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Fulltext The Gut-Brain-Axis on the Manifestation of Depressive Symptoms in Epilepsy: An Evidence-Driven Hypothesis

Shaikh MF, Lee CY, Chen WN, Shaikh FA

Front Pharmacol, 2020;11:465.
PMID: 32322213 DOI: 10.3389/fphar.2020.00465

Epilepsy is a severe neurological disorder involving 70 million people around the globe. Epilepsy-related neuropsychiatric comorbidities such as depression, which is the most common, is an additional factor that negatively impacts the living quality of epilepsy patients. There are many theories and complexities associated with both epilepsy and associated comorbidities, one of which is the gut-brain-axis influence. The gut microbiome is hypothesized to be linked with many neurological disorders; however, little conclusive evidence is available in this area. Thus, highlighting the role will create interest in researchers to conduct detailed research in comprehending the influence of gut-brain-axis in the manifestation of depressive symptoms in epilepsy. The hypothesis which is explored in this review is that the gut-brain-axis do play an important role in the genesis of epilepsy and associated depression. The correction of this dysbiosis might be beneficial in treating both epilepsy and related depression. This hypothesis is illustrated through extensive literature discussion, proposed experimental models, and its applicability in the field. There is indirect evidence which revealed some specific bacterial strains that might cause depression in epilepsy.
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.
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.
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.
Fulltext Zebrafish as a Model for Epilepsy-Induced Cognitive Dysfunction: A Pharmacological, Biochemical and Behavioral Approach

Kundap UP, Kumari Y, Othman I, Shaikh MF

Front Pharmacol, 2017;8:515.
PMID: 28824436 DOI: 10.3389/fphar.2017.00515

Epilepsy is a neuronal disorder allied with distinct neurological and behavioral alterations characterized by recurrent spontaneous epileptic seizures. Impairment of the cognitive performances such as learning and memory is frequently observed in epileptic patients. Anti-epileptic drugs (AEDs) are efficient to the majority of patients. However, 30% of this population seems to be refractory to the drug treatment. These patients are not seizure-free and frequently they show impaired cognitive functions. Unfortunately, as a side effect, some AEDs could contribute to such impairment. The major problem associated with conducting studies on epilepsy-related cognitive function is the lack of easy, rapid, specific and sensitive in vivo testing models. However, by using a number of different techniques and parameters in the zebrafish, we can incorporate the unique feature of specific disorder to study the molecular and behavior basis of this disease. In the view of current literature, the goal of the study was to develop a zebrafish model of epilepsy induced cognitive dysfunction. In this study, the effect of AEDs on locomotor activity and seizure-like behavior was tested against the pentylenetetrazole (PTZ) induced seizures in zebrafish and epilepsy associated cognitive dysfunction was determined using T-maze test followed by neurotransmitter estimation and gene expression analysis. It was observed that all the AEDs significantly reversed PTZ induced seizure in zebrafish, but had a negative impact on cognitive functions of zebrafish. AEDs were found to modulate neurotransmitter levels, especially GABA, glutamate, and acetylcholine and gene expression in the drug treated zebrafish brains. Therefore, combination of behavioral, neurochemical and genenetic information, makes this model a useful tool for future research and discovery of newer and safer AEDs.
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.
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.
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.
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.
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.
Fulltext Melatonin receptor agonist Piper betle L. ameliorates dexamethasone-induced early life stress in adult zebrafish

Kumari Y, Choo BKM, Shaikh MF, Othman I

Exp Ther Med, 2019 Aug;18(2):1407-1416.
PMID: 31363378 DOI: 10.3892/etm.2019.7685

Early life exposure to stress has been suggested to be a crucial factor for the development of the brain and its functions. It is well documented that childhood stress is a risk factor for sleep problems in adulthood. Piper betle L. leaf extract (PB) has been used in several traditional medicines to cure various ailments. Recently, PB has been proved to have antidepressant activity. The literature suggests that antidepressants affect the synthesis and release of melatonin through several mechanisms. Thus, this study investigated the potential role of PB for the treatment of sleep disruption after early life stress exposure. Firstly, dexamethasone (DEX) (2 and 20 mg/l for 24 h) was administered to zebrafish larvae on the 4th day post-fertilization (dpf) to induce early life stress. The effects of stress on behaviour during adulthood, melatonin level and stress-related gene expression (nfkb) in the brain were then studied. Next, the possible role of PB (10 and 30 mg/Kg) was studied by measuring its effect on behaviour and by quantifying the expression levels of several melatonin-related (MT1, MT2, aanat1, aanat2) and stress-related (nfkb) genes by qPCR. DEX-treated zebrafish exhibited anxious behaviour, along with a lower level of melatonin and a higher mRNA expression of nfkb. After treatment with PB, a similar effect on behaviour and gene expression levels as the melatonin treatment group (10 mg/kg; positive control) was seen in adult zebrafish. These molecular confirmations of the observed behavioural effects of the PB indicate a possible role in the treatment of early life stress-induced sleep disruption.
Fulltext Amelioration of Cognitive Deficit by Embelin in a Scopolamine-Induced Alzheimer's Disease-Like Condition in a Rat Model

