Search results for: neurodegenerative

Authors: Nitin Dwivedi, Jigna Shah

Abstract:

Aim and objective of study: This article indicates a comparison among various generations of dendrimers, a dendrimer is a bioactive material has repetitively branched molecule and used for delivery of various therapeutic active agents. This debut report compares the effect various generations of PPI dendrimers for brain targeting and management of neurodegenerative disorders potential on single platform. This report involves the study of the various mechanism of synthesis ligand anchored various generations PPI dendrimers deliver the drug directly to the CNS, prove their effectiveness in the management of the various neurodegenerative disease. Material and Methods: The Memantine an anti-Alzheimer drug loaded in different generations (3.0G, 4.0G, and 5.0G) of PPI dendrimers which were synthesized were synthesized. The various studies investigate the effect of PPI dendrimers generation on different characteristic parameters i.e. synthesis procedure, drug loading, release behavior, hemolysis profile at different concentration, MRI study for determine the route drug from olfactory transfer, animal model study in vitro, as well as in vivo performance. The outcomes of the investigation indicate drug delivery benefit as well as superior biocompatibility of 4.0G PPI dendrimer over 3.0G and 5.0G dendrimer, respectively. Results and Conclusion: The above study indicate the superiority of in drug delivery system with maximum drug utilization and minimize the drug dose for neurodegenerative disorder over 5.0G PPI dendrimers. So, 4.0G PPI dendrimers are the safe formulations for the symptomatic treatment of the neurodegenerative disorder. The fifth-generation poly(propyleneimine) (PPI) dendrimers, inherent toxicity due to the presence of many peripheral cationic groups is the major issue that limits their applicability.

Keywords: Alzheimer disease, generation, memantine, PPI

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Authors: Mahdi Rahaie

Abstract:

MicroRNAs are a novel class of small RNAs which regulate gene expression by translational repression or degradation of messenger RNAs. To produce sensitive, simple and cost-effective assays for microRNAs, detection is in urgent demand due to important role of these biomolecules in progression of human disease such as Alzheimer’s, Multiple sclerosis, and some other neurodegenerative diseases. Herein, we report several novel, sensitive and specific microRNA nanobiosensors which were designed based on colorimetric and fluorescence detection of nanoparticles and hybridization chain reaction amplification as an enzyme-free amplification. These new strategies eliminate the need for enzymatic reactions, chemical changes, separation processes and sophisticated equipment whereas less limit of detection with most specify are acceptable. The important features of these methods are high sensitivity and specificity to differentiate between perfectly matched, mismatched and non-complementary target microRNAs and also decent response in the real sample analysis with blood plasma. These nanobiosensors can clinically be used not only for the early detection of neuro diseases but also for every sickness related to miRNAs by direct detection of the plasma microRNAs in real clinical samples, without a need for sample preparation, RNA extraction and/or amplification.

Keywords: hybridization chain reaction, microRNA, nanobiosensor, neurodegenerative diseases

Procedia PDF Downloads 126

Authors: Edward Poluyi, Eghosa Morgan, Charles Poluyi, Chibuikem Ikwuegbuenyi, Grace Imaguezegie

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Background: Current epidemiological studies have examined the associations between moderate and severe traumatic brain injury (TBI) and their risks of developing neurodegenerative diseases. Concussion, also known as mild TBI (mTBI), is however quite distinct from moderate or severe TBIs. Only few studies in this burgeoning area have examined concussion—especially repetitive episodes—and neurodegenerative diseases. Thus, no definite relationship has been established between them. Objectives : This review will discuss the available literature linking concussion and amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease (AD). Materials and Methods: Given the complexity of this subject, a realistic review methodology was selected which includes clarifying the scope and developing a theoretical framework, developing a search strategy, selection and appraisal, data extraction, and synthesis. A detailed literature matrix was set out in order to get relevant and recent findings on this topic. Results: Presently, there is no objective clinical test for the diagnosis of concussion because the features are less obvious on physical examination. Absence of an objective test in diagnosing concussion sometimes leads to skepticism when confirming the presence or absence of concussion. Intriguingly, several possible explanations have been proposed in the pathological mechanisms that lead to the development of some neurodegenerative disorders (such as ALS and AD) and concussion but the two major events are deposition of tau proteins (abnormal microtubule proteins) and neuroinflammation, which ranges from glutamate excitotoxicity pathways and inflammatory pathways (which leads to a rise in the metabolic demands of microglia cells and neurons), to mitochondrial function via the oxidative pathways.

Keywords: amyotrophic lateral sclerosis, Alzheimer's disease, mild traumatic brain injury, neurodegeneration

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Authors: Lourdes Hanna, Edward Poluyi, Chibuikem Ikwuegbuenyi, Eghosa Morgan, Grace Imaguezegie

Abstract:

Background: Degeneration of the central nervous system (CNS), also known as neurodegeneration, describes an age-associated progressive loss of the structure and function of neuronal materials, leading to functional and mental impairments. Main body: Neuroinflammation contributes to the continuous worsening of neurodegenerative states which are characterised by functional and mental impairments due to the progressive loss of the structure and function of neu-ronal materials. Some of the most common neurodegenerative diseases include Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS). Whilst neuroinflammation is a key contributor to the progression of such disease states, it is not the single cause as there are multiple factors which contribute. Theoretically, non-steroidal anti-inflammatory drugs (NSAIDs) have potential to target neuroinflammation to reduce the severity of disease states. Whilst some animal models investigating the effects of NSAIDs on the risk of neurodegenerative diseases have shown a beneficial effect, this is not the same finding. Conclusion: Further investigation using more advanced research methods is required to better understand neuroinflammatory pathways and understand if there is still a potential window for NSAID efficacy.

Keywords: intervention, central nervous system, neurodegeneration, neuroinflammation

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Authors: J. DeBoard, R. Dietrich, J. Hughes, K. Yurko, G. Harms

Abstract:

Alzheimer’s disease (AD) is a predominant type of dementia and is likely a major cause of neural network impairment. The pathogenesis of this neurodegenerative disorder has yet to be fully elucidated. There are currently no known cures for the disease, and the best hope is to be able to detect it early enough to impede its progress. Beyond age and genetics, another prevalent risk factor for AD might be traumatic brain injury (TBI), which has similar neurodegenerative hallmarks. Our research focuses on obtaining information and methods to be able to predict when neurodegenerative effects might occur at a clinical level by observation of events at a cellular and molecular level in model mice. First, we wish to introduce our evidence that brain damage can be observed via brain imaging prior to the noticeable loss of neuromuscular control in model mice of AD. We then show our evidence that some blood biomarkers might be able to be early predictors of AD in the same model mice. Thus, we were interested to see if we might be able to predict which mice might show long-term neurodegenerative effects due to differing degrees of TBI and what level of TBI causes further damage and earlier death to the AD model mice. Upon application of TBIs via an apparatus to effectively induce extremely mild to mild TBIs, wild-type (WT) mice and AD mouse models were tested for cognition, neuromuscular control, olfactory ability, blood biomarkers, and brain imaging. Experiments are currently still in process, and more results are therefore forthcoming. Preliminary data suggest that neuromotor control diminishes as well as olfactory function for both AD and WT mice after the administration of five consecutive mild TBIs. Also, seizure activity increases significantly for both AD and WT after the administration of the five TBI treatment. If future data supports these findings, important implications about the effect of TBI on those at risk for AD might be possible.

