Displaying publications 21 - 40 of 98 in total

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  1. Pivotal Role of Fyn Kinase in Parkinson's Disease and Levodopa-Induced Dyskinesia: a Novel Therapeutic Target?
    Angelopoulou E, Paudel YN, Julian T, Shaikh MF, Piperi C
    Mol Neurobiol, 2021 Apr;58(4):1372-1391.
    PMID: 33175322 DOI: 10.1007/s12035-020-02201-z
    The exact etiology of Parkinson's disease (PD) remains obscure, although many cellular mechanisms including α-synuclein aggregation, oxidative damage, excessive neuroinflammation, and dopaminergic neuronal apoptosis are implicated in its pathogenesis. There is still no disease-modifying treatment for PD and the gold standard therapy, chronic use of levodopa is usually accompanied by severe side effects, mainly levodopa-induced dyskinesia (LID). Hence, the elucidation of the precise underlying molecular mechanisms is of paramount importance. Fyn is a tyrosine phospho-transferase of the Src family nonreceptor kinases that is highly implicated in immune regulation, cell proliferation and normal brain development. Accumulating preclinical evidence highlights the emerging role of Fyn in key aspects of PD and LID pathogenesis: it may regulate α-synuclein phosphorylation, oxidative stress-induced dopaminergic neuronal death, enhanced neuroinflammation and glutamate excitotoxicity by mediating key signaling pathways, such as BDNF/TrkB, PKCδ, MAPK, AMPK, NF-κB, Nrf2, and NMDAR axes. These findings suggest that therapeutic targeting of Fyn or Fyn-related pathways may represent a novel approach in PD treatment. Saracatinib, a nonselective Fyn inhibitor, has already been tested in clinical trials for Alzheimer's disease, and novel selective Fyn inhibitors are under investigation. In this comprehensive review, we discuss recent evidence on the role of Fyn in the pathogenesis of PD and LID and provide insights on additional Fyn-related molecular mechanisms to be explored in PD and LID pathology that could aid in the development of future Fyn-targeted therapeutic approaches.
  2. Fulltext Plant Derived Phytocompound, Embelin in CNS Disorders: A Systematic Review
    Kundap UP, Bhuvanendran S, Kumari Y, Othman I, Shaikh MF
    Front Pharmacol, 2017;8:76.
    PMID: 28289385 DOI: 10.3389/fphar.2017.00076
    A Central nervous system (CNS) disease is the one which affects either the spinal cord or brain and causing neurological or psychiatric complications. During the nineteenth century, modern medicines have occupied the therapy for many ailments and are widely used these days. Herbal medicines have often maintained popularity for historical and cultural reasons and also considered safer as they originate from natural sources. Embelin is a plant-based benzoquinone which is the major active constituent of the fruits of Embelia ribes Burm. It is an Indo-Malaysian species, extensively used in various traditional medicine systems for treating various diseases. Several natural products including quinone derivatives, which are considered to possess better safety and efficacy profile, are known for their CNS related activity. The bright orange hydroxybenzoquinone embelin-rich fruits of E. ribes have become popular in ethnomedicine. The present systematic review summarizes the effects of embelin on central nervous system and related diseases. A PRISMA model for systematic review was utilized for search. Various electronic databases such as Pubmed, Springer, Scopus, ScienceDirect, and Google Scholar were searched between January 2000 and February 2016. Based on the search criteria for the literature, 13 qualified articles were selected and discussed in this review. The results of the report showed that there is a lack of translational research and not a single study was found in human. This report gives embelin a further way to be explored in clinical trials for its safety and efficacy.
  3. Fulltext Effect of Pelargonidin isolated from Ficus benghalensis L. on phenotypic changes in zebrafish (Danio rerio) embryos
    Kundap U, Jaiswal Y, Sarawade R, Williams L, Shaikh MF
    Saudi Pharm J, 2017 Feb;25(2):249-257.
