CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 20, Issue 1, 2021

The underlying mechanism of cerebral injury occurring in patients with acute ischemic stroke involves a key pathophysiological role of oxidative stress. Thus, reactive oxygen species are related to the development of brain edema, calcium overload, mitochondrial dysfunction, excitotoxicity, iron release and inflammation. Nevertheless, although experimental studies have tested the use of antioxidants as an adjuvant therapy in this setting, clinical data and randomized trials are still lacking. Current approved pharmacological therapy is aimed at reperfusion strategies; however, the therapeutic window is limited and also challenged by the injury known to result from the reperfusion. We have recently defined a time-course occurrence of pathological events triggered by reperfusion-dependent increased reactive oxygen species, thus suggesting the beneficial role of the pertinent use of antioxidants. The present study was aimed to support the hypothesis that an enhanced antioxidant neuroprotection could be achieved by the use of two or more antioxidants opportunely provided to ischemic stroke patients focused against the specific mechanism occurring throughout the pathophysiological process. From this paradigm, using an underexplored therapeutic principle, it could be suggested that antioxidant-based therapy is a novel, promising, safe, available and cost-effective strategy against the deleterious effects of ischemic stroke that needs to be further studied in clinical protocols.

Brain-Derived Neurotrophic Factor (BDNF) serves as a modulator for neurotransmitters by participating in neuronal plasticity, essential for their growth and neuronal survival. It also shows a wide range of expression patterns in the systemic and peripheral tissues; thereby, its biological actions are not just limited to the CNS but may a vital role in peripheral disorders, such as Diabetes Mellitus (DM). Platelets serve as one of the major sources of BDNF, which regulates energy homeostasis and glucose metabolism by participating in the expression of specific pro-survival genes. It also prevents β cell exhaustion, thus may prove to be a key factor for the management of DM. The current article reviews the intricate role of BDNF in Type 2 DM (T2DM) by involving platelet reactivity and its association with these selected inflammatory platelet activator mediators. Besides, certain adipocytokines, such as adiponectin and leptin, are also involved in the metabolism of glucose during diabetes, which has been clearly proven by recent experimental studies and thus relating BDNF with adipocytokines. It is also involved in the modulation of secretion of various neurotransmitters, peptides and hormones like gherin, leptin and insulin, suggesting its association with T2DM. Thus, based on various evidence, BDNF can be categorised as a potential biomarker in predicting the development of T2DM and may have a distinctive role in the management of this disorder.

Neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington disease have serious concern due to its effect on the quality of life of affected persons. They have some limitations at diagnostic as well as the treatment level. Introducing nanotechnology, for the treatment of these diseases may contribute significantly to solve the problem. There are several treatment strategies for the neurodegenerative diseases, but most of them fail to cross the Blood-Brain Barrier (BBB). The present review highlights the application of nanotechnology during last the 20 years for the treatment of neurodegenerative diseases.

Neurodegenerative diseases, including Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Amyotrophic Lateral Sclerosis (ALS) and Huntington's Disease (HD), are characterized by progressive neuronal dysfunction and death. Recent studies have established detrimental modifications in the structure and function of brain proteins, which stimulate their aggregation, misfolding and deposition in and around the neurons an important hallmark of neurodegenerative diseases. Post-Translational Modification (PTM) of proteins, including phosphorylation, acetylation, glycosylation, palmitoylation, SUMOylation, and ubiquitination, are important regulators of protein characteristics, including stability, intracellular distribution, activity, interactions, aggregation and clearance. Despite clear evidence that altered protein modifications emerging from impromptu chemical modifications to side chains of amino acid are associated with neurodegeneration, the underlying mechanisms that promote aberrant PTM remain poorly understood. Therefore, elucidating PTM of specific disease-associated proteins can prove to be a significant step in evaluating the functional alteration of proteins and their association with neurodegeneration. This review describes how aberrant PTM of various proteins is linked with the neurodegenerative disease pathogenesis, as well as molecular strategies targeting these modifications for treating such diseases, which are yet incurable.

