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Fulltext Editorial: Experimental models of epilepsy and related comorbidities, Volume II

Shaikh MF, Ngadimon IW, Chakraborti A, Abdullah JM, Russo E

Front Pharmacol, 2023;14:1182958.
PMID: 37033657 DOI: 10.3389/fphar.2023.1182958
Fulltext Nanoparticle-Terpene Fusion: A Game-Changer in Combating Primary Amoebic Meningoencephalitis Caused by Naegleria fowleri

Rajendran K, Ahmed U, Meunier AC, Shaikh MF, Siddiqui R, Anwar A

ACS Omega, 2024 Mar 12;9(10):11597-11607.
PMID: 38497026 DOI: 10.1021/acsomega.3c08844

Pathogenic Naegleria fowleri (N. fowleri) are opportunistic free-living amoebae and are the causative agents of a very rare but severe brain infection called primary amoebic meningoencephalitis (PAM). The fatality rate of PAM in reported cases is more than 95%. Most of the drugs used againstN. fowleri infections are repurposed drugs. Therefore, a large number of compounds have been tested againstN. fowleri in vitro, but most of the tested compounds showed high toxicity and an inability to cross the blood-brain barrier. Andrographolide, forskolin, and borneol are important natural compounds that have shown various valuable biological properties. In the present study, the nanoconjugates (AND-AgNPs, BOR-AgNPs, and FOR-AgNPs) of these compounds were synthesized and assessed against both stages (trophozoite and cyst) ofN. fowleri for their antiamoebic and cysticidal potential in vitro. In addition, cytotoxicity and host cell pathogenicity were also evaluated in vitro. FOR-AgNPs were the most potent nanoconjugate and showed potent antiamoebic activity againstN. fowleriwith an IC50 of 26.35 μM. Nanoconjugates FOR-AgNPs, BOR-AgNPs, and AND-AgNPs also significantly inhibit the viability of N. fowleri cysts. Cytotoxicity assessment showed that these nanoconjugates caused minimum damage to human keratinocyte cells (HaCaT cells) at 100 μg/mL, while also effectively reducing the cytopathogenicity of N. fowleri trophozoites to the HaCaT cells. The outcomes of our experiments have unveiled substantial potential for AND-AgNPs, BOR-AgNPs, and FOR-AgNPs in the realm of developing innovative alternative therapeutic agents to combat infections caused by N. fowleri. This study represents a significant step forward in the pursuit of advanced strategies for managing such amoebic infections, laying the foundation for the development of novel and more effective therapeutic modalities in the fight against free-living amoebae.
Repurposing Anakinra for Alzheimer's Disease: The In Vitro and In Vivo Effects of Anakinra on LPS- and AC-Induced Neuroinflammation

Retinasamy T, Lee ALY, Lee HS, Lee VLL, Shaikh MF, Yeong KY

ACS Chem Neurosci, 2024 Sep 18;15(18):3298-3310.
PMID: 39213521 DOI: 10.1021/acschemneuro.4c00205

Alzheimer's disease is a significant global health issue, and studies suggest that neuroinflammation plays a vital role in the advancement of this disease. In this study, anakinra has been shown to display a time- and concentration-dependent antineuroinflammatory effect. In the in vitro studies, it diminished the gene expressions of tumor necrosis factor-alpha (TNF-α) and nitric oxide (NO) synthase 2 stimulated by lipopolysaccharide (LPS). Anakinra also reduced the LPS-induced production of NO and reactive oxygen species. Thus, the hypertrophic state of LPS-activated BV2 microglial cells was reversed by anakinra. Furthermore, acrylamide (ACR)-induced activation of nuclear transcription factor-κB, TNF-α, and interleukin-1β was downregulated, while cAMP response element binding protein and brain-derived neurotrophic factor expression levels were markedly enhanced in ACR-treated zebrafish larvae. It was also observed that anakinra improved the uncoordinated swimming behaviors in ACR-exposed zebrafish larvae. Overall, anakinra demonstrated potential antineuroinflammatory and antioxidative effects.
The Role of HMGB1 in Infection-Related Cognitive Deficits