    PMID: 28344476 DOI: 10.1016/j.jsps.2016.06.010
    In the present study, the extraction and isolation of Pelargonidin, an anthocyanin compound from stem bark of Ficus benghalensis are described. The study also involves evaluation of the effect of Pelargonidin on phenotypic variations in zebra fish embryos. Extraction and isolation of Pelargonidin were carried out by employing liquid-liquid extraction technique, phytochemical tests, column chromatography, UV and FT-IR. In the zebra fish embryo model, Paclitaxel was employed as a negative control. A series of phenotypic changes in different stages of embryonic development were studied with treatment concentrations of Pelargonidin between 3.0 and 20 ppm at 0-72-hour post-fertilization (hpf). The results of our studies indicate that, after exposure of zebra fish embryos to 3.3-20 ppm concentration of Pelargonidin for 72 h, a significant reduction in aortic development occurs. At the dose level of 0.5 ppm Paclitaxel and Pelargonidin in the dose range between 3.3 and 20 ppm, the zebra fish embryos were found to have bent tail, malformed eyes and developmental delays in vasculature. Based on the results obtained, we infer that Pelargonidin can exhibit phenotypic anti-angiogenic variations in embryonic stage of fish embryos and it can be applied in future for exploration of its anti-angiogenic potential. Furthermore, Pelargonidin could serve as a candidate drug for in vivo inhibition of angiogenesis and can be applied for the treatment of neovascular diseases and tumor.
  4. Fulltext Orthosiphon stamineus Proteins Alleviate Hydrogen Peroxide Stress in SH-SY5Y Cells
    Chung YS, Ahmed PK, Othman I, Shaikh MF
    Life (Basel), 2021 Jun 20;11(6).
    PMID: 34202937 DOI: 10.3390/life11060585
    The neuroprotective potential of Orthosiphon stamineus leaf proteins (OSLPs) has never been evaluated in SH-SY5Y cells challenged by hydrogen peroxide (H2O2). This work thus aims to elucidate OSLP neuroprotective potential in alleviating H2O2 stress. OSLPs at varying concentrations were evaluated for cytotoxicity (24 and 48 h) and neuroprotective potential in H2O2-induced SH-SY5Y cells (24 h). The protective mechanism of H2O2-induced SH-SY5Y cells was also explored via mass-spectrometry-based label-free quantitative proteomics (LFQ) and bioinformatics. OSLPs (25, 50, 125, 250, 500, and 1000 µg/mL; 24 and 48 h) were found to be safe. Pre-treatments with OSLP doses (250, 500, and 1000 µg/mL, 24 h) significantly increased the survival of SH-SY5Y cells in a concentration-dependent manner and improved cell architecture-pyramidal-shaped cells, reduced clumping and shrinkage, with apparent neurite formations. OSLP pre-treatment (1000 µg/mL, 24 h) lowered the expressions of two major heat shock proteins, HSPA8 (heat shock protein family A (Hsp70) member 8) and HSP90AA1 (heat shock protein 90), which promote cellular stress signaling under stress conditions. OSLP is, therefore, suggested to be anti-inflammatory by modulating the "signaling of interleukin-4 and interleukin-13" pathway as the predominant mechanism in addition to regulating the "attenuation phase" and "HSP90 chaperone cycle for steroid hormone receptors" pathways to counteract heat shock protein (HSP)-induced damage under stress conditions.
  5. Melatonin as an Antiepileptic Molecule: Therapeutic Implications via Neuroprotective and Inflammatory Mechanisms
    Akyuz E, Kullu I, Arulsamy A, Shaikh MF
    ACS Chem Neurosci, 2021 04 21;12(8):1281-1292.
    PMID: 33813829 DOI: 10.1021/acschemneuro.1c00083
    Epilepsy is a result of unprovoked, uncontrollable, and repetitive outburst of abnormal and excessive electrical discharges, known as seizures, in the neurons. Epilepsy is a devastating neurological condition that affects 70 million people globally. Unfortunately, only two-thirds of epilepsy patients respond to antiepileptic drugs while others become drug resistant and may be more prone to epilepsy comorbidities such as SUDEP. Oxidative stress, mitochondrial dysfunction, imbalance in the excitatory and inhibitory neurotransmitters, and neuroinflammation are some of the common pathologies of neurological disorders and epilepsy. Studies suggests that melatonin, a pineal hormone that governs sleep-wake cycles, may be neuroprotective against neurological disorders and thus may be translated as an antiepileptic as well. Melatonin has been shown to be an antioxidant, antiexcitotoxic, and anti-inflammatory hormone/molecule in neurodegenerative diseases, which may contribute to its antiepileptic and neuroprotective properties in epilepsy as well. In addition, melatonin has evidently been shown to play a regulatory role in the cardiorespiratory system and sleep-wake cycles, which may have positive implications toward epilepsy associated comorbidities, such as SUDEP. However, studies investigating the changes in melatonin release due to epilepsy and melatonin's antiepileptic role have been inconclusive and scarce, respectively. Thus, this comprehensive review aims to summarize and elucidate the potential role of melatonin in the pathogenesis of epilepsy and its comorbidities, in hopes to develop new diagnostic and therapeutic approaches that will improve the lives of epileptic patients, particularly those who are drug resistant.
