Displaying publications 21 - 31 of 31 in total

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  1. The NLRP3 inflammasome is involved in the neuroprotective mechanism of neural stem cells against microglia-mediated toxicity in SH-SY5Y cells via the attenuation of tau hyperphosphorylation and amyloidogenesis
    Chan EWL, Krishnansamy S, Wong C, Gan SY
    Neurotoxicology, 2019 01;70:91-98.
    PMID: 30408495 DOI: 10.1016/j.neuro.2018.11.001
    The cognitive impairment caused by Alzheimer's disease (AD) is associated with beta-amyloid (Aβ) and tau proteins, and is accompanied by inflammation. Recently, a novel inflammasome signaling pathway has been uncovered. Inflammasomes are implicated in the execution of inflammatory responses and pyroptotic death leading to neurodegeneration. Thus, the inflammasome signaling pathway could be a potential therapeutic target for AD. Neural stem cells (NSCs) are multipotent cells that can self-renew and differentiate into distinct neural cells. NSC therapy has been considered to be a promising therapeutic approach in protecting the central nervous system and restoring it following damage. However, the mechanisms involved remain unclear. The aims of this study were to investigate the protective effects of NE4C neural stem cells against microglia-mediated neurotoxicity and to explore molecular mechanisms mediating their actions. NE4C decreased the levels of caspase-1 and IL-1β, and attenuated the level of the NLRP3 inflammasome and its associated protein adapter, apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) in LPS-stimulated BV2 microglial cells, possibly by regulating the phosphorylation of p38α MAPK. The conditioned media obtained from co-culture of LPS-stimulated BV2 and NE4C cells exhibited protective effects on SH-SY5Y cells against microglia-mediated neurotoxicity; this was associated with an attenuation of tau phosphorylation and amyloidogenesis and accompanied by down-regulation of GSK-3β and p38α MAPK signalling pathways. In conclusion, the present study suggested that NSC therapy could be a potential strategy against microglia-mediated neurotoxicity. NSCs regulate NLRP3 activation and IL-1β secretion, which are critical in the initiation of the inflammatory responses, hence preventing the release of neurotoxic pro-inflammatory factors by microglia. This eventually reduces tau hyperphosphylation and amyloidogenesis, possibly through the regulation of GSK-3β and p38α MAPK signalling pathways, and thus protects SH-SY5Y cells against microglia-mediated neurotoxicity.
    Matched MeSH terms: Neuroprotection/drug effects; Neuroprotection/physiology*
  2. Neuroprotection by Human Dental Pulp Mesenchymal Stem Cells: From Billions to Nano
    Venugopal C, K S, Rai KS, Pinnelli VB, Kutty BM, Dhanushkodi A
    Curr Gene Ther, 2018;18(5):307-323.
    PMID: 30209999 DOI: 10.2174/1566523218666180913152615
    INTRODUCTION: Mesenchymal Stem Cell (MSC) therapy in recent years has gained significant attention. Though the functional outcomes following MSC therapy for neurodegenerative diseases are convincing, various mechanisms for the functional recovery are being debated. Nevertheless, recent studies convincingly demonstrated that recovery following MSC therapy could be reiterated with MSC secretome per se thereby shifting the dogma from cell therapy to cell "based" therapy. In addition to various functional proteins, stem cell secretome also includes extracellular membrane vesicles like exosomes. Exosomes which are of "Nano" size have attracted significant interest as they can pass through the bloodbrain barrier far easily than macro size cells or growth factors. Exosomes act as a cargo between cells to bring about significant alterations in target cells. As the importance of exosomes is getting unveil, it is imperial to carry out a comprehensive study to evaluate the neuroprotective potential of exosomes as compared to conventional co-culture or total condition medium treatments.

    OBJECTIVE: Thus, the present study is designed to compare the neuroprotective potential of MSC derived exosomes with MSC-condition medium or neuron-MSC-co-culture system against kainic acid induced excitotoxicity in in vitro condition. The study also aims at comparing the neuroprotective efficacy of exosomes/condition medium/co-culture of two MSC viz., neural crest derived human Dental Pulp Stem Cells (hDPSC) and human Bone-Marrow Mesenchymal Stem Cells (hBM-MSC) to identify the appropriate MSC source for treating neurodegenerative diseases.