Keywords: Alzheimer's disease, blood biomarker, neurodegeneration, neuromuscular control, olfaction, traumatic brain injury

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Authors: W. Soufi, F. Boukli Hacene, S. Ghalem

Abstract:

Alzheimer's disease (AD) is a neurodegenerative disease that leads to a progressive and permanent deterioration of nerve cells. This disease is progressively accompanied by an intellectual deterioration leading to psychological manifestations and behavioral disorders that lead to a loss of autonomy. It is the most frequent of degenerative dementia. Alzheimer's disease (AD), which affects a growing number of people, has become a major public health problem in a few years. In the context of the study of the mechanisms governing the evolution of AD disease, we have found that natural flavonoids are good acetylcholinesterase inhibitors that reduce the rate of ßA secretion in neurons. This work is to study the inhibition of acetylcholinesterase (AChE) which is an enzyme involved in Alzheimer's disease, by methods of molecular modeling. These results will probably help in the development of an effective therapeutic tool in the fight against the development of Alzheimer's disease. Our goal of the research is to study the inhibition of acetylcholinesterase (AChE) by molecular modeling methods.

Keywords: Alzheimer's disease, acetylcholinesterase, flavonoids, molecular modeling

Procedia PDF Downloads 75

Authors: Jungkyun Im

Abstract:

Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective for relieving pain and reducing inflammation. They are nonselective inhibitors of two isoforms of COX, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), and thereby inhibiting the production of hormone-like lipid compounds such as, prostaglandins and thromboxanes which cause inflammation, pain, fever, platelet aggregation, etc. In addition, recently there are many research articles reporting the neuroprotective effect of NSAIDs in neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). However, the clinical use of NSAIDs in these diseases is limited by low brain distribution. Therefore, in order to assist the in-depth investigation on the pharmaceutical mechanism of flurbiprofen in neuroprotection and to make flurbiprofen a more potent drug to prevent or alleviate neurodegenerative diseases, delivery of flurbiprofen to brain should be effective and sufficient amount of flurbiprofen must penetrate the BBB thus gaining access into the patient’s brain. We have recently developed several types of guanidine-rich molecular carriers with high molecular weights and good water solubility that readily cross the blood-brain barrier (BBB) and display efficient distributions in the mouse brain. The G8 (having eight guanidine groups) molecular carrier based on D-sorbitol was found to be very effective in delivering anticancer drugs to a mouse brain. In the present study, employing the same molecular carrier, we prepared the flurbiprofen conjugate and studied its BBB permeation by mouse tissue distribution study. Flurbiprofen was attached to a molecular carrier with a fluorescein probe and multiple terminal guanidiniums. The conjugate was found to internalize into live cells and readily cross the BBB to enter the mouse brain. Our novel synthetic flurbiprofen conjugate will hopefully delivery NSAIDs into brain, and is therefore applicable to the neurodegenerative diseases treatment or prevention.

Keywords: flurbiprofen, drug delivery, molecular carrier, organic synthesis

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Authors: Kambiz Hassanzadeh, Seyedeh Shohreh Ebrahimi, Shahrbanoo Oryan, Arman Rahimmi, Esmael Izadpanah

Abstract:

Parkinson’s disease is one of the most prevalent neurodegenerative diseases which occurs in elderly. There are convincing evidences that oxidative stress has an important role in both the initiation and progression of Parkinson’s disease. Thymoquinone (TQ) is shown to have antioxidant and anti-inflammatory properties in invitro and invivo studies. It is well documented that TQ acts as a free radical scavenger and prevents the cell damage. Therefore this study aimed to evaluate the effect of TQ on motor and non-motor symptoms in animal model of Parkinson’s disease. Male Wistar rats (10-12 months) received rotenone (1mg/kg/day, sc) to induce Parkinson’s disease model. Pretreatment with TQ (7.5 and 15 mg/kg/day, po) was administered one hour before the rotenone injection. Three motor tests (rotarod, rearing and bar tests) and two non-motor tests (forced swimming and elevated plus maze) were performed for behavioral assessment. Our results indicated that TQ significantly ameliorated the rotenone-induced motor dysfunction in rotarod and rearing tests also it could prevent the non-motor dysfunctions in forced swimming and elevated plus maze tests. In conclusion we found that TQ delayed the Parkinson's disease induction by rotenone and this effect might be related to its proved antioxidant effect.

Keywords: Parkinson's disease, thymoquinone, motor and non-motor symptoms, neurodegenerative disease

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Authors: Janneth Gonzalez, Andrés Pinzon Velasco, Maria Angarita

Abstract:

Astrocytes play an important role in various processes in the brain, including pathological conditions such as neurodegenerative diseases. Recent studies have shown that the increase in saturated fatty acids such as palmitic acid (PA) triggers pro-inflammatorypathways in the brain. The use of synthetic neurosteroids such as tibolone has demonstrated neuro-protective mechanisms. However, broad studies with a systemic point of view on the neurodegenerative role of PA and the neuro-protective mechanisms of tibolone are lacking. In this study, we performed the integration of multi-omic data (transcriptome and proteome) into a human astrocyte genomic scale metabolic model to study the astrocytic response during palmitate treatment. We evaluated metabolic fluxes in three scenarios (healthy, induced inflammation by PA, and tibolone treatment under PA inflammation). We also applied a control theory approach to identify those reactions that exert more control in the astrocytic system. Our results suggest that PA generates a modulation of central and secondary metabolism, showing a switch in energy source use through inhibition of folate cycle and fatty acid β‐oxidation and upregulation of ketone bodies formation. We found 25 metabolic switches under PA‐mediated cellular regulation, 9 of which were critical only in the inflammatory scenario but not in the protective tibolone one. Within these reactions, inhibitory, total, and directional coupling profiles were key findings, playing a fundamental role in the (de)regulation of metabolic pathways that may increase neurotoxicity and represent potential treatment targets. Finally, the overall framework of our approach facilitates the understanding of complex metabolic regulation, and it can be used for in silico exploration of the mechanisms of astrocytic cell regulation, directing a more complex future experimental work in neurodegenerative diseases.