  6. Elucidating the Potential Side Effects of Current Anti-Seizure Drugs for Epilepsy
    Akyüz E, Köklü B, Ozenen C, Arulsamy A, Shaikh MF
    Curr Neuropharmacol, 2021;19(11):1865-1883.
    PMID: 34525933 DOI: 10.2174/1570159X19666210826125341
    Over the decades, various interventions have been developed and utilized to treat epilepsy. However, the majority of epileptic patients are often first prescribed anti-epileptic drugs (AED), now known as anti-seizure drugs (ASD), as the first line of defense to suppress their seizures and regain their quality of life. ASDs exert their anti-convulsant effects through various mechanisms of action, including regulation of ion channels, blocking glutamate-mediated stimulating neurotransmitter interaction, and enhancing the inhibitory GABA transmission. About one-third of epileptic patients are often resistant to anti-convulsant drugs, while others develop numerous side effects, which may lead to treatment discontinuation and further deterioration of quality of life. Common side effects of ASDs include headache, nausea and dizziness. However, more adverse effects, such as auditory and visual problems, skin problems, liver dysfunction, pancreatitis and kidney disorders may also be witnessed. Some ASDs may even result in life-threatening conditions as well as serious abnormalities, especially in patients with comorbidities and in pregnant women. Nevertheless, some clinicians had observed a reduction in the development of side effects post individualized ASD treatment. This suggests that a careful and well-informed ASD recommendation to patients may be crucial for an effective and side-effect-free control of their seizures. Therefore, this review aimed to elucidate the anticonvulsant effects of ASDs as well as their side effect profile by discussing their mechanism of action and reported adverse effects based on clinical and preclinical studies, thereby providing clinicians with a greater understanding of the safety of current ASDs.
  7. Fulltext Fruits for Seizures? A Systematic Review on the Potential Anti-Convulsant Effects of Fruits and their Phytochemicals
    Siang LH, Arulsamy A, Yoon YK, Shaikh MF
    Curr Neuropharmacol, 2022;20(10):1925-1940.
    PMID: 34517803 DOI: 10.2174/1570159X19666210913120637
    Epilepsy is a devastating neurological disorder. Current anti-convulsant drugs are only effective in about 70% of patients, while the rest remain drug-resistant. Thus, alternative methods have been explored to control seizures in these drug-resistant patients. One such method may be through the utilization of fruit phytochemicals. These phytochemicals have been reported to have beneficial properties such as anti-convulsant, anti-oxidant, and anti-inflammatory activities. However, some fruits may also elicit harmful effects. This review aims to summarize and elucidate the anti- or pro-convulsant effects of fruits used in relation to seizures in hopes of providing a good therapeutic reference to epileptic patients and their carers. Three databases, SCOPUS, ScienceDirect, and PubMed, were utilized for the literature search. Based on the PRISMA guidelines, a total of 40 articles were selected for critical appraisal in this review. Overall, the extracts and phytochemicals of fruits managed to effectively reduce seizure activities in various preclinical seizure models, acting mainly through the activation of the inhibitory neurotransmission and blocking the excitatory neurotransmission. Only star fruit has been identified as a pro-convulsant fruit due to its caramboxin and oxalate compounds. Future studies should focus more on utilizing these fruits as possible treatment strategies for epilepsy.
  8. Naturally Occurring HMGB1 Inhibitor, Glycyrrhizin, Modulates Chronic Seizures-Induced Memory Dysfunction in Zebrafish Model
    Paudel YN, Khan SU, Othman I, Shaikh MF
    ACS Chem Neurosci, 2021 09 15;12(18):3288-3302.