Bhuvanendran S, Kumari Y, Othman I, Shaikh MF

Front Pharmacol, 2018;9:665.
PMID: 29988493 DOI: 10.3389/fphar.2018.00665

Embelin (2,5-dihydroxy-3-undecyl-1,4-benzoquinone) is one of the active components (2.3%) found in Embelia ribes Burm fruits. As determined via in vitro AChE inhibition assay, embelin can inhibit the acetylcholinesterase enzyme. Therefore, embelin can be utilized as a therapeutic compound, after further screening has been conducted for its use in the treatment of Alzheimer's disease (AD). In this study, the nootropic and anti-amnesic effects of embelin on scopolamine-induced amnesia in rats were evaluated. Rats were treated once daily with embelin (0.3 mg/kg, 0.6 mg/kg, 1.2 mg/kg) and donepezil (1 mg/kg) intraperitoneally (i.p.) for 17 days. During the final 9 days of treatment, a daily injection of scopolamine (1 mg/kg) was administered to induce cognitive deficits. Besides that, behavioral analysis was carried out to assess the rats' learning and memory functions. Meanwhile, hippocampal tissues were extracted for gene expression, neurotransmitter, and immunocytochemistry studies. Embelin was found to significantly improve the recognition index and memory retention in the novel object recognition (NOR) and elevated plus maze (EPM) tests, respectively. Furthermore, embelin at certain doses (0.3 mg/kg, 0.6 mg/kg, and 1.2 mg/kg) significantly exhibited a memory-enhancing effect in the absence of scopolamine, besides improving the recognition index when challenged with chronic scopolamine treatment. Moreover, in the EPM test, embelin treated rats (0.6 mg/kg) showed an increase in inflection ratio in nootropic activity. However, the increase was not significant in chronic scopolamine model. In addition, embelin contributed toward the elevated expression of BDNF, CREB1, and scavengers enzymes (SOD1 and CAT) mRNA levels. Next, pretreatment of rats with embelin mitigated scopolamine-induced neurochemical and histological changes in a manner comparable to donepezil. These research findings suggest that embelin is a nootropic compound, which also possesses an anti-amnesic ability that is displayed against scopolamine-induced memory impairment in rats. Hence, embelin could be a promising compound to treat AD.
Fulltext The anti-neuroinflammatory effects of Clinacanthus nutans leaf extract on metabolism elucidated through 1H NMR in correlation with cytokines microarray

Ahmad Azam A, Ismail IS, Kumari Y, Shaikh MF, Abas F, Shaari K

PLoS One, 2020;15(9):e0238503.
PMID: 32925968 DOI: 10.1371/journal.pone.0238503

Clinacanthus nutans (CN) (Acanthaceae) is well-known for its anti-inflammatory properties among Asian communities; however, there are currently no data specifically focused on the anti-inflammatory effects of CN on the brain tissue. Neuroinflammation is a common consequence of toxin intrusion to any part of the central nervous system (CNS). As an innate immune response, the CNS may react through both protective and/or toxic actions due to the activation of neuron cells producing pro- and/or anti-inflammatory cytokines in the brain. The unresolved activation of the inflammatory cytokines' response is associated with the pathogenesis of neurological disorders. The present study aimed to decipher the metabolic mechanism on the effects of 14 days oral treatment with CN aqueous extract in induced-lipopolysaccharides (LPS) rats through 1H NMR spectroscopic biomarker profiling of the brain tissue and the related cytokines. Based on the principal component analysis (PCA) of the nuclear magnetic resonance (NMR) spectral data, twenty-one metabolites in the brain tissue were profiled as biomarkers for the LPS (10 μL)-induced neuroinflammation following intracerebroventricular injection. Among the twenty-one biomarkers in the neuroinflammed rats, CN treatment of 1000 and 500 mg/kg BW successfully altered lactate, pyruvate, phosphorylcholine, glutamine, and α-ketoglutarate when compared to the negative control. Likewise, statistical isolinear multiple component analysis (SIMCA) showed that treatments by CN and the positive control drug, dextromethorphan (DXM, 5 mg/kg BW), have anti-neuroinflammatory potential. A moderate correlation, in the orthogonal partial least squares (OPLS) regression model, was found between the spectral metabolite profile and the cytokine levels. The current study revealed the existence of high levels of pro-inflammatory cytokines, namely IL-1α, IL-1β, and TNF-α in LPS-induced rats. Both CN dose treatments lowered IL-1β significantly better than DXM Interestingly, DXM and CN treatments both exhibited the upregulation of the anti-inflammatory cytokines IL-2 and 4. However, DXM has an advantage over CN in that the former also increased the expression of IL-10 of anti-inflammatory cytokines. In this study, a metabolomics approach was successfully applied to discover the mechanistic role of CN in controlling the neuroinflammatory conditions through the modulation of complex metabolite interactions in the rat brain.
Fulltext Embelin Improves the Spatial Memory and Hippocampal Long-Term Potentiation in a Rat Model of Chronic Cerebral Hypoperfusion