Irzan FI, Retinasamy T, Wen WR, Sheng ETM, Shaikh MF, Arulsamy A

Front Biosci (Landmark Ed), 2025 Feb 18;30(2):25544.
PMID: 40018921 DOI: 10.31083/FBL25544

Infectious diseases caused by fungi, viruses, or bacteria can have a profound impact on human cognition. This can be due to either direct spread to the central nervous system (CNS) or indirect neuroinflammation. Ultimately causing neuronal damage and even neurodegeneration. Deteriorations in cognition, such as poor encoding and attention deficits, have been reported secondary to infectious diseases. Preclinical studies have identified the underlying mechanisms of these infection-related cognitive effects, such as through blood-brain barrier (BBB) disruption and M1 microglial polarization. These mechanisms are spearheaded by inflammatory markers that are released/initiated by the pathogens over the course of the infection. Among them, the high mobility group box 1 (HMGB1) protein is a common biomarker implicated across several infection-related cognitive deficits. Understanding these effects and mechanisms is crucial for the development of strategies to prevent and treat infection-related cognitive impairment. This review will thus consolidate and elucidate the current knowledge on the potential role of HMGB1 as a therapeutic target for infection-related cognitive impairments. This review will not only advance scientific understanding but also have significant clinical and public health implications, especially considering recent global health challenges. Based on the selected articles, extracellular HMGB1, as opposed to intracellular HMGB1, acts as damage-associated molecular patterns (DAMPs) or alarmins when released in the peripheries secondary to inflammasome activation. Due to their low molecular weight, they then enter the CNS through routes such as retrograde transport along the afferent nerves, or simple diffusion across the impaired BBB. This results in further disruption of the brain microenvironment due to the dysregulation of other regulatory pathways. The outcome is structural neuronal changes and cognitive impairment. Given its key role in neuroinflammation, HMGB1 holds promise as both a biomarker for diagnostic detection and a potential therapeutic target candidate for preventing infection-related cognitive impairment.
Fulltext Mapping epilepsy biomarkers: a bibliometric and content analysis

Ngadimon IW, Shaikh MF, Mohan D, Cheong WL, Khoo CS

Drug Discov Today, 2024 Dec;29(12):104247.
PMID: 39571887 DOI: 10.1016/j.drudis.2024.104247

Epilepsy, a complex global neurological disorder, has spurred extensive research efforts focused on enhancing diagnostic and therapeutic strategies, with a growing emphasis on the identification of biomarkers. This bibliometric study examines 1,774 publications from 2000 to 2023, revealing a notable increase in research activity, particularly in the past decade. The US, China, and the UK lead contributions, with Asian countries exhibiting growing potential. Keyword co-occurrence analysis reveals a shift towards investigations of neuroinflammatory and genetic biomarkers, as well as emerging areas such as artificial intelligence and epigenetics. Content analysis links specific epilepsy aetiologies to biomarkers, offering promising possibilities for personalised diagnostics and treatments. These findings yield valuable insights into current trends, guiding future research and informing the development of targeted approaches for the diagnosis and treatment of epilepsy.
Synaptic Function and Dysfunction: New Frontiers in CNS Disorders