    RESULT: Our results demonstrated that neuroprotective efficacy of MSC-exosomes is as efficient as MSC-condition medium or neuron-MSC co-culture system and treating degenerating hippocampal neurons with all three MSC based approaches could up-regulate host's endogenous growth factor expressions and prevent apoptosis by activating cell survival PI3K-B-cell lymphoma-2 (Bcl-2) pathway.

    CONCLUSION: Thus, the current study highlights the possibilities of treating neurodegenerative diseases with "Nano" size exosomes as opposed to transplanting billions of stem cells which inherit several disadvantages.

    Matched MeSH terms: Neuroprotection*
  3. Fulltext From the Molecular Mechanism to Pre-clinical Results: Anti-epileptic Effects of Fingolimod
    Paudel YN, Angelopoulou E, Piperi C, Gnatkovsky V, Othman I, Shaikh MF
    Curr Neuropharmacol, 2020;18(11):1126-1137.
    PMID: 32310049 DOI: 10.2174/1570159X18666200420125017
    Epilepsy is a devastating neurological condition characterized by long-term tendency to generate unprovoked seizures, affecting around 1-2 % of the population worldwide. Epilepsy is a serious health concern which often associates with other neurobehavioral comorbidities that further worsen disease conditions. Despite tremendous research, the mainstream anti-epileptic drugs (AEDs) exert only symptomatic relief leading to 30% of untreatable patients. This reflects the complexity of the disease pathogenesis and urges the precise understanding of underlying mechanisms in order to explore novel therapeutic strategies that might alter the disease progression as well as minimize the epilepsy-associated comorbidities. Unfortunately, the development of novel AEDs might be a difficult process engaging huge funds, tremendous scientific efforts and stringent regulatory compliance with a possible chance of end-stage drug failure. Hence, an alternate strategy is drug repurposing, where anti-epileptic effects are elicited from drugs that are already used to treat non-epileptic disorders. Herein, we provide evidence of the anti-epileptic effects of Fingolimod (FTY720), a modulator of sphingosine-1-phosphate (S1P) receptor, USFDA approved already for Relapsing-Remitting Multiple Sclerosis (RRMS). Emerging experimental findings suggest that Fingolimod treatment exerts disease-modifying anti-epileptic effects based on its anti-neuroinflammatory properties, potent neuroprotection, anti-gliotic effects, myelin protection, reduction of mTOR signaling pathway and activation of microglia and astrocytes. We further discuss the underlying molecular crosstalk associated with the anti-epileptic effects of Fingolimod and provide evidence for repurposing Fingolimod to overcome the limitations of current AEDs.
    Matched MeSH terms: Neuroprotection
  4. Virgin Coconut Oil-Induced Neuroprotection in Lipopolysaccharide-Challenged Rats is Mediated, in Part, Through Cholinergic, Anti-Oxidative and Anti-Inflammatory Pathways
    Rahim NS, Lim SM, Mani V, Hazalin NAMN, Majeed ABA, Ramasamy K
    J Diet Suppl, 2020 Oct 14.
    PMID: 33962540 DOI: 10.1080/19390211.2020.1830223
    Neuroinflammation is associated with neuronal cell death and could lead to chronic neurodegeneration. This study investigated the neuroprotective potential of virgin coconut oil (VCO) against lipopolysaccharide (LPS)-induced cytotoxicity of neuroblastoma SK-N-SH cells. The findings were validated using Wistar rats, which were fed with 1-10 g/kg VCO for 31 days, exposed to LPS (0.25 mg/kg) and subjected to the Morris Water Maze Test. Brain homogenate was subjected to biochemical analyses and gene expression studies. α-Tocopherol (α-T; 150 mg/kg) served as the positive control. VCO (100 µg/mL) significantly (p 
    Matched MeSH terms: Neuroprotection
  5. Protective Effect of Natural Products against Huntington's Disease: An Overview of Scientific Evidence and Understanding Their Mechanism of Action
    Lum PT, Sekar M, Gan SH, Bonam SR, Shaikh MF
    ACS Chem Neurosci, 2021 Feb 03;12(3):391-418.