Keywords: astrocytes, data integration, palmitic acid, computational model, multi-omics

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Authors: Laura Gantley, Vanessa M. Conn, Stuart Webb, Kirsty Kirk, Marta Gabryelska, Duncan Holds, Brett W. Stringer, Simon J. Conn

Abstract:

Trinucleotide repeat disorders comprise ~20 severe, inherited human neuromuscular and neurodegenerative disorders, which are a result of an abnormal expansion of repetitive sequences in the DNA. The most common of these, Huntington’s disease, results from the expansion of the CAG repeat region in exon 1 of the HTT gene via an unknown mechanism. Non-coding RNAs have been implicated in the initiation and progression of many diseases; thus, we focus on one circular RNA (circRNA) molecule arising from non-canonical splicing (back splicing) of HTT pre-mRNA. This circRNA and its mouse orthologue were transgenically overexpressed in human cells (SHSY-5Y and HEK293T) and mouse cells (Mb1), respectively. High-content imaging and flow cytometry demonstrated the overexpression of this circRNA reduces cell proliferation, reduces nuclear size independent of cellular size, and alters cell cycle progression. Analysis of protein by western blot and immunofluorescence demonstrated no change to HTT protein levels but altered nuclear-cytoplasmic distribution without impacting the expansion of the HTT repeat region. As these phenotypic and genotypic changes are found in Huntington’s disease patients, these results may suggest that this circRNA may play a functional role in the progression of Huntington’s disease.

Keywords: cell biology, circular RNAs, Huntington’s disease, molecular biology, neurodegenerative disorders

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Authors: Mohammadjavad Sotoudeheian

Abstract:

COVID-19, which began in December 2019, uses the angiotensin-converting enzyme 2 (ACE2) receptor to enter and spread through the cells. ACE2 mRNA is present in almost every organ, including nasopharynx, lung, as well as the brain. Ports of entry of SARS-CoV-2 into the central nervous system (CNS) may include arterial circulation, while viremia is remarkable. However, it is imperious to develop neurological symptoms evaluation CSF analysis in patients with COVID-19, but theoretically, ACE2 receptors are expressed in cerebellar cells and may be a target for SARS-CoV-2 infection in the brain. Recent evidence agrees that SARS-CoV-2 can impact the brain through direct and indirect injury. Two biomarkers for CNS injury, glial fibrillary acidic protein (GFAP) and neurofilament light chain (NFL) detected in the plasma of patients with COVID-19. NFL, an axonal protein expressed in neurons, is related to axonal neurodegeneration, and GFAP is over-expressed in CNS inflammation. GFAP cytoplasmic accumulation causes Schwan cells to misfunction, so affects myelin generation, reduces neuroskeletal support over NfLs during CNS inflammation, and leads to axonal degeneration. Interleukin-6 (IL-6), which extensively over-express due to interleukin storm during COVID-19 inflammation, regulates gene expression, as well as GFAP through STAT molecular pathway. IL-6 also impresses the phosphoinositide 3-kinase (PI3K)/STAT/smads pathway. The PI3K/ protein kinase B (Akt) pathway is the main modulator upstream of the mammalian target of rapamycin (mTOR), and alterations in this pathway are common in neurodegenerative diseases. Most neurodegenerative diseases show a disruption of autophagic function and display an abnormal increase in protein aggregation that promotes cellular death. Therefore, induction of autophagy has been recommended as a rational approach to help neurons clear abnormal protein aggregates and survive. The mTOR is a major regulator of the autophagic process and is regulated by cellular stressors. The mTORC1 pathway and mTORC2, as complementary and important elements in mTORC1 signaling, have become relevant in the regulation of the autophagic process and cellular survival through the extracellular signal-regulated kinase (ERK) pathway.

Keywords: mTORC1, COVID-19, PI3K, autophagy, neurodegeneration

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Authors: Ireneusz Majsterek, Dariusz Pytel, J. Alan Diehl

Abstract:

PKR-like ER kinase (PERK) is serine/threonie endoplasmic reticulum (ER) transmembrane kinase activated during ER-stress. PERK can activate signaling pathways known as unfolded protein response (UPR). Attenuation of translation is mediated by PERK via phosphorylation of eukaryotic initiation factor 2α (eIF2α), which is necessary for translation initiation. PERK activation also directly contributes to activation of Nrf2 which regulates expression of anti-oxidant enzymes. An increased phosphorylation of eIF2α has been reported in Alzheimer disease (AD) patient hippocampus, indicating that PERK is activated in this disease. Recent data have revealed activation of PERK signaling in non-Hodgkins lymphomas. Results also revealed that loss of PERK limits mammary tumor cell growth in vitro and in vivo. Consistent with these observations, activation of UPR in vitro increases levels of the amyloid precursor protein (APP), the peptide from which beta-amyloid plaques (AB) fragments are derived. Finally, proteolytic processing of APP, including the cleavages that produce AB, largely occurs in the ER, and localization coincident with PERK activity. Thus, we expect that PERK-dependent signaling is critical for progression of many types of diseases (human cancer, neurodegenerative disease and other). Therefore, modulation of PERK activity may be a useful therapeutic target in the treatment of different diseases that fail to respond to traditional chemotherapeutic strategies, including Alzheimer’s disease. Our goal will be to developed therapeutic modalities targeting PERK activity.

Keywords: PERK kinase, small molecule inhibitor, neurodegenerative disease, Alzheimer’s disease

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Authors: Tivani Phosa Mashamba-Thompson, Mahmoud E. S. Soliman

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To date, the cause of neurodegeneration is not well understood and diseases that stem from neurodegeneration currently have no known cures. Cathepsin B (CB) enzyme is known to be involved in the production of peptide neurotransmitters and toxic peptides in neurodegenerative diseases (NDs). CA-074Me is a membrane-permeable irreversible selective cathepsin B (CB) inhibitor as confirmed by in vivo studies. Due to the lack of the crystal structure, the binding mode of CA-074Me with the human CB at molecular level has not been previously reported. The main aim of this study is to gain an insight into the binding mode of CB CA-074Me to human CB using various computational tools. Herein, molecular dynamics simulations, binding free energy calculations and per-residue energy decomposition analysis were employed to accomplish the aim of the study. Another objective was to identify novel CB inhibitors based on the structure of CA-074Me using fragment based drug design using scaffold hoping drug design approach. Results showed that two of the designed ligands (hit 1 and hit 2) were found to have better binding affinities than the prototype inhibitor, CA-074Me, by ~2-3 kcal/mol. Per-residue energy decomposition showed that amino acid residues Cys29, Gly196, His197 and Val174 contributed the most towards the binding. The Van der Waals binding forces were found to be the major component of the binding interactions. The findings of this study should assist medicinal chemist towards the design of potential irreversible CB inhibitors.