Aslan FS, Akdag MB, Doganyigit Z, Okan A, Shaikh MF, Akyuz E

J Neurosci Res, 2025 Apr;103(4):e70033.
PMID: 40172089 DOI: 10.1002/jnr.70033

Central nervous system (CNS) disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and migraines, rank among the most prevalent and concerning conditions worldwide. Despite ongoing research, the pathophysiology of these disorders remains incompletely understood, primarily due to their complex etiology. Current pharmacological treatments mainly focus on alleviating symptoms rather than addressing the underlying causes of these diseases. CNS disorders are marked by impairments in neurocognitive and neuromuscular functions, and cognitive processes like learning and memory. This deterioration not only impacts the quality of life of affected individuals but also places a significant burden on their families. Neuroplasticity is a key property of the nervous system that enables brain repair and functional recovery. However, in CNS disorders, neuroplasticity is often compromised. Neuroplasticity, which is regulated by gene expression, is also modulated by environmental factors and epigenetic mechanisms, thereby reshaping neuronal networks in response to various biological and environmental stimuli and brain function. Importantly, neuroplasticity plays a critical role in repairing the brain, especially in the context of neurodegenerative diseases, where damaged neurons can reorganize and re-establish lost functions. Targeting neuroplasticity mechanisms holds significant potential for developing therapeutic interventions to improve treatment outcomes and prevent CNS disorders. A deeper understanding of neuroplasticity in neurological diseases could open new avenues for enhancing patient quality of life. This review aims to provide a comprehensive overview of synaptic function and the neuroplasticity mechanisms that are disrupted in neurological disorders.
Fulltext HMGB1: A Common Biomarker and Potential Target for TBI, Neuroinflammation, Epilepsy, and Cognitive Dysfunction

Paudel YN, Shaikh MF, Chakraborti A, Kumari Y, Aledo-Serrano Á, Aleksovska K, et al.

Front Neurosci, 2018;12:628.
PMID: 30271319 DOI: 10.3389/fnins.2018.00628

High mobility group box protein 1 (HMGB1) is a ubiquitous nuclear protein released by glia and neurons upon inflammasome activation and activates receptor for advanced glycation end products (RAGE) and toll-like receptor (TLR) 4 on the target cells. HMGB1/TLR4 axis is a key initiator of neuroinflammation. In recent days, more attention has been paid to HMGB1 due to its contribution in traumatic brain injury (TBI), neuroinflammatory conditions, epileptogenesis, and cognitive impairments and has emerged as a novel target for those conditions. Nevertheless, HMGB1 has not been portrayed as a common prognostic biomarker for these HMGB1 mediated pathologies. The current review discusses the contribution of HMGB1/TLR4/RAGE signaling in several brain injury, neuroinflammation mediated disorders, epileptogenesis and cognitive dysfunctions and in the light of available evidence, argued the possibilities of HMGB1 as a common viable biomarker of the above mentioned neurological dysfunctions. Furthermore, the review also addresses the result of preclinical studies focused on HMGB1 targeted therapy by the HMGB1 antagonist in several ranges of HMGB1 mediated conditions and noted an encouraging result. These findings suggest HMGB1 as a potential candidate to be a common biomarker of TBI, neuroinflammation, epileptogenesis, and cognitive dysfunctions which can be used for early prediction and progression of those neurological diseases. Future study should explore toward the translational implication of HMGB1 which can open the windows of opportunities for the development of innovative therapeutics that could prevent several associated HMGB1 mediated pathologies discussed herein.
Effect of newer anti-epileptic drugs (AEDs) on the cognitive status in pentylenetetrazol induced seizures in a zebrafish model

Choo BKM, Kundap UP, Johan Arief MFB, Kumari Y, Yap JL, Wong CP, et al.

Prog Neuropsychopharmacol Biol Psychiatry, 2019 06 08;92:483-493.
PMID: 30844417 DOI: 10.1016/j.pnpbp.2019.02.014

Epilepsy is marked by seizures that are a manifestation of excessive brain activity and is symptomatically treatable by anti-epileptic drugs (AEDs). Unfortunately, the older AEDs have many side effects, with cognitive impairment being a major side effect that affects the daily lives of people with epilepsy. Thus, this study aimed to determine if newer AEDs (Zonisamide, Levetiracetam, Perampanel, Lamotrigine and Valproic Acid) also cause cognitive impairment, using a zebrafish model. Acute seizures were induced in zebrafish using pentylenetetrazol (PTZ) and cognitive function was assessed using the T-maze test of learning and memory. Neurotransmitter and gene expression levels related to epilepsy as well as learning and memory were also studied to provide a better understanding of the underlying processes. Ultimately, impaired cognitive function was seen in AED treated zebrafish, regardless of whether seizures were induced. A highly significant decrease in γ-Aminobutyric Acid (GABA) and glutamate levels was also discovered, although acetylcholine levels were more variable. The gene expression levels of Brain-Derived Neurotrophic Factor (BDNF), Neuropeptide Y (NPY) and Cyclic Adenosine Monophosphate (CAMP) Responsive Element Binding Protein 1 (CREB-1) were not found to be significantly different in AED treated zebrafish. Based on the experimental results, a decrease in brain glutamate levels due to AED treatment appears to be at least one of the major factors behind the observed cognitive impairment in the treated zebrafish.
Fulltext Alcohol Use Disorder, Neurodegeneration, Alzheimer's and Parkinson's Disease: Interplay Between Oxidative Stress, Neuroimmune Response and Excitotoxicity