    PMID: 34463468 DOI: 10.1021/acschemneuro.0c00825
    Glycyrrhizin (GL) is a well-known pharmacological inhibitor of high mobility group box 1 (HMGB1) and is abundantly present in the licorice root (Glycyrrhiza radix). HMGB1 protein, a key mediator of neuroinflammation, has been implicated in several neurological disorders, including epilepsy. Epilepsy is a devastating neurological disorder with no effective disease-modifying treatment strategies yet, suggesting a pressing need for exploring novel therapeutic options. In the current investigation, using a second hit pentylenetetrazol (PTZ) induced chronic seizure model in adult zebrafish, regulated mRNA expression of HMGB1 was inhibited by pretreatment with GL (25, 50, and 100 mg/kg, ip). A molecular docking study suggests that GL establishes different binding interactions with the various amino acid chains of HMGB1 and Toll-like receptor-4 (TLR4). Our finding suggests that GL pretreatment reduces/suppresses second hit PTZ induced seizure, as shown by the reduction in the seizure score. GL also regulates the second hit PTZ induced behavioral impairment and rescued second hit PTZ related memory impairment as demonstrated by an increase in the inflection ratio (IR) at the 3 h and 24 h T-maze trial. GL inhibited seizure-induced neuronal activity as demonstrated by reduced C-fos mRNA expression. GL also modulated mRNA expression of BDNF, CREB-1, and NPY. The possible mechanism underlying the anticonvulsive effect of GL could be attributed to its anti-inflammatory activity, as demonstrated by the downregulated mRNA expression level of HMGB1, TLR4, NF-kB, and TNF-α. Overall, our finding suggests that GL exerts an anticonvulsive effect and ameliorates seizure-related memory disruption plausibly through regulating of the HMGB1-TLR4-NF-kB axis.
  9. Cardiorespiratory findings in epilepsy: A recent review on outcomes and pathophysiology
    Akyüz E, Üner AK, Köklü B, Arulsamy A, Shaikh MF
    J Neurosci Res, 2021 09;99(9):2059-2073.
    PMID: 34109651 DOI: 10.1002/jnr.24861
    Epilepsy is a debilitating disorder of uncontrollable recurrent seizures that occurs as a result of imbalances in the brain excitatory and inhibitory neuronal signals, that could stem from a range of functional and structural neuronal impairments. Globally, nearly 70 million people are negatively impacted by epilepsy and its comorbidities. One such comorbidity is the effect epilepsy has on the autonomic nervous system (ANS), which plays a role in the control of blood circulation, respiration and gastrointestinal function. These epilepsy-induced impairments in the circulatory and respiratory systems may contribute toward sudden unexpected death in epilepsy (SUDEP). Although, various hypotheses have been proposed regarding the role of epilepsy on ANS, the linking pathological mechanism still remains unclear. Channelopathies and seizure-induced damages in ANS-control brain structures were some of the causal/pathological candidates of cardiorespiratory comorbidities in epilepsy patients, especially in those who were drug resistant. However, emerging preclinical research suggest that neurotransmitter/receptor dysfunction and synaptic changes in the ANS may also contribute to the epilepsy-related autonomic disorders. Thus, pathological mechanisms of cardiorespiratory dysfunction should be elucidated by considering the modifications in anatomy and physiology of the autonomic system caused by seizures. In this regard, we present a comprehensive review of the current literature, both clinical and preclinical animal studies, on the cardiorespiratory findings in epilepsy and elucidate the possible pathological mechanisms of these findings, in hopes to prevent SUDEP especially in patients who are drug resistant.
  10. The Role of High Mobility Group Box 1 (HMGB1) in Neurodegeneration: A Systematic Review
    Ikram FZ, Arulsamy A, Retinasamy T, Shaikh MF
    Curr Neuropharmacol, 2022;20(11):2221-2245.
    PMID: 35034598 DOI: 10.2174/1570159X20666220114153308
    BACKGROUND: High mobility group box 1 (HMGB1) protein is a damage-associated molecular pattern (DAMP) that plays an important role in the repair and regeneration of tissue injury. It also acts as a pro-inflammatory cytokine through the activation of toll-like receptor 4 (TLR4) and receptor for advanced glycation end products (RAGE), to elicit the neuroinflammatory response. HMGB1 may aggravate several cellular responses, which may lead to pathological inflammation and cellular death. Thus, there have been a considerable amount of research into the pathological role of HMGB1 in diseases. However, whether the mechanism of action of HMGB1 is similar in all neurodegenerative disease pathology remains to be determined.

    OBJECTIVE: Therefore, this systematic review aimed to critically evaluate and elucidate the role of HMGB1 in the pathology of neurodegeneration based on the available literature.

    METHODS: A comprehensive literature search was performed on four databases; EMBASE, PubMed, Scopus, and CINAHL Plus.

    RESULTS: A total of 85 articles were selected for critical appraisal, after subjecting to the inclusion and exclusion criteria in this study. The selected articles revealed that HMGB1 levels were found elevated in most neurodegeneration except in Huntington's disease and Spinocerebellar ataxia, where the levels were found decreased. This review also showcased that HMGB1 may act on distinctive pathways to elicit its pathological response leading to the various neurodegeneration processes/ diseases.