Background & Objective: Autism Spectrum Disorders (ASD) is known as a neurodevelopmental disorder showing communication impairments and unusual patterns of behavior. Presently, it seems that ASD frequency is on the increase. Therefore, diagnostic tools that help detect the disease in the early stages can be very useful in better management of the disease. Recent studies demonstrate that miRNAs as novel biomarkers can be used to find out the process and etiology of ASD by regulating various genes of multiple pathways. However, ASD associated pathway targeted by miRNA is still in infancy. Methods: In this in silico study taking into consideration the importance of miRNAs, we reviewed bioinformatics databases for finding possible pathways and potential miRNAs related to selected pathways. Results: The results displayed some prominent pathways involved in ASD, as well as some experimental and predicted miRNAs that may regulate targets associated with these pathways such as neuroactive ligand-receptor interaction, serotonergic synapse, calcium signaling pathway, cAMP Signaling Pathway, PI3K-Akt signaling pathway. Conclusion: This study showed that the identified miRNAs may be involved in ASD-related pathways and may be considered as a new diagnostic tool and provide potential targets for the treatment of ASD.

Background: Atorvastatin is a member of statins, which has shown positive vascular effects, anti-oxidant, anti-platelet, and anti-apoptotic properties. Objective: In this study, we hypothesized that atorvastatin could prevent the neurons lost in the hippocampal dentate gyrus region after transient global Ischemia/Reperfusion (I/R) through its anti- oxidant and anti-apoptotic activities. Method: Twenty-four male Wistar rats, 12-13 weeks old and weighing 250–300 g, were divided randomly into four groups: control, I/R, vehicle (I/R treated with NaCl) and experiment (I/R treated with atorvastatin, 10 mg/kg); rats were sacrificed 96 hours after I/R. Quantitative expression of genes (caspase 8, p53, bax, bcl2, cytochrome c) was studied. The MDA level, SOD, CAT, and GPx activities were measured with biochemical tests. To detect apoptotic cells, TUNEL and Nissl staining were performed. Mitochondria were prepared from the hippocampus rats and used for the quantification of mitochondrial ROS, ATP level, GSH content, membrane potential, cytochrome c release, and determination of mitochondrial swelling. Results: Atorvastatin attenuated the overexpression of bax, cytochrome C, p53, and caspase8 mRNAs and induced expression of bcl-2 mRNA (P<0.001). Atorvastatin treatment increased anti-oxidant enzyme levels (P<0.01). Treatment with atorvastatin reduced the number of TUNEL-positive cells. It could decrease the cytochrome c release (P<0.01), inhibit the decrease of MMP (P<0.001) and increase the ATP level (P<0.001) in hippocampal mitochondria compared with the I/R group. Conclusion: Atorvastatin treatment in I/R rats decreases oxidative stress, production of ROS, apoptosis rate in neuronal cells, and improves the mitochondrial function. Hence, atorvastatin has a proper neuronal protective effect against the I/R injury in the brain.

Background: Lacosamide is characterized by its novel dual mode of action on account of its structural components; its molecule contains a functional amino acid that selectively and slowly promotes the inactivation of voltage-gated sodium channels. Objective: This study aims to assess the effectiveness and tolerability of Lacosamide with respect to its use in the treatment of focal epileptic patients. Methods: This retrospective cohort study used data collected from the clinical notes or diaries of all epileptic patients who were treated in King Abdullah Medical City during the time period from 2014 to 2019. The multivariate Generalized Estimating Equation (GEE) repeated measure logistic regression analysis was used to assess the odds of having an improvised seizure rate. Results: Majority of the focal epileptic patients (57.9%) were diagnosed with temporal epilepsy, while 26.3% patients had frontal epileptic lesion/diagnoses. Majority of the patients (54.4%) had received a combination of old and new treatment. Out of the seven patients who reported side effects, 57.14% experienced dizziness and headache, tremors (n = 1), loss of balance (n = 1) and increased seizure with abnormal vision acuity and psychosis (n = 1). 84.2% patients experienced reduced median seizure frequency in 12-month period. However, on the basis of clinical characteristics, no significant difference was observed in the seizure control rate. No statistically significant differences were observed between male and female patients with respect to their average improvement rate across the four time points. Conclusion: Lacosamide is an effective and well tolerable drug for patients with focal epilepsy.