    PMID: 33475334 DOI: 10.1021/acschemneuro.0c00824
    Huntington's disease (HD), a neurodegenerative disease, normally starts in the prime of adult life, followed by a gradual occurrence of characteristic psychiatric disturbances and cognitive and motor dysfunction. To the best of our knowledge, there is no treatment available to completely mitigate the progression of HD. Among various therapeutic approaches, exhaustive literature reports have confirmed the medicinal benefits of natural products in HD experimental models. Building on this information, this review presents a brief overview of the neuroprotective mechanism(s) of natural products against in vitro/in vivo models of HD. Relevant studies were identified from several scientific databases, including PubMed, ScienceDirect, Scopus, and Google Scholar. After screening through literature from 2005 to the present, a total of 14 medicinal plant species and 30 naturally isolated compounds investigated against HD based on either in vitro or in vivo models were included in the present review. Behavioral outcomes in the HD in vivo model showed that natural compounds significantly attenuated 3-nitropropionic acid (3-NP) induced memory loss and motor incoordination. The biochemical alteration has been markedly alleviated with reduced lipid peroxidation, increased endogenous enzymatic antioxidants, reduced acetylcholinesterase activity, and increased mitochondrial energy production. Interestingly, following treatment with certain natural products, 3-NP-induced damage in the striatum was ameliorated, as seen histologically. Overall, natural products afforded varying degrees of neuroprotection in preclinical studies of HD via antioxidant and anti-inflammatory properties, preservation of mitochondrial function, inhibition of apoptosis, and induction of autophagy.
    Matched MeSH terms: Neuroprotection
  6. Glutamate receptors and transporters as comparative cues to the glutamatergic circuits of the avian and mammalian brain
    Islam, M.R., Muzaimi, M., Abdullah, J.M.
    Orient Neuron Nexus, 2011;2(1):2-9.
    MyJurnal
    Glutamate is the principal excitatory neurotransmitter in the central nervous system, and plays important roles in both physiological and pathological neuronal processes. Current understanding of the exact mechanisms involved in glutamate-induced neuronal excitotoxicity, in which excessive glutamate causes neuronal dysfunction and degeneration, whether acute or chronic, remain elusive. Conditions, due to acute insults such as ischaemia and traumatic brain injury, and chronic neurodegenerative disorders such as multiple sclerosis and motor neuron disease, suffer from the lack of translational neuroprotection in clinical setting to tackle glutamate excitotoxicity despite steady growth of animal studies that revealed complex cell death pathway interactions. In addition, glutamates are also released by non-neuronal cells including astrocytes and oligodendroglia. Thus, attempts to elucidate this complexity are closely related to our understanding of the glutamatergic circuitry in the brain. Neuronal cells develop a glutamatergic system at glutamatergic synapses that utilise glutamate as an intercellular signaling molecule to characterise the output, input, and termination of this signaling. As to signal input, various kinds of glutamate receptors have been identified and characterized. Na+-dependent glutamate transporters at the plasma membrane are responsible for the signal termination through sequestration of glutamate from the synaptic cleft. The signal output systems comprise vesicular storage and subsequent exocytosis of glutamate by using vesicular glutamate transporters. Similar to the mammalian brain, the regional differences of glutamatergic neurons and glutamate receptor neurons suggest many glutamatergic projections in the avian brain, as supported by recent evidence of glutamate-related genes distribution. Glutamatergic target areas are expected to show high activity of glutamate transporters that remove released glutamate from the synaptic clefts. This review summarises and compares glutamatergic circuits in the avian and mammalian brain, particularly in the olfactory pathway, the paffial organization of glutamatergic neurons and connection with the striatum, hippocampal-septal pathway, visual and auditory pathways, and granule cell-Purkinje cell pathway in the cerebellum. Comparative appreciation of these glutamatergic circuits, particularly with the localisation and/or expression of specific subtypes of glutamate transporters, would provide the morphological basis for physiological and pharmacological designs that supplement existing animal studies of the current proposed mechanisms that underlie glutamate-induced neuronal excitotoxicity.
    Matched MeSH terms: Neuroprotection
  7. Fulltext Brain Lipopolysaccharide Preconditioning-Induced Gene Reprogramming Mediates a Tolerance State in Electroconvulsive Shock Model of Epilepsy
    Amini E, Golpich M, Farjam AS, Kamalidehghan B, Mohamed Z, Ibrahim NM, et al.
    Front Pharmacol, 2018;9:416.
