientific production in neuroscience. Research articles on the scope of the potential role of endocannabinoid systems in central appetite control and in obesity management and the potential of minocycline use in schizophrenia are paramount examples of innovation. Final results will help scientific researchers to know the current interests in neuroscience and provide useful information for further investigation and publication strategies.

Background & Objective: NSCs therapy is considered one of the most potential methods for spinal cord injury (SCI). Methods: We build the SCI model rats to investigate the therapeutic effect of fire needle acupuncture in improving the locomotor function of SCI rats and its possible mechanism. BBB scale was used for the motor ability of rats. The expression of Nestin, NSE, Gal-C, and GFAP was detected by immunohistochemistry. Wnt, GSK3β, β-catenin, ERK1/2, CyclinD1, and ngn1 were detected by western blot and PCR. The BBB score of both model group (1.20±0.94, 3.12±0.67, 5.34±1.57, 7.12±1.49) and fire needle group (1.70±0.58, 4.50±1.63, 7.53±2.41, 9.24±0.63) gradually increased after SCI. Furthermore, at d10 and d14, the fire needle group showed a significantly high score compared with that in model group at the same time (P<0.05). Fire needle increased Nestin, NSE, and Gal-C expression inhibited GFAP expression after SCI. Also, fire needle could up-regulate Wnt3a, GSK3β, β-catenin, and ngn1, and down-regulate ERK1/2, cyclinD1 gene and protein expression. Conclusion: In conclusion, fire needle could improve lower limb locomotor function of SCI rats. Also, fire needles could promote endogenous NSCs proliferation differentiating into neurons, and the mechanism might be mediated by promoting the activation of Wnt/β-catenin and inhibiting the overexpression of ERK.