Bhuvanendran S, Bakar SNS, Kumari Y, Othman I, Shaikh MF, Hassan Z

Sci Rep, 2019 10 10;9(1):14507.
PMID: 31601902 DOI: 10.1038/s41598-019-50954-y

Alzheimer's disease (AD) is the second most occurring neurological disorder after stroke and is associated with cerebral hypoperfusion, possibly contributing to cognitive impairment. In the present study, neuroprotective and anti-AD effects of embelin were evaluated in chronic cerebral hypoperfusion (CCH) rat model using permanent bilateral common carotid artery occlusion (BCCAO) method. Rats were administered with embelin at doses of 0.3, 0.6 or 1.2 mg/kg (i.p) on day 14 post-surgery and tested in Morris water maze (MWM) followed by electrophysiological recordings to access cognitive abilities and synaptic plasticity. The hippocampal brain regions were extracted for gene expression and neurotransmitters analysis. Treatment with embelin at the doses of 0.3 and 0.6 mg/kg significantly reversed the spatial memory impairment induced by CCH in rats. Embelin treatment has significantly protected synaptic plasticity impairment as assessed by hippocampal long-term potentiation (LTP) test. The mechanism of this study demonstrated that embelin treatment alleviated the decreased expression of BDNF, CREB1, APP, Mapt, SOD1 and NFκB mRNA levels caused by CCH rats. Furthermore, treatment with embelin demonstrated neuromodulatory activity by its ability to restore hippocampal neurotransmitters. Overall these data suggest that embelin improve memory and synaptic plasticity impairment in CCH rats and can be a potential drug candidate for neurodegenerative disease-related cognitive disorders.
Fulltext Pilocarpine Induced Behavioral and Biochemical Alterations in Chronic Seizure-Like Condition in Adult Zebrafish

Paudel YN, Kumari Y, Abidin SAZ, Othman I, Shaikh MF

Int J Mol Sci, 2020 Apr 03;21(7).
PMID: 32260203 DOI: 10.3390/ijms21072492

Epilepsy is a devastating neurological condition exhibited by repeated spontaneous and unpredictable seizures afflicting around 70 million people globally. The basic pathophysiology of epileptic seizures is still elusive, reflecting an extensive need for further research. Developing a novel animal model is crucial in understanding disease mechanisms as well as in assessing the therapeutic target. Most of the pre-clinical epilepsy research has been focused on rodents. Nevertheless, zebrafish disease models are relevant to human disease pathophysiology hence are gaining increased attention nowadays. The current study for the very first time developed a pilocarpine-induced chronic seizure-like condition in adult zebrafish and investigated the modulation in several neuroinflammatory genes and neurotransmitters after pilocarpine exposures. Seizure score analysis suggests that compared to a single dose, repeated dose pilocarpine produces chronic seizure-like effects maintaining an average seizure score of above 2 each day for a minimum of 10 days. Compared to the single dose pilocarpine treated group, there was increased mRNA expression of HMGB1, TLR4, TNF-α, IL-1, BDNF, CREB-1, and NPY; whereas decreased expression of NF-κB was upon the repeated dose of pilocarpine administration. In addition, the epileptic group demonstrates modulation in neurotransmitters levels such as GABA, Glutamate, and Acetylcholine. Moreover, proteomic profiling of the zebrafish brain from the normal and epileptic groups from LCMS/MS quantification detected 77 and 13 proteins in the normal and epileptic group respectively. Summing up, the current investigation depicted that chemically induced seizures in zebrafish demonstrated behavioral and molecular alterations similar to classical rodent seizure models suggesting the usability of adult zebrafish as a robust model to investigate epileptic seizures.
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.
Potential Neuroprotective Effect of the HMGB1 Inhibitor Glycyrrhizin in Neurological Disorders

Paudel YN, Angelopoulou E, Semple B, Piperi C, Othman I, Shaikh MF

ACS Chem Neurosci, 2020 02 19;11(4):485-500.
PMID: 31972087 DOI: 10.1021/acschemneuro.9b00640