Keywords: cathepsin B, scaffold hopping, docking, molecular dynamics, binding-free energy, neurodegerative diseases

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Authors: Danish Idrees, Vijay Kumar, Samudrala Gourinath

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by misfolding and aggregation of Cu, Zn superoxide dismutase (SOD1). The use of small molecules has been shown to stabilize the SOD1 dimer and preventing its dissociation and aggregation. In this study, we employed molecular docking, molecular dynamics simulation and surface plasmon resonance (SPR) to study the interactions between SOD1 and natural polyphenolic compounds. In order to explore the noncovalent interaction between SOD1 and natural polyphenolic compounds, molecular docking and molecular dynamic (MD) simulations were employed to gain insights into the binding modes and free energies of SOD1-polyphenolic compounds. MM/PBSA methods were used to calculate free energies from obtained MD trajectories. The compounds, Hesperidin, Ergosterol, and Rutin showed the excellent binding affinity in micromolar range with SOD1. Ergosterol and Hesperidin have the strongest binding affinity to SOD1 and was subjected to further characterization. Biophysical experiments using Circular Dichroism and Thioflavin T fluorescence spectroscopy results show that the binding of these two compounds can stabilize SOD1 dimer and inhibit the aggregation of SOD1. Molecular simulation results also suggest that these compounds reduce the dissociation of SOD1 dimers through direct interaction with the dimer interface. This study will be helpful to develop other drug-like molecules which may have the effect to reduce the aggregation of SOD1.

Keywords: amyotrophic lateral sclerosis, molecular dynamics simulation, surface plasmon resonance, superoxide dismutase

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Authors: Bhuvanesh Baniya

Abstract:

Alzheimer disease is illnesses that are responsible for neuronal cell death and resulting in lifelong cognitive problems. Due to their unclear mechanism, there are no effective drugs available for the treatment. For a long time, herbal drugs have been used as a role model in the field of the drug discovery process. Holy basil in the Indian medicinal system (Ayurveda) is used for several neuronal disorders like insomnia and memory loss for decades. This study aims to identify active components of holy basil as potential inhibitors for the treatment of Alzheimer disease. To fulfill this objective, the Network pharmacology approach, gene ontology, pharmacokinetics analysis, molecular docking, and molecular dynamics simulation (MDS) studies were performed. A total of 7 active components in holy basil, 12 predicted neurodegenerative targets of holy basil, and 8063 Alzheimer-related targets were identified from different databases. The network analysis showed that the top ten targets APP, EGFR, MAPK1, ESR1, HSPA4, PRKCD, MAPK3, ABL1, JUN, and GSK3B were found as significant target related to Alzheimer disease. On the basis of gene ontology and topology analysis results, APP was found as a significant target related to Alzheimer’s disease pathways. Further, the molecular docking results to found that various compounds showed the best binding affinities. Further, MDS top results suggested could be used as potential inhibitors against APP protein and could be useful for the treatment of Alzheimer’s disease.

Keywords: holy basil, network pharmacology, neurodegeneration, active phytochemicals, molecular docking and simulation

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Authors: O. H. Gebril, N. A. Meguid

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Background: Iron had been a focus of interest recently as a main exaggerating factor for oxidative stresses in the central nervous system and a link to various neurological disorders is suspected. Many studies with various techniques showed evidence of disturbed iron-related proteins in the cell in human and animal models of neurodegenerative disorders. Also, linkage to significant pathological changes had been evidenced e.g. apoptosis and cell signaling. On the other hand, the role of iron in neurodevelopmental disorders is still unclear. With increasing prevalence of autism worldwide, some changes in iron parameters and its stores were documented in many studies. This study includes Haemochromatosis HFE gene polymorphisms (p.H63D and p.C282Y) and ferroportin gene (SLC40A1) Q248H polymorphism in autism and control children. Materials and Methods: Whole genome DNA was extracted; p.H63D and p.C282Y genotyping was studied using specific sequence amplification followed by restriction enzyme digestion on a sample of autism patients (25 cases) and twenty controls. Results: The p.H63D is seen more than the C282Y among both autism and control samples, with no significant association of p.H63D or p.C282Y polymorphism and autism was revealed. Also, no association with Q248H polymorphism was evidenced. Conclusion: The study results do not prove the role of cellular iron genes polymorphisms as risk factors for neurodevelopmental disorders, and in turn highlights the specificity of cellular iron related pathways in neurodegeneration. These results demand further gene expression studies to elucidate the main pathophysiological pathways that are disturbed in autism and other neurodevelopmental disorders.

Keywords: iron, neurodevelopmental, oxidative stress, haemohromatosis, ferroportin, genes

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Authors: Konrad Rejdak

Abstract:

Introduction: Neurodegenerative diseases are frequently accompanied by loss and unwanted change in functional independence, social relationships, and economic circumstances. Currently, the achievements of social robots to date is being projected to improve multidimensional quality of life among people with cognitive impairment and others. Objectives: Identification of particular human needs in the context of the changes occurring in course of neurodegenerative diseases. Methods: Based on the 110 surveys performed in the Medical University of Lublin from medical staff, patients, and caregivers we made prioritization of the users' needs as high, medium, and low. The issues included in the surveys concerned four aspects: user acceptance, functional requirements, the design of the robotic assistant and preferred types of human-robot interaction. Results: We received completed questionnaires; 50 from medical staff, 30 from caregivers and 30 from potential users. Above 90% of the respondents from each of the three groups, accepted a robotic assistant as a potential caregiver. High priority functional capability of assistive technology was to handle emergencies in a private home-like recognizing life-threatening situations and reminding about medication intake. With reference to the design of the robotic assistant, the majority of the respondent would like to have an anthropomorphic appearance with a positive emotionally expressive face. The most important type of human-robot interaction was a voice-operated system and by touchscreen. Conclusion: The results from our study might contribute to a better understanding of the system and users’ requirements for the development of a service robot intended to support patients with dementia.