    CONCLUSION: While there have been promising findings in HMGB1 intervention research, further studies may still be required before any HMGB1 intervention may be recommended as a therapeutic target for neurodegenerative diseases.

  11. Fulltext Embelin prevents amyloid-beta accumulation via modulation of SOD1 in a Streptozotocin-induced AD-like condition: An evidence from in vitro investigation
    Bhuvanendran S, Paudel YN, Kumari Y, Othman I, Shaikh MF
    Curr Res Neurobiol, 2022;3:100032.
    PMID: 36518345 DOI: 10.1016/j.crneur.2022.100032
    Embelin is a neuroprotective compound with therapeutic benefit against experimental Alzheimer's disease (AD)-like condition. In the quest of untangling the underlying mechanism behind the neuroprotective effect of Embelin in AD, an in-vitro study of Embelin against neuronal damage induced by Streptozotocin (STZ) in rat hippocampal neuronal culture was performed. Current findings demonstrated that Embelin (2.5-10 μM) has efficiently protected hippocampal neurons against STZ (8 mM)-induced neurotoxicity. An increase in amyloid precursor protein (APP), microtubule-associated protein tau (MAPT), glycogen synthase kinase 3 alpha (GSK-3α) and glycogen synthase kinase 3 beta (GSK-3β) expression levels was observed when STZ (8 mM) stimulation was done for 24 h in the hippocampal neurons. A significant downregulation in the mRNA expression levels of APP, MAPT, GSK-3α, and GSK-3β upon pre-treatment with different doses of Embelin (2.5 μM, 5 μM and 10 μM) reflects that Embelin attenuated STZ-induced dysfunction of insulin signaling (IR). Embelin significantly modulated the mRNA expression of scavenger enzyme Superoxide dismutase (SOD1). Furthermore, STZ had significantly upregulates an expression of Aβ. On the contrary, pre-treatment with three doses of Embelin reversed an Aβ-induced neuronal death. Our findings suggest that, Embelin prevents Aβ accumulation via SOD1 pathway to protect against AD-like condition.
  12. Elucidating the visual phenomena in epilepsy: A mini review
    Akyuz E, Arulsamy A, Hasanli S, Yilmaz EB, Shaikh MF
    Epilepsy Res, 2023 Feb;190:107093.
    PMID: 36652852 DOI: 10.1016/j.eplepsyres.2023.107093
    Epilepsy is one of the most recognizable neurological diseases, globally. Epilepsy may be accompanied by various complications, including vision impairments, which may severely impact one's quality of life. These visual phenomena may occur in the preictal, ictal and/or postictal periods of seizures. Examples of epilepsy associated visual phenomena include visual aura, visual hallucinations, transient visual loss and amaurosis (blindness). These ophthalmologic signs/symptoms of epilepsy may be temporary or permanent and may vary depending of the type of epilepsy and location of the seizure foci (occipital or temporal lobe). Some visual phenomena may even be utilized to diagnose the epilepsy type, although solely depending on visual symptoms for diagnosis may lead to mistreatment. Some antiseizure medications (ASMs) may also contribute to certain visual disturbances, thereby impacting its therapeutic efficiency for patients with epilepsy (PWE). Although the development of visual comorbidities has been observed diversely among PWE, there may still be a lack of understanding on their relevance and manifestation in epilepsy, which may contribute to the rate of misdiagnosis and the current scarcity in therapeutic relieve. Therefore, this mini narrative review aimed to discuss the common epilepsy associated visual phenomena, based on the available literature. This review also showcased the relationship between the type of visual complications and the site of seizure onset, as well as compared the visual phenomena between occipital lobe epilepsy and temporal lobe epilepsy. Evaluation of these findings may be crucial in reducing the risk of permanent seizure/epilepsy related vision deficits among PWE.
  13. Fulltext Treatment, Therapy and Management of Metabolic Epilepsy: A Systematic Review
    Lin Lin Lee V, Kar Meng Choo B, Chung YS, P Kundap U, Kumari Y, Shaikh MF
    Int J Mol Sci, 2018 Mar 15;19(3).