Glycyrrhizin (glycyrrhizic acid), a bioactive triterpenoid saponin constituent of Glycyrrhiza glabra, is a traditional medicine possessing a plethora of pharmacological anti-inflammatory, antioxidant, antimicrobial, and antiaging properties. It is a known pharmacological inhibitor of high mobility group box 1 (HMGB1), a ubiquitous protein with proinflammatory cytokine-like activity. HMGB1 has been implicated in an array of inflammatory diseases when released extracellularly, mainly by activating intracellular signaling upon binding to the receptor for advanced glycation end products (RAGE) and toll-like receptor 4 (TLR4). HMGB1 neutralization strategies have demonstrated disease-modifying outcomes in several preclinical models of neurological disorders. Herein, we reveal the potential neuroprotective effects of glycyrrhizin against several neurological disorders. Emerging findings demonstrate the therapeutic potential of glycyrrhizin against several HMGB1-mediated pathological conditions including traumatic brain injury, neuroinflammation and associated conditions, epileptic seizures, Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Glycyrrhizin's effects in neurological disorders are mainly attributed to the attenuation of neuronal damage by inhibiting HMGB1 expression and translocation as well as by downregulating the expression of inflammatory cytokines. A large number of preclinical findings supports the notion that glycyrrhizin might be a promising therapeutic alternative to overcome the shortcomings of the mainstream therapeutic strategies against neurological disorders, mainly by halting disease progression. However, future research is warranted for a deeper exploration of the precise underlying molecular mechanism as well as for clinical translation.
Re-visiting pH-adjusted potassium to avoid hypokalemic crisis during management of diabetic ketoacidosis: A conceptual framework

Usman A, Shaikh MF, Dujaili JA, Mustafa N, Gan SH

Diabetes Metab Syndr, 2021 Mar 05;15(2):573-580.
PMID: 33706189 DOI: 10.1016/j.dsx.2021.03.001

BACKGROUND AND AIMS: Diabetic ketoacidosis (DKA) treatment guidelines recommend to initiate potassium-replacement when serum potassium (SK) drops within normal range, and to withhold insulin if SK is below normal. Despite strict recommendations, hypokalemia is frequently observed in DKA.
METHODS: Scientific literature was thoroughly searched to find 1) DKA treatment guidelines, 2) studies reporting hypokalemia in DKA, 3) and literature elaborating mechanisms involved in hypokalemia.
RESULTS: Acidosis affects SK and its regulators including insulin, catecholamines and aldosterone. Current conceptual framework is an argument to gauge the degree of hypokalemia before it strikes DKA patients utilizing SK level after adjusting it with pH. Suggested approach will reduce hypokalemia risk and its associated complications. The nomogram calculates pH-adjusted potassium and expected potassium loss. It also ranks hypokalemia associated risk, and proposes the potassium-replacement rate over given time period. The differences between current DKA treatment guidelines and proposed strategy are also discussed. Moreover, reasons and risk of hyperkalemia due to early initiation of potassium replacement and remedial actions are debated.
CONCLUSION: In light of proposed strategy, utilizing the nomogram ensures reduced incidence of hypokalemia in DKA resulting in improved clinical and patient outcomes. Pharmacoeconomic benefits can also be expected when avoiding hypokalemia ensures early discharge.
Gut Microbiota and Epilepsy: A Systematic Review on Their Relationship and Possible Therapeutics

Arulsamy A, Tan QY, Balasubramaniam V, O'Brien TJ, Shaikh MF

ACS Chem Neurosci, 2020 Nov 04;11(21):3488-3498.
PMID: 33064448 DOI: 10.1021/acschemneuro.0c00431

Dysbiosis of gut microbiota may lead to a range of diseases including neurological disorders. Thus, it is hypothesized that regulation of the intestinal microbiota may prevent or treat epilepsy. The purpose of this systematic review is to evaluate the evidence investigating the relationship between gut microbiota and epilepsy and possible interventions. A systematic review of the literature was done on four databases (PubMed, Scopus, EMBASE, and Web of Science). Study selection was restricted to original research articles while following the PRISMA guidelines. Six studies were selected. These studies cohesively support the interaction between gut microbiota and epileptic seizures. Gut microbiota analysis identified increases in Firmicutes, Proteobacteria, Verrucomicrobia, and Fusobacteria with decreases in Bacteroidetes and Actinobacteria in epileptic patients. Ketogenic diet, probiotics, and fecal microbiota transplantation (FMT) improved the dysbiosis of the gut microbiota and seizure activity. However, the studies either had a small sample size, lack of subject variability, or short study or follow-up period, which may question their reliability. Nevertheless, these limited studies conclusively suggest that gut microbiota diversity and dysbiosis may be involved in the pathology of epilepsy. Future studies providing more reliable and in depth insight into the gut microbial community will spark promising alternative therapies to current epilepsy treatment.
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.

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