Keywords: assistant robot, dementia, long term care, patients

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Authors: B. Sadek, N. Khan, Shreesh K. Ojha, Adel Sadeq, D. Lazewska, K. Kiec-Kononowicz

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The involvement of Histamine H3 receptors (H3Rs) in memory and the potential role of H3R antagonists in pharmacological control of neurodegenerative disorders, e.g., Alzheimer disease (AD) is well established. Therefore, the memory-enhancing effects of the H3R antagonist DL77 on MK801-induced cognitive deficits were evaluated in passive avoidance paradigm (PAP) and novel object recognition (NOR) tasks in adult male rats, applying donepezil (DOZ) as a reference drug. Animals pretreated with acute systemic administration of DL77 (2.5, 5, and 10 mg/kg, i.p.) were significantly ameliorated in regard to MK801-induced memory deficits in PAP. The ameliorative effect of most effective dose of DL77 (5 mg/kg, i.p.) was abrogated when animals were pretreated with a co-injection with the H3R agonist R-(α)-methylhistamine (RAMH, 10 mg/kg, i.p.). Moreover, and in the NOR paradigm, DL77 (5 mg/kg, i.p.) reversed MK801-induced deficits long-term memory (LTM), and the DL77-provided procognitive effect was comparable to that of reference drug DOZ, and was reversed when animals were co-injected with RAMH (10 mg/kg, i.p.). However, DL77(5 mg/kg, i.p.) failed to alter short-term memory (STM) impairment in NOR test. Furthermore, DL77 (5 mg/kg) failed to induce any alterations of anxiety and locomotor behaviors of animals naive to elevated-plus maze (EPM), indicating that the ameliorative effects observed in PAP or NOR tests were not associated to alterations in emotions or in natural locomotion of tested animals. These results reveal the potential contribution of H3Rs in modulating CNS neurotransmission systems associated with neurodegenerative disorders, e.g., AD.

Keywords: histamine H3 receptor, antagonist, learning and memory, Alzheimer's disease, neurodegeneration, passive avoidance paradigm, novel object recognition, behavioral research

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Authors: Urvi Panwar, Kanchan Mishra, Kanjaksha Ghosh, ShankerLal Kothari

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Background: Day-by-day the increasing prevalence of neurodegenerative diseases have become a global issue to manage them by medical sciences. The adult neural stem cells are rare and require an invasive and painful procedure to obtain it from central nervous system. Mesenchymal stem cell (MSCs) therapies have shown remarkable application in treatment of various cell injuries and cell loss. MSCs can be derived from various sources like adult tissues, human bone marrow, umbilical cord blood and cord tissue. MSCs have similar proliferation and differentiation capability, but the human umbilical cord-derived mesenchymal stem cells (hUCMSCs) are proved to be more beneficial with respect to cell procurement, differentiation to other cells, preservation, and transplantation. Material and method: Human umbilical cord is easily obtainable and non-controversial comparative to bone marrow and other adult tissues. The umbilical cord can be collected after delivery of baby, and its tissue can be cultured using explant culture method. Cell culture medium such as DMEMF12+10% FBS and DMEMF12+Neural growth factors (bFGF, human noggin, B27) with antibiotics (Streptomycin/Gentamycin) were used to culture and differentiate mesenchymal stem cells into neural cells, respectively. The characterisations of MSCs were done with Flow Cytometer for surface markers CD90, CD73 and CD105 and colony forming unit assay. The differentiated various neural cells will be characterised by fluorescence markers for neurons, astrocytes, and oligodendrocytes; quantitative PCR for genes Nestin and NeuroD1 and Western blotting technique for gap43 protein. Result and discussion: The high quality and number of MSCs were isolated from human umbilical cord via explant culture method. The obtained MSCs were differentiated into neural cells like neurons, astrocytes and oligodendrocytes. The differentiated neural cells can be used to treat neural injuries and neural cell loss by delivering cells by non-invasive administration via cerebrospinal fluid (CSF) or blood. Moreover, the MSCs can also be directly delivered to different injured sites where they differentiate into neural cells. Therefore, human umbilical cord is demonstrated to be an inexpensive and easily available source for MSCs. Moreover, the hUCMSCs can be a potential source for neural cell therapies and neural cell regeneration for neural cell injuries and neural cell loss. This new way of research will be helpful to treat and manage neural cell damages and neurodegenerative diseases like Alzheimer and Parkinson. Still the study has a long way to go but it is a promising approach for many neural disorders for which at present no satisfactory management is available.

Keywords: bone marrow, cell therapy, explant culture method, flow cytometer, human umbilical cord, mesenchymal stem cells, neurodegenerative diseases, neuroprotective, regeneration

Procedia PDF Downloads 178

Authors: Konrad Rejdak, Agnieszka Korchut, Sebastian Szklener, Urszula Skrobas, Justyna Gerlowska, Katarzyna Grabowska-Aleksandrowicz, Dorota Szczesniak-Stanczyk

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Introduction: Neurodegenerative diseases are frequently accompanied by loss and unwanted change in functional independence, social relationships, and economic circumstances. Currently, the achievements of social robots to date is being projected to improve multidimensional quality of life among people with cognitive impairment and others. Objectives: Identification of particular human needs in context of the changes occurring in course of neurodegenerative diseases. Methods: Based on the 110 surveys performed in Medical University of Lublin from medical staff, patients, and caregivers we made prioritization of the users' needs as: high, medium, and low. The issues included in the surveys concerned four aspects: user acceptance, functional requirements, design of the robotic assistant and preferred types of human-robot interaction. Results: We received completed questionnaires: 50 from medical staff, 30 from caregivers and 30 from potential users. Above 90% of the respondents from each of the three groups, accepted robotic assistant as a potential caregiver. High priority functional capability of assistive technology was to handle emergencies in a private home like recognizing life-threatening situations and reminding about medication intake. With reference to design of the robotic assistant, the majority of the respondent would like to have an anthropomorphic appearance with positive emotionally expressive face. The most important type of human-robot interaction was voice-operated system and by touchscreen. Conclusion: The results from our study might contribute to a better understanding of the system and users’ requirements for the development of a service robot intended to support patients with dementia.

Keywords: social robot, dementia, requirements, patients needs

Procedia PDF Downloads 241

Authors: T. Heikkinen, J. Oksman, T. Bragge, A. Nurmi, O. Kontkanen, T. Ahtoniemi