    PMID: 29543761 DOI: 10.3390/ijms19030871
    Metabolic epilepsy is a metabolic abnormality which is associated with an increased risk of epilepsy development in affected individuals. Commonly used antiepileptic drugs are typically ineffective against metabolic epilepsy as they do not address its root cause. Presently, there is no review available which summarizes all the treatment options for metabolic epilepsy. Thus, we systematically reviewed literature which reported on the treatment, therapy and management of metabolic epilepsy from four databases, namely PubMed, Springer, Scopus and ScienceDirect. After applying our inclusion and exclusion criteria as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we reviewed a total of 43 articles. Based on the reviewed articles, we summarized the methods used for the treatment, therapy and management of metabolic epilepsy. These methods were tailored to address the root causes of the metabolic disturbances rather than targeting the epilepsy phenotype alone. Diet modification and dietary supplementation, alone or in combination with antiepileptic drugs, are used in tackling the different types of metabolic epilepsy. Identification, treatment, therapy and management of the underlying metabolic derangements can improve behavior, cognitive function and reduce seizure frequency and/or severity in patients.
  14. Fulltext Orthosiphon stamineus Leaf Extract Affects TNF-α and Seizures in a Zebrafish Model
    Choo BKM, Kundap UP, Kumari Y, Hue SM, Othman I, Shaikh MF
    Front Pharmacol, 2018;9:139.
    PMID: 29527169 DOI: 10.3389/fphar.2018.00139
    Epileptic seizures result from abnormal brain activity and can affect motor, autonomic and sensory function; as well as, memory, cognition, behavior, or emotional state. Effective anti-epileptic drugs (AEDs) are available but have tolerability issues due to their side effects. The Malaysian herbOrthosiphon stamineus, is a traditional epilepsy remedy and possesses anti-inflammatory, anti-oxidant and free-radical scavenging abilities, all of which are known to protect against seizures. This experiment thus aimed to explore if an ethanolic leaf extract ofO. stamineushas the potential to be a novel symptomatic treatment for epileptic seizures in a zebrafish model; and the effects of the extract on the expression levels of several genes in the zebrafish brain which are associated with seizures. The results of this study indicate thatO. stamineushas the potential to be a novel symptomatic treatment for epileptic seizures as it is pharmacologically active against seizures in a zebrafish model. The anti-convulsive effect of this extract is also comparable to that of diazepam at higher doses and can surpass diazepam in certain cases. Treatment with the extract also counteracts the upregulation of NF-κB, NPY and TNF-α as a result of a Pentylenetetrazol (PTZ) treated seizure. The anti-convulsive action for this extract could be at least partially due to its downregulation of TNF-α. Future work could include the discovery of the active anti-convulsive compound, as well as determine if the extract does not cause cognitive impairment in zebrafish.
  15. Fulltext A Systematic Review on Non-mammalian Models in Epilepsy Research
    Johan Arief MF, Choo BKM, Yap JL, Kumari Y, Shaikh MF
    Front Pharmacol, 2018;9:655.
    PMID: 29997502 DOI: 10.3389/fphar.2018.00655
    Epilepsy is a common neurological disorder characterized by seizures which result in distinctive neurobiological and behavioral impairments. Not much is known about the causes of epilepsy, making it difficult to devise an effective cure for epilepsy. Moreover, clinical studies involving epileptogenesis and ictogenesis cannot be conducted in humans due to ethical reasons. As a result, animal models play a crucial role in the replication of epileptic seizures. In recent years, non-mammalian models have been given a primary focus in epilepsy research due to their advantages. This systematic review aims to summarize the importance of non-mammalian models in epilepsy research, such as in the screening of anti-convulsive compounds. The reason for this review is to integrate currently available information on the use and importance of non-mammalian models in epilepsy testing to aid in the planning of future studies as well as to provide an overview of the current state of this field. A PRISMA model was utilized and PubMed, Springer, ScienceDirect and SCOPUS were searched for articles published between January 2007 and November 2017. Fifty-one articles were finalized based on the inclusion/exclusion criteria and were discussed in this review. The results of this review demonstrated the current use of non-mammalian models in epilepsy research and reaffirmed their potential to supplement the typical rodent models of epilepsy in future research into both epileptogenesis and the treatment of epilepsy. This review also revealed a preference for zebrafish and fruit flies in lieu of other non-mammalian models, which is a shortcoming that should be corrected in future studies due to the great potential of these underutilized animal models.
  16. High mobility group box 1 (HMGB1) as a novel frontier in epileptogenesis: from pathogenesis to therapeutic approaches
    Paudel YN, Semple BD, Jones NC, Othman I, Shaikh MF
    J Neurochem, 2019 12;151(5):542-557.