    PMID: 29765321 DOI: 10.3389/fphar.2018.00416
    There is increasing evidence pointing toward the role of inflammatory processes in epileptic seizures, and reciprocally, prolonged seizures induce more inflammation in the brain. In this regard, effective strategies to control epilepsy resulting from neuroinflammation could be targeted. Based on the available data, preconditioning (PC) with low dose lipopolysaccharide (LPS) through the regulation of the TLR4 signaling pathway provides neuroprotection against subsequent challenge with injury in the brain. To test this, we examined the effects of a single and chronic brain LPS PC, which is expected to lead to reduction of inflammation against epileptic seizures induced by electroconvulsive shock (ECS). A total of 60 male Sprague Dawley rats were randomly assigned to five groups: control, vehicle (single and chronic), and LPS PC (single and chronic). We first recorded the data regarding the behavioral and histological changes. We further investigated the alterations of gene and protein expression of important mediators in relation to TLR4 and inflammatory signaling pathways. Interestingly, significant increased presence of NFκB inhibitors [Src homology 2-containing inositol phosphatase-1 (SHIP1) and Toll interacting protein (TOLLIP)] was observed in LPS-preconditioned animals. This result was also associated with over-expression of IRF3 activity and anti-inflammatory markers, along with down-regulation of pro-inflammatory mediators. Summarizing, the analysis revealed that PC with LPS prior to seizure induction may have a neuroprotective effect possibly by reprogramming the signaling response to injury.
    Matched MeSH terms: Neuroprotection
  8. Fulltext Stem cell therapy as a potential treatment for glaucoma
    Kamal, M., Amini, F., Ramasamy, TS
    JUMMEC, 2016;19(1):23-32.
    MyJurnal
    Glaucoma is a common eye disease that can cause irreversible damage if left undiagnosed and untreated. It is one of the most common neurodegenerative diseases causing blindness. Pre-clinical studies have been carried out on animal models of glaucoma for stem cell therapy. We carried out a systematic review to determine whether stem cell therapy had the potential to treat glaucoma. Nine studies were selected based on the predetermined inclusion and exclusion criteria. Of these nine studies, eight focused on neuroprotection conferred by stem cells, and the remaining one on neuroregeneration. Results from these studies showed that there was a potential in stem cell based therapy in treating glaucoma, especially regarding neuroprotection via neurotrophic factors. The studies revealed that a brain-derived neurotrophic factor expressed by stem cells promoted the survival of retinal ganglion cells in murine glaucoma models. The transplanted cells survived without any side effects. While these studies proved that stem cells provided neuroprotection in glaucoma, improvement of vision could not be determined. Clinical studies would be required to determine whether the protection of RGC correlated with improvement in visual function. Furthermore, these murine studies could not be translated into clinical therapy due to the heterogeneity of the experimental methods and the
    use of different cell lines. In conclusion, the use of stem cells in the clinical therapy of glaucoma will be an important step in the future as it will transform present-day treatment with the hope of restoring sight to patients with glaucoma.
    Matched MeSH terms: Neuroprotection
  9. Fulltext Embelin Protects Against Acute Pentylenetetrazole-Induced Seizures and Positively Modulates Cognitive Function in Adult Zebrafish
    Kundap UP, Choo BKM, Kumari Y, Ahmed N, Othman IB, Shaikh MF
    Front Pharmacol, 2019;10:1249.
    PMID: 31708779 DOI: 10.3389/fphar.2019.01249
    Purpose of the research: Epilepsy is a continuous process of neurodegeneration categorized by an enduring tendency to generate uncontrolled electrical firing known as seizures causing involuntary movement all over the body. Cognitive impairment and behavioral disturbances are among the more alarming co-morbidities of epilepsy. Anti-epileptic drugs (AEDs) were found to be successful in controlling epilepsy but are reported to worsen cognitive status in patients. Embelin (EMB) is a benzoquinone derived from the plant Embelia ribes and is reported to have central nervous system (CNS) activity. This study aims to evaluate the effectiveness of EMB against pentylenetetrazole (PTZ) induced acute seizures and its associated cognitive dysfunction. This was done via docking studies as well as evaluating neurotransmitter and gene expression in the zebrafish brain. The principal results: Behavioral observations showed that EMB reduced epileptic seizures and the T-maze study revealed that EMB improved the cognitive function of the fish. The docking study of EMB showed a higher affinity toward gamma-aminobutyric acid (GABAA) receptor as compared to the standard diazepam, raising the possibility of EMB working via the alpha subunit of the GABA receptor. EMB was found to modulate several genes, neurotransmitters, and also neuronal growth, all of which play an important role in improving cognitive status after epileptic seizures. Healthy zebrafish treated with EMB alone were found to have no behavioral and biochemical interference or side effects. The immunohistochemistry data suggested that EMB also promotes neuronal protection and neuronal migration in zebrafish brains. Major Conclusions: It was perceived that EMB suppresses seizure-like behavior via GABAA receptor pathway and has a positive impact on cognitive functions. The observed effect was supported by docking study, T-maze behavior, neurotransmitter and gene expression levels, and immunohistology study. The apparatus such as the T-maze and seizure scoring behavior tank were found to be a straightforward technique to score seizure and test learning ability after acute epileptic seizures. These research findings suggest that EMB could be a promising molecule for epilepsy induced learning and memory dysfunction.