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Motor impairment is an inherent phenotypic feature of several chronic neurodegenerative diseases, and pharmacological therapies aimed to counterbalance the motor disability have a great market potential. Animal models of chronic neurodegenerative diseases display a number deteriorating motor phenotype during the disease progression. There is a wide array of behavioral tools to evaluate motor functions in rodents. However, currently existing methods to study motor functions in rodents are often limited to evaluate gross motor functions only at advanced stages of the disease phenotype. The most commonly applied traditional motor assays used in CNS rodent models, lack the sensitivity to capture fine motor impairments or improvements. Fine motor skill characterization in rodents provides a more sensitive tool to capture more subtle motor dysfunctions and therapeutic effects. Importantly, similar approach, kinematic movement analysis, is also used in clinic, and applied both in diagnosis and determination of therapeutic response to pharmacological interventions. The aim of this study was to apply kinematic gait analysis, a novel and automated high precision movement analysis system, to characterize phenotypic deficits in three different chronic neurodegenerative animal models, a transgenic mouse model (SOD1 G93A) for amyotrophic lateral sclerosis (ALS), and R6/2 and Q175KI mouse models for Huntington’s disease (HD). The readouts from walking behavior included gait properties with kinematic data, and body movement trajectories including analysis of various points of interest such as movement and position of landmarks in the torso, tail and joints. Mice (transgenic and wild-type) from each model were analyzed for the fine motor kinematic properties at young ages, prior to the age when gross motor deficits are clearly pronounced. Fine motor kinematic Evaluation was continued in the same animals until clear motor dysfunction with conventional motor assays was evident. Time course analysis revealed clear fine motor skill impairments in each transgenic model earlier than what is seen with conventional gross motor tests. Motor changes were quantitatively analyzed for up to ~80 parameters, and the largest data sets of HD models were further processed with principal component analysis (PCA) to transform the pool of individual parameters into a smaller and focused set of mutually uncorrelated gait parameters showing strong genotype difference. Kinematic fine motor analysis of transgenic animal models described in this presentation show that this method isa sensitive, objective and fully automated tool that allows earlier and more sensitive detection of progressive neuromuscular and CNS disease phenotypes. As a result of the analysis a comprehensive set of fine motor parameters for each model is created, and these parameters provide better understanding of the disease progression and enhanced sensitivity of this assay for therapeutic testing compared to classical motor behavior tests. In SOD1 G93A, R6/2, and Q175KI mice, the alterations in gait were evident already several weeks earlier than with traditional gross motor assays. Kinematic testing can be applied to a wider set of motor readouts beyond gait in order to study whole body movement patterns such as with relation to joints and various body parts longitudinally, providing a sophisticated and translatable method for disseminating motor components in rodent disease models and evaluating therapeutic interventions.

Keywords: Gait analysis, kinematic, motor impairment, inherent feature

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Authors: Efstratios Karavasilis, Foteini Christidi, Georgios Velonakis, Agapi Plousi, Kalliopi Platoni, Nikolaos Kelekis, Ioannis Evdokimidis, Efstathios Efstathopoulos

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Introduction: Advanced structural and functional neuroimaging techniques contribute to the study of anatomical and functional brain connectivity and its role in the pathophysiology and symptoms’ heterogeneity in several neurodegenerative disorders, including multiple sclerosis (MS). Aim: In the present study, we applied multiparametric neuroimaging techniques to investigate the structural and functional cortico-cerebellar changes in MS patients. Material: We included 51 MS patients (28 with clinically isolated syndrome [CIS], 31 with relapsing-remitting MS [RRMS]) and 51 age- and gender-matched healthy controls (HC) who underwent MRI in a 3.0T MRI scanner. Methodology: The acquisition protocol included high-resolution 3D T1 weighted, diffusion-weighted imaging and echo planar imaging sequences for the analysis of volumetric, tractography and functional resting state data, respectively. We performed between-group comparisons (CIS, RRMS, HC) using CAT12 and CONN16 MATLAB toolboxes for the analysis of volumetric (cerebellar gray matter density) and functional (cortico-cerebellar resting-state functional connectivity) data, respectively. Brainance suite was used for the analysis of tractography data (cortico-cerebellar white matter integrity; fractional anisotropy [FA]; axial and radial diffusivity [AD; RD]) to reconstruct the cerebellum tracts. Results: Patients with CIS did not show significant gray matter (GM) density differences compared with HC. However, they showed decreased FA and increased diffusivity measures in cortico-cerebellar tracts, and increased cortico-cerebellar functional connectivity. Patients with RRMS showed decreased GM density in cerebellar regions, decreased FA and increased diffusivity measures in cortico-cerebellar WM tracts, as well as a pattern of increased and mostly decreased functional cortico-cerebellar connectivity compared to HC. The comparison between CIS and RRMS patients revealed significant GM density difference, reduced FA and increased diffusivity measures in WM cortico-cerebellar tracts and increased/decreased functional connectivity. The identification of decreased WM integrity and increased functional cortico-cerebellar connectivity without GM changes in CIS and the pattern of decreased GM density decreased WM integrity and mostly decreased functional connectivity in RRMS patients emphasizes the role of compensatory mechanisms in early disease stages and the disintegration of structural and functional networks with disease progression. Conclusions: In conclusion, our study highlights the added value of multimodal neuroimaging techniques for the in vivo investigation of cortico-cerebellar brain changes in neurodegenerative disorders. An extension and future opportunity to leverage multimodal neuroimaging data inevitably remain the integration of such data in the recently-applied mathematical approaches of machine learning algorithms to more accurately classify and predict patients’ disease course.

Keywords: advanced neuroimaging techniques, cerebellum, MRI, multiple sclerosis

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Authors: Ali Bayram, Remzi Yiğiter

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Objective: Alzheimer's disease (AD), the most common cause of dementia, is a progressive neurodegenerative disease. At present, diagnosis of AD is rather late in the disease. Therefore, we attempted to find peripheral biomarkers for the early diagnosis of AD. Herein, we conducted a study to investigate the unc-51 like autophagy activating kinase-1 (ULK1) mRNA expression levels in human peripheral blood mononuclear cells from patients with Alzheimer's disease. Method: To determine whether ULK1 gene expression are altered in AD patients, we measured their gene expression in human peripheral blood cell in 50 patients with AD and 50 age and gender matched healthy controls by quantitative real-time PCR technique. Results: We found that both ULK1 gene expression in peripheral blood cell were significantly decreased in patients with AD as compared with controls (p <0.05). Lower levels of ULK1 gene expression were significantly associated with the increased risk for AD. Conclusions: Serine/threonine-protein kinase involved in autophagy in response to starvation. Acts upstream of phosphatidylinositol 3-kinase PIK3C3 to regulate the formation of autophagophores, the precursors of autophagosomes. Part of regulatory feedback loops in autophagy: acts both as a downstream effector and negative regulator of mammalian target of rapamycin complex 1 (mTORC1) via interaction with RPTOR. Activated via phosphorylation by AMPK and also acts as a regulator of AMPK by mediating phosphorylation of AMPK subunits PRKAA1, PRKAB2, and PRKAG1, leading to negatively regulate AMPK activity. May phosphorylate ATG13/KIAA0652 and RPTOR; however such data need additional evidences. Plays a role early in neuronal differentiation and is required for granule cell axon formation. Alzheimer is the most common neurodegenerative disease. Our results provide useful information that the ULK1 gene expression is decreased in the neurodegeneration and AD patients with, indicating their possible systemic involvement in AD.