    PMID: 30644560 DOI: 10.1111/jnc.14663
    Epilepsy is a serious neurological condition exhibiting complex pathology and deserving of more serious attention. More than 30% of people with epilepsy are not responsive to more than 20 anti-epileptic drugs currently available, reflecting an unmet clinical need for novel therapeutic strategies. Not much is known about the pathogenesis of epilepsy, but evidence indicates that neuroinflammation might contribute to the onset and progression of epilepsy following acquired brain insults. However, the molecular mechanisms underlying these pathophysiological processes are yet to be fully understood. The emerging research suggests that high-mobility group box protein 1 (HMGB1), a DNA-binding protein that is both actively secreted by inflammatory cells and released by necrotic cells, might contribute to the pathogenesis of epilepsy. HMGB1 as an initiator and amplifier of neuroinflammation, and its activation is implicated in the propagation of seizures in animal models. The current review will highlight the potential role of HMGB1 in the pathogenesis of epilepsy, and implications of HMGB1-targeted therapies against epilepsy. HMGB1 in this context is an emerging concept deserving further exploration. Increased understanding of HMGB1 in seizures and epilepsy will pave the way in designing novel and innovative therapeutic strategies that could modify the disease course or prevent its development.
  17. Fulltext Embelin Prevents Seizure and Associated Cognitive Impairments in a Pentylenetetrazole-Induced Kindling Zebrafish Model
    Kundap UP, Paudel YN, Kumari Y, Othman I, Shaikh MF
    Front Pharmacol, 2019;10:315.
    PMID: 31057394 DOI: 10.3389/fphar.2019.00315
    Epilepsy is a neuronal disorder associated with several neurological and behavioral alterations characterized by recurrent spontaneous epileptic seizures. Despite having more than 20 anti-epileptic drugs (AEDs), they only provide a symptomatic treatment. As well as, currently available AEDs also displayed cognitive alterations in addition to retarding seizure. This leads to the need for exploring new molecules that not only retard seizure but also improve cognitive impairment. Embelin (EMB) is a benzoquinone derivative which has already demonstrated its pharmacological potentials against arrays of neurological conditions. The current study developed a chronic kindling model in adult zebrafish by using repeated administration of small doses of pentylenetetrazole (PTZ) and a single dose of Kainic acid (KA) to investigate the associated memory impairment. This has been done by using the three-axis maze which is a conventional method to test the learning ability and egocentric memory in zebrafish. As well as, the ameliorative potential of EMB has been evaluated against chronic epilepsy-related memory alterations. Moreover the expression level of pro-inflammatory genes such as C-C motif ligand 2 (CCL2), toll-like receptor-4 (TLR4), tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1) and interferon-γ (IFN-γ) were evaluated. The level of several neurotransmitters such as γ-aminobutyric acid (GABA), acetylcholine (Ach) and glutamate (Glu) was evaluated by liquid chromatography-mass spectrometry (LC-MS). The results showed that daily dose of PTZ 80 mg/kg for 10 days successfully induces a kindling effect in zebrafish, whereas the single dose of KA did not. As compared to control, the PTZ and KA group demonstrates impairment in memory as demonstrated by the three-axis maze. The PTZ group treated with a series of EMB doses (ranging from 0.156 to 0.625 mg/kg) was found to have retarded seizure as well as significantly reduces epilepsy-induced memory alteration. In addition, EMB treatment reduces the expression of inflammatory markers implicating its anti-inflammatory potential. Moreover, levels of GABA, Ach, and glutamate are increased in EMB administered group as compared to the PTZ administered group. Overall, findings demonstrate that EMB might be a potential candidate against chronic epilepsy-related cognitive dysfunction as EMB prevents the seizures, so we expect it to prevent the associated neuroinflammation and learning deficit.
  18. Effects of Clinacanthus nutans leaf extract on lipopolysaccharide -induced neuroinflammation in rats: A behavioral and 1H NMR-based metabolomics study
    Ahmad Azam A, Ismail IS, Shaikh MF, Shaari K, Abas F
    Avicenna J Phytomed, 2019;9(2):164-186.
    PMID: 30984581
    OBJECTIVE: This research revealed the biochemical outcomes of metabolic dysregulation in serum associated with physiological sickness behavior following lipopolysaccharide (LPS)-induced neuroinflammation in rats, and treatment with Clinacanthus nutans (CN). Verification of 1H NMR analysis of the CN aqueous extract proved the existence of bioactive phytochemical constituents' in extract.

