CNS & Neurological Disorders - Drug Targets - Volume 18, Issue 5, 2019

Luteolin is a naturally occurring, yellow crystalline flavonoid found in numerous dietary supplements we frequently have in our meals. Studies in the last 2 decades have revealed its therapeutic potential to reduce the Alzheimer’s disease (AD) symptoms in various in vitro and in vivo models. The anti-Alzheimer’s potential of luteolin is attributed to its ability to suppress Aβ as well as tau aggregation or promote their disaggregation, down-regulate the expression of COX-2, NOS, MMP-9, TNF-α, interleukins and chemokines, reduce oxidative stress by scavenging ROS, modulate the activities of transcription factors CREB, cJun, Nrf-1, NF-ΚB, p38, p53, AP-1 and β-catenine and inhibiting the activities of various protein kinases. In several systems, luteolin has been described as a potent antioxidant and anti-inflammatory agent. In addition, we have also discussed about the bio-availability of the luteolin in the plasma. After being metabolized luteolin persists in plasma as glucuronides and sulphate-conjugates. Human clinical trials indicated no dose limiting toxicity when administered at a dose of 100 mg/day. Improvements in the formulations and drug delivery systems may further enhance the bioavailability and potency of luteolin. The current review describes in detail the data supporting these studies.

Background & Objective: Amyotrophic lateral sclerosis is a progressive neurodegenerative disease that specifically affects motor neurons in the brain and in the spinal cord. Patients with amyotrophic lateral sclerosis usually die from respiratory failure within 3 to 5 years from when the symptoms first appear. Currently, there is no cure for amyotrophic lateral sclerosis. Accumulating evidence suggests that dismantling of neuromuscular junction is an early event in the pathogenesis of amyotrophic lateral sclerosis. Conclusion: It is starting to realized that macrophage malfunction contributes to the disruption of neuromuscular junction. Modulation of macrophage activation states may stabilize neuromuscular junction and provide protection against motor neuron degeneration in amyotrophic lateral sclerosis.

Background & Objective: Oxidative stress (OS) is the secondary source of an injury in consequence to the earlier caused primary injury; it is the condition of an imbalance between oxidants and antioxidants within the physiological system. OS causes alterations in proteins and DNA structure, leading to inflammation, apoptotic cell death, and tissue damage. Neurodegenerative diseases (NDDs) such as Alzheimer's disease, Parkinson's disease, Glioma-induced neurodegeneration and the normal aging-related neuro-degeneration are primarily associated with the increased OS. The present review article is committed to delivering a comprehensive overview of the current neuroimaging modalities which estimates an indirect correlate of OS in the brain. OS-induced changes in white matter tracts and the gray matter volumes are reviewed assessing the role of diffusion tensor imaging (DTI) and voxel-based morphometry (VBM) respectively. Further, the role of magnetic resonance spectroscopy (MRS) to assess the OS-induced alterations of chemical moieties, and thus the resultant structural implications in the neurological disorders are also briefly as well as precisely reviewed. Conclusion: In the present review article we present an overview of the role of neuroimaging modalities in the diagnosis, and longitudinal assessment during treatment of the OS induced changes.

Background & Objective: Kunitz-type venoms are bioactive proteins isolated from a wide variety of venomous animals. These venoms are involved in protease inhibitory activity or potassium channel blocking activity. Therefore, they are reported as an important source for lead drug candidates towards protease or channel associated diseases like neurological, metabolic and cardiovascular disorders. Methods: This study aimed to check the inhibitory action of Kunitz-type venoms against potassium channels using computational tools. Results: Among potassium channels, Human Voltage-Gated Potassium Channel 1.2 (hKv1.2) was used as a receptor whereas Kunitz-type peptides from the venoms of various species were selected as ligand dataset. Conclusion: This study helped in finding the binding interface between the receptor and ligand dataset for their potential therapeutic use in treating potassium channelopathies.

Background: Gliomas are aggressive and resilient tumors. Progression to advanced stages of malignancy, characterized by cell anaplasia, necrosis, and reduced response to conventional surgery or therapeutic adjuvant, are critical challenges in glioma therapy. Relapse of the disease poses a considerable challenge for management. Hence, new compounds are required to improve therapeutic response. As hydrolyzed rutin (HR), a compound modified via rutin deglycosylation, as well as some flavonoids demonstrated antiproliferative effect for glioblastoma, these are considered potential epigenetic drugs. Objective: The purpose of this study was to determine the antitumor activity and evaluate the potential for modifying tumor aggressivity of rutin hydrolysates for treating both primary and relapsed glioblastoma. Methods: The glioblastoma cell line, U251, was used for analyzing cell cycle inhibition and apoptosis and for establishing the GBM mouse model. Mice with GBM were treated with HR to verify antitumor activity. Histological analysis was used to evaluate HR interference in aggressive behavior and glioma grade. Immunohistochemistry, comet assay, and thiobarbituric acid reactive substance (TBARS) values were used to evaluate the mechanism of HR action. Results: HR is an antiproliferative and antitumoral compound that inhibits the cell cycle via a p53- independent pathway. HR reduces tumor growth and aggression, mainly by decreasing mitosis and necrosis rates without genotoxicity, which is suggestive of epigenetic modulation. Conclusion: HR possesses antitumor activity and decreases anaplasia in glioblastoma, inhibiting progression to malignant stages of the disease. HR can improve the effectiveness of response to conventional therapy, which has a crucial role in recurrent glioma.

Background: Autism Spectrum Disorders (ASD) as a considerable health obstacle in kids is characterized by compromised social collaboration and stereotyped behavior. Autism is triggered by an interactive impact of environmental and genetic influences. Presumably, some inborn errors of metabolism are implicated in a sector of developmental disabilities. Also, several trace elements may have an important role in human behavior and neurological development. This study was designed to verify the frequency of inherited metabolic disorders and/or trace element abnormalities in children with ASD. Methods: In a retrospective analytical study, 320 children diagnosed with ASD according to the DSM-V criteria and Childhood Autism Rating Scale criteria were enrolled in this study. Serum ammonia, blood lactate, and arterial blood gases, plasma amino acid profile by tandem mass spectrophotometry, and a urinary organic acid assay were performed in all the patients. Likewise, the estimation of a number of trace elements in the form of serum lead, mercury, copper, and plasma zinc was done in all the patients. Results: A total of 320 children with ASD, inherited metabolic disorders were identified in eight (2.5%) patients as follows: seven (2.19%) patients with phenylketonuria, and one (0.31%) patient with glutaric aciduria type 1. Regarding the trace element deficiency, sixteen (5%) patients presented low plasma zinc level, five (1.56%) children presented a high serum copper level, two (0.62%) children presented a high serum lead level and only one (0.31%) autistic child presented high serum mercury level. Electroencephalogram (EEG) abnormalities were reported in 13.12% and Magnetic Resonant Imaging (MRI) abnormalities in 8.43% of cases. Conclusion: Screening for metabolic diseases and trace elements is required in all children diagnosed with ASD irrespective of any apparent clinical attributes of metabolic complaints and trace elements discrepancies.