Keywords: Alzheimer’s sisease, ULK1, mRNA expression, RT-PCR

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Authors: Hanan Khojah, RuAngelie Edrada-Ebel

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Neurodegenerative disease including Alzheimer’s disease is a major cause of long-term disability. Oxidative stress is frequently implicated as one of the key contributing factors to neurodegenerative diseases. Protection against neuronal damage remains a great challenge for researchers. Ficus carica (commonly known as fig) is a species of great antioxidant nutritional value comprising a protective mechanism against innumerable health disorders related to oxidative stress as well as Alzheimer’s disease. The purpose of this work was to characterize the non-polar active metabolites in Ficus carica endocarp, mesocarp, and exocarp. Crude extracts were prepared using several extraction solvents, which included 1:1 water: ethylacetate, acetone and methanol. The dried extracts were then solvent partitioned between equivalent amounts of water and ethylacetate. Purification and fractionation were accomplished by high-throughput chromatography. The isolated metabolites were tested on their effect on human neuroblastoma cell line by cell viability test and cell cytotoxicity assay with acrolein. Molecular weights of the active metabolites were determined via LC–HRESIMS and GC-EIMS. Metabolomic profiling was performed to identify the active metabolites by using differential expression analysis software (Mzmine) and SIMCA for multivariate analysis. Structural elucidation and identification of the interested active metabolites were studied by 1-D and 2-D NMR. Significant differences in bioactivity against a concentration-dependent assay on acrolein radicals were observed between the three fruit parts. However, metabolites obtained from mesocarp and the endocarp demonstrated bioactivity to scavenge ROS radical. NMR profiling demonstrated that aliphatic compounds such as γ-sitosterol tend to induce neuronal bioactivity and exhibited bioactivity on the cell viability assay. γ-Sitosterol was found in higher concentrations in the mesocarp and was considered as one of the major phytosterol in Ficus carica.

Keywords: alzheimer, Ficus carica, γ-Sitosterol, metabolomics

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Authors: Richa Shri, Varinder Singh, Kundan Singh Bora, Abhishek Bhanot, Rahul Kumar, Amit Kumar, Ravinder Kaur

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The term ‘neuroprotection’ means preserving/salvaging function and structure of neurons. Neuroprotection is an adjunctive treatment option for neurodegenerative disorders. Oxidative stress is considered a major culprit in neurodegenerative disorders; hence, management strategies include use of antioxidants. Our search for a neuroprotective agent began with Allium cepa L. or onions, (family Amaryllidaceae) - a potent antioxidant. We have investigated the neuroprotective potential of onions in experimental models of ischemic stroke, diabetic neuropathy, neuropathic pain, and dementia. In pre and post-ischemic stroke model, the methanol extract of outer scales of onion bulbs (MEOS) prevented memory loss and motor in-coordination; reduced oxidative stress and cerebral infarct size. This also prevented and ameliorated diabetic neuropathy in mice. The MEOS was fractionated to yield a flavonoid rich fraction (FRF) that successfully reversed ischemia-reperfusion induced neuronal damage, thereby demonstrating that the flavonoids are responsible for the activity. The FRF effectively ameliorated chronic constriction induced neuropathic pain in rats. The FRF was subjected to bioactivity-guided fractionated. It was seen that FRF is more effective as compared to the isolated components probably due to synergism among the constituents (i.e., quercetin and quercetin glucosides) in the FRF. The outer scales of onion bulbs have great potential for prevention as well as for treatment of neuronal disorders. Red onions, with higher amounts of flavonoids as compared to the white onions, produced more significant neuroprotection. Thus, the standardized FRF from the waste material of a commonly used vegetable, especially the red variety, may be developed as a valuable neuroprotective agent.

Keywords: Allium cepa, antioxidant activity, flavonoid rich fraction, neuroprotection

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Authors: Janneth Gonzalez, Andres Pinzon Velasco, Maria Angarita, Nicolas Mendoza

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Astrocytes play an important role in various processes in the brain, including pathological conditions such as neurodegenerative diseases. Recent studies have shown that the increase in saturated fatty acids such as palmitic acid (PA) triggers pro-inflammatory pathways in the brain. The use of synthetic neurosteroids such as tibolone has demonstrated neuro-protective mechanisms. However, there are few studies on the neuro-protective mechanisms of tibolone, especially at the systemic (omic) level. In this study, we performed the integration of multi-omic data (transcriptome and proteome) into a human astrocyte genomic scale metabolic model to study the astrocytic response during palmitate treatment. We evaluated metabolic fluxes in three scenarios (healthy, induced inflammation by PA, and tibolone treatment under PA inflammation). We also use control theory to identify those reactions that control the astrocytic system. Our results suggest that PA generates a modulation of central and secondary metabolism, showing a change in energy source use through inhibition of folate cycle and fatty acid β-oxidation and upregulation of ketone bodies formation.We found 25 metabolic switches under PA-mediated cellular regulation, 9 of which were critical only in the inflammatory scenario but not in the protective tibolone one. Within these reactions, inhibitory, total, and directional coupling profiles were key findings, playing a fundamental role in the (de)regulation in metabolic pathways that increase neurotoxicity and represent potential treatment targets. Finally, this study framework facilitates the understanding of metabolic regulation strategies, andit can be used for in silico exploring the mechanisms of astrocytic cell regulation, directing a more complex future experimental work in neurodegenerative diseases.

Keywords: astrocytes, data integration, palmitic acid, computational model, multi-omics, control theory

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Authors: Lalita Subedi, Jae Kyoung Chae, Yong Un Park, Cho Kyo Hee, Lee Jae Hyuk, Kang Min Cheol, Sun Yeou Kim

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Neuroinflammation may mediate the relationship between low levels of estrogens and neurodegenerative disease. Estrogens are neuroprotective and anti-inflammatory in neurodegenerative disease models. Due to the long term side effects of estrogens, researches have been focused on finding an effective phytoestrogens for biological activities. Daidzein present in soybeans and its active metabolite equol (7-hydroxy-3-(4'-hydroxyphenyl)-chroman) bears strong antioxidant and anticancer showed more potent anti-inflammatory and neuroprotective role in neuroinflammatory model confirmed its in vitro activity with molecular mechanism through NF-κB pathway. Three major CNS cells Microglia (BV-2), Astrocyte (C6), Neuron (N2a) were used to find the effect of equol in inducible nitric oxide synthase (iNOS), cyclooxygenase (COX-2), MAPKs signaling proteins, apoptosis related proteins by western blot analysis. Nitric oxide (NO) and prostaglandin E2 (PGE2) was measured by the Gries method and ELISA, respectively. Cytokines like tumor necrosis factor-α (TNF-α) and IL-6 were also measured in the conditioned medium of LPS activated cells with or without equol. Equol inhibited the NO production, PGE-2 production and expression of COX-2 and iNOS in LPS-stimulated microglial cells at a dose dependent without any cellular toxicity. At the same time Equol also showed promising effect in modulation of MAPK’s and nuclear factor kappa B (NF-κB) expression with significant inhibition of the production of proinflammatory cytokine like interleukin -6 (IL-6), and tumor necrosis factor -α (TNF-α). Additionally, it inhibited the LPS activated microglia-induced neuronal cell death by downregulating the apoptotic phenomenon in neuronal cells. Furthermore, equol increases the production of neurotrophins like NGF and increase the neurite outgrowth as well. In conclusion the natural daidzein metabolite equol are more active than daidzein, which showed a promising effectiveness as an anti-neuroinflammatory and neuroprotective agent via downregulating the LPS stimulated microglial activation and neuronal apoptosis. This work was supported by Brain Korea 21 Plus project and High Value-added Food Technology Development Program 114006-4, Ministry of Agriculture, Food and Rural Affairs.