    MATERIALS AND METHODS: Twenty-five rats were subjected to unilateral stereotaxic injection of 10 µL LPS (1 mg/mL), while another ten rats were injected with phosphate-buffered saline (PBS, 10 µL) as control. Then, 29 parameters of rat behavior related to sickness were tracked by a device software (SMART 3.0.1) on days 0 and 14 of CN treatment. The acquired and accumulated data were analyzed using multivariate data analysis with the SIMCA Software package (version 13, Umetrics AB; Umeå, Sweden). The pattern trends of related groups were documented using PCA and OPLS analysis.

    RESULTS: A similar ameliorated correlation pattern was detected between improvement in physiological sickness behavior and anti-inflammatory biomarkers by the 1H NMR spectra of the sera following treatment with CN (500 and 1000 mg/kg body weight (bw)) and the control drug (dextromethorphan hydrobromide, 5 mg/kg of rats bw) in rats. Here, 21 biomarkers were detected for neuroinflammation. Treatment with the aqueous CN extract resulted in a statistically significant alteration in neuroinflammation metabolite biomarkers, including ethanol, choline, and acetate.

    CONCLUSION: This result denotes that the metabolomics approach is a reliable tool to disclose the relationship between central neuroinflammation, and systemic metabolic and physiological disturbances which could be used for future ethno-pharmacological assessments.

  19. Fulltext Embelin, a Potent Molecule for Alzheimer's Disease: A Proof of Concept From Blood-Brain Barrier Permeability, Acetylcholinesterase Inhibition and Molecular Docking Studies
    Bhuvanendran S, Hanapi NA, Ahemad N, Othman I, Yusof SR, Shaikh MF
    Front Neurosci, 2019;13:495.
    PMID: 31156375 DOI: 10.3389/fnins.2019.00495
    Embelin is well-known in ethnomedicine and reported to have central nervous system activities. However, there is no report on blood-brain barrier (BBB) permeability of embelin. Here the BBB permeability of embelin was evaluated using in vitro primary porcine brain endothelial cell (PBEC) model of the BBB. Embelin was also evaluated for acetylcholinesterase (AChE) inhibitory activity and docking prediction for interaction with AChE and amyloid beta (Aβ) binding sites. Embelin was found to be non-toxic to the PBECs and did not disturb the PBEC barrier function. The PBECs showed restrictive tight junctions with average transendothelial electrical resistance of 365.37 ± 113.00 Ω.cm2, for monolayers used for permeability assays. Permeability assays were conducted from apical-to-basolateral direction (blood-to-brain side). Embelin showed apparent permeability (Papp) value of 35.46 ± 20.33 × 10-6 cm/s with 85.53% recovery. In vitro AChE inhibitory assay demonstrated that embelin could inhibit the enzyme. Molecular docking study showed that embelin binds well to active site of AChE with CDOCKER interaction energy of -65.75 kcal/mol which correlates with the in vitro results. Docking of embelin with Aβ peptides also revealed the promising binding with low CDOCKER interaction energy. Thus, findings from this study indicate that embelin could be a suitable molecule to be further developed as therapeutic molecule to treat neurological disorders particularly Alzheimer's disease.
  20. Tau Related Pathways as a Connecting Link between Epilepsy and Alzheimer's Disease
    Paudel YN, Angelopoulou E, Jones NC, O'Brien TJ, Kwan P, Piperi C, et al.
    ACS Chem Neurosci, 2019 10 16;10(10):4199-4212.
    PMID: 31532186 DOI: 10.1021/acschemneuro.9b00460
    Emerging findings point toward an important interconnection between epilepsy and Alzheimer's disease (AD) pathogenesis. Patients with epilepsy (PWE) commonly exhibit cognitive impairment similar to AD patients, who in turn are at a higher risk of developing epilepsy compared to age-matched controls. To date, no disease-modifying treatment strategy is available for either epilepsy or AD, reflecting an immediate need for exploring common molecular targets, which can delineate a possible mechanistic link between epilepsy and AD. This review attempts to disentangle the interconnectivity between epilepsy and AD pathogenesis via the crucial contribution of Tau protein. Tau protein is a microtubule-associated protein (MAP) that has been implicated in the pathophysiology of both epilepsy and AD. Hyperphosphorylation of Tau contributes to the different forms of human epilepsy and inhibition of the same exerted seizure inhibitions and altered disease progression in a range of animal models. Moreover, Tau-protein-mediated therapy has demonstrated promising outcomes in experimental models of AD. In this review, we discuss how Tau-related mechanisms might present a link between the cause of seizures in epilepsy and cognitive disruption in AD. Untangling this interconnection might be instrumental in designing novel therapies that can minimize epileptic seizures and cognitive deficits in patients with epilepsy and AD.
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