    Matched MeSH terms: Neuroprotection
  10. Fulltext Kainic Acid-Induced Excitotoxicity Experimental Model: Protective Merits of Natural Products and Plant Extracts
    Mohd Sairazi NS, Sirajudeen KN, Asari MA, Muzaimi M, Mummedy S, Sulaiman SA
    Evid Based Complement Alternat Med, 2015;2015:972623.
    PMID: 26793262 DOI: 10.1155/2015/972623
    Excitotoxicity is well recognized as a major pathological process of neuronal death in neurodegenerative diseases involving the central nervous system (CNS). In the animal models of neurodegeneration, excitotoxicity is commonly induced experimentally by chemical convulsants, particularly kainic acid (KA). KA-induced excitotoxicity in rodent models has been shown to result in seizures, behavioral changes, oxidative stress, glial activation, inflammatory mediator production, endoplasmic reticulum stress, mitochondrial dysfunction, and selective neurodegeneration in the brain upon KA administration. Recently, there is an emerging trend to search for natural sources to combat against excitotoxicity-associated neurodegenerative diseases. Natural products and plant extracts had attracted a considerable amount of attention because of their reported beneficial effects on the CNS, particularly their neuroprotective effect against excitotoxicity. They provide significant reduction and/or protection against the development and progression of acute and chronic neurodegeneration. This indicates that natural products and plants extracts may be useful in protecting against excitotoxicity-associated neurodegeneration. Thus, targeting of multiple pathways simultaneously may be the strategy to maximize the neuroprotection effect. This review summarizes the mechanisms involved in KA-induced excitotoxicity and attempts to collate the various researches related to the protective effect of natural products and plant extracts in the KA model of neurodegeneration.
    Matched MeSH terms: Neuroprotection
  11. Fulltext Recent Updates in Neuroprotective and Neuroregenerative Potential of Centella asiatica
    Lokanathan Y, Omar N, Ahmad Puzi NN, Saim A, Hj Idrus R
    Malays J Med Sci, 2016 Jan;23(1):4-14.
    PMID: 27540320 MyJurnal
    Centella asiatica, locally well known in Malaysia as pegaga, is a traditional herb that has been used widely in Ayurvedic medicine, traditional Chinese medicine, and in the traditional medicine of other Southeast Asian countries including Malaysia. Although consumption of the plant is indicated for various illnesses, its potential neuroprotective properties have been well studied and documented. In addition to past studies, recent studies also discovered and/or reconfirmed that C. asiatica acts as an antioxidant, reducing the effect of oxidative stress in vitro and in vivo. At the in vitro level, C. asiatica promotes dendrite arborisation and elongation, and also protects the neurons from apoptosis. In vivo studies have shown that the whole extract and also individual compounds of C. asiatica have a protective effect against various neurological diseases. Most of the in vivo studies on neuroprotective effects have focused on Alzheimer's disease, Parkinson's disease, learning and memory enhancement, neurotoxicity and other mental illnesses such as depression and anxiety, and epilepsy. Recent studies have embarked on finding the molecular mechanism of neuroprotection by C. asiatica extract. However, the capability of C. asiatica in enhancing neuroregeneration has not been studied much and is limited to the regeneration of crushed sciatic nerves and protection from neuronal injury in hypoxia conditions. More studies are still needed to identify the compounds and the mechanism of action of C. asiatica that are particularly involved in neuroprotection and neuroregeneration. Furthermore, the extraction method, biochemical profile and dosage information of the C. asiatica extract need to be standardised to enhance the economic value of this traditional herb and to accelerate the entry of C. asiatica extracts into modern medicine.
    Matched MeSH terms: Neuroprotection
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