Keywords: apoptosis, equol, neuroinflammation, phytoestrogen

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Authors: Fatih Sonmez

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Alzheimer’s disease (AD) is a progressive neurodegenerative disease and it is the most common form of dementia that affects aged people. Acetylcholinesterase is a hydrolase involved in the termination of impulse transmission at cholinergic synapses by rapid hydrolysis of the neurotransmitter ACh in the central and peripheral nervous system. Carvacrol (5-iso-propyl-2-methyl-phenol) is a main bioactive monoterpene isolated from many medicinal herbs, such as Thymus vulgaris, Monarda punctate and Origanum vulgare spp. It is known that carvacrol has been widely used as an active anti-inflammatory ingredient, which can inhibit the isoproterenol induced inflammation in myocardial infarcted rats. In this paper, a series of 12 carvacrol substituted carbamate derivatives (2a-l) was synthesized and their inhibitory activities on AChE and BuChE were evaluated. Among them, 2d exhibited the strongest inhibition against AChE with an IC50 value of 2.22 µM, which was 130-fold more than that of carvacrol (IC50 = 288.26 µM).

Keywords: Acetylcholinesterase, Butyrylcholinesterase, Carbamate, Carvacrol

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Authors: Elene Zhuravliova, Tamar Barbakadze, Irina Kalandadze, Elnari Zaalishvili, Lali Shanshiashvili, David Mikeladze

Abstract:

Background: Multiple sclerosis (MS) is an inflammatory, neurodegenerative disease, which is accompanied by demyelination and autoimmune response to myelin proteins. Among post-translational modifications, which mediate the modulation of inflammatory pathways during MS, methylation is the main one. The methylation of DNA, also amino acids lysine and arginine, occurs in the cell. It was found that decreased trans-methylation is associated with neuroinflammatory diseases. Therefore, abnormal regulation of the methyl cycle could induce demyelination through the action on PAD (peptidyl-arginine-deiminase) gene promoter. PAD takes part in protein citrullination and targets myelin basic protein (MBP), which is affected during demyelination. To determine whether MBP charge isomers are changing the methyl cycle, we have estimated the concentrations of methyl cycle metabolites in MBP-activated primary astrocytes and oligodendrocytes. For this purpose, the action of the citrullinated MBP- C8 and the most cationic MBP-C1 isomers on the primary cells were investigated. Methods: Primary oligodendrocyte and astrocyte cell cultures were prepared from whole brains of 2-day-old Wistar rats. The methyl cycle metabolites, including homocysteine, S-adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH), were estimated by HPLC analysis using fluorescence detection and prior derivatization. Results: We found that the action of MBP-C8 and MBP-C1 induces a decrease in the concentration of both methyl cycle metabolites, S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH), in astrocytes compared to the control cells. As for oligodendrocytes, the concentration of SAM was increased by the addition of MBP-C1, while MBP-C8 has no significant effect. As for SAH, its concentration was increased compared to the control cells by the action of both MBP-C1 and MBP-C8. A significant increase in homocysteine concentration was observed by the action of the MBP-C8 isomer in both oligodendrocytes and astrocytes. Conclusion: These data suggest that MBP charge isomers change the concentration of methyl cycle metabolites. MBP-C8 citrullinated isomer causes elevation of homocysteine in astrocytes and oligodendrocytes, which may be the reason for decreased astrocyte proliferation and increased oligodendrocyte cell death which takes place in neurodegenerative processes. Elevated homocysteine levels and subsequent abnormal regulation of methyl cycles in oligodendrocytes possibly change the methylation of DNA that activates PAD gene promoter and induces the synthesis of PAD, which in turn provokes the process of citrullination, which is the accompanying process of demyelination. Acknowledgment: This research was supported by the SRNSF Georgia RF17_534 grant.

Keywords: myelin basic protein, astrocytes, methyl cycle metabolites, homocysteine, oligodendrocytes

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Authors: Sulemana Saibu, Moses Ikpeme

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Background: The severity of the COVID-19 pandemic, brought on by the SARS-CoV-2 coronavirus, has been unprecedented since the 1918 influenza pandemic. SARS-CoV-2 cases of CNS and peripheral nervous system disease, including neurodegenerative disorders and chronic immune-mediated diseases, may be anticipated based on knowledge of past coronaviruses, particularly those that caused the severe acute respiratory syndrome and Middle East respiratory syndrome outbreaks. Although respiratory symptoms are the most common clinical presentation, neurological symptoms are becoming increasingly recognized, raising concerns about their potential role in causing Parkinson's disease, Multiple sclerosis, and Narcolepsy. This systematic review aims to summarize the current evidence by exploring the association between COVID-19 infection and how it may overlap with etiological mechanisms resulting in Narcolepsy, Parkinson's disease, and Multiple sclerosis. Methods: A systematic search was conducted using electronic databases ((PubMed/MedLine, Embase, PsycINFO, ScieLO, Web of Science, ProQuest (Biotechnology, Virology, and AIDS), Scopus, and CINAHL)) to identify studies published between January 2020 and December 2022 that investigated the association between COVID-19 and Parkinson's disease, multiple sclerosis, and Narcolepsy. Per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, the review was performed and reported. Study quality was assessed using the Critical Appraisal Skills Programme Checklist and the Joanna Briggs Institute Critical appraisal tools. Results: A total of 21 studies out of 1025 met the inclusion criteria, including 8 studies reporting Parkinson's disease, 11 on multiple sclerosis, and 2 on Narcolepsy. In COVID-19 individuals compared to the general population, Narcolepsy, Parkinson's disease, and multiple sclerosis were shown to have a higher incidence. The findings imply that COVID-19 may worsen the signs or induce multiple sclerosis and Parkinson's disease and may raise the risk of developing Narcolepsy. Further research is required to confirm these connections because the available data is insufficient. Conclusion: According to the existing data, COVID-19 may raise the risk of Narcolepsy and have a causative relationship with Parkinson's disease, multiple sclerosis, and other diseases. More study is required to confirm these correlations and pinpoint probable mechanisms behind these interactions. Clinicians should be aware of how COVID-19 may affect various neurological illnesses and should treat patients who are affected accordingly.

Keywords: COVID-19, parkinson’s disease, multiple sclerosis, narcolepsy, neurological disorders, sars-cov-2, neurodegenerative disorders, chronic immune-mediated diseases

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