Kamal H, Tan GC, Ibrahim SF, Shaikh MF, Mohamed IN, Mohamed RMP, et al.

Front Cell Neurosci, 2020;14:282.
PMID: 33061892 DOI: 10.3389/fncel.2020.00282

Alcohol use disorder (AUD) has been associated with neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Prolonged excessive alcohol intake contributes to increased production of reactive oxygen species that triggers neuroimmune response and cellular apoptosis and necrosis via lipid peroxidation, mitochondrial, protein or DNA damage. Long term binge alcohol consumption also upregulates glutamate receptors, glucocorticoids and reduces reuptake of glutamate in the central nervous system, resulting in glutamate excitotoxicity, and eventually mitochondrial injury and cell death. In this review, we delineate the following principles in alcohol-induced neurodegeneration: (1) alcohol-induced oxidative stress, (2) neuroimmune response toward increased oxidants and lipopolysaccharide, (3) glutamate excitotoxicity and cell injury, and (4) interplay between oxidative stress, neuroimmune response and excitotoxicity leading to neurodegeneration and (5) potential chronic alcohol intake-induced development of neurodegenerative diseases, including Alzheimer's and Parkinson's disease.
Fulltext Immunoreactivity of Muscarinic Acetylcholine M2 and Serotonin 5-HT2B Receptors, Norepinephrine Transporter and Kir Channels in a Model of Epilepsy

Akyuz E, Doganyigit Z, Paudel YN, Koklu B, Kaymak E, Villa C, et al.

Life (Basel), 2021 Mar 26;11(4).
PMID: 33810231 DOI: 10.3390/life11040276

Epilepsy is characterized by an imbalance in neurotransmitter activity; an increased excitatory to an inhibitory activity. Acetylcholine (ACh), serotonin, and norepinephrine (NE) may modulate neural activity via several mechanisms, mainly through its receptors/transporter activity and alterations in the extracellular potassium (K+) concentration via K+ ion channels. Seizures may disrupt the regulation of inwardly rectifying K+ (Kir) channels and alter the receptor/transporter activity. However, there are limited data present on the immunoreactivity pattern of these neurotransmitter receptors/transporters and K+ channels in chronic models of epilepsy, which therefore was the aim of this study. Changes in the immunoreactivity of epileptogenesis-related neurotransmitter receptors/transporters (M2, 5-HT2B, and NE transporter) as well as Kir channels (Kir3.1 and Kir6.2) were determined in the cortex, hippocampus and medulla of adult Wistar rats by utilizing a Pentylenetetrazol (PTZ)-kindling chronic epilepsy model. Increased immunoreactivity of the NE transporter, M2, and 5-HT2B receptors was witnessed in the cortex and medulla. While the immunoreactivity of the 5-HT2B receptor was found increased in the cortex and medulla, it was decreased in the hippocampus, with no changes observed in the M2 receptor in this region. Kir3.1 and Kir6.2 staining showed increase immunoreactivity in the cerebral cortex, but channel contrasting findings in the hippocampus and medulla. Our results suggest that seizure kindling may result in significant changes in the neurotransmitter system which may contribute or propagate to future epileptogenesis, brain damage and potentially towards sudden unexpected death in epilepsy (SUDEP). Further studies on the pathogenic role of these changes in neurotransmitter receptors/transporters and K+ channel immunoreactivity may identify newer possible targets to treat seizures or prevent epilepsy-related comorbidities.
Fulltext Feasibility of cardiac-based seizure detection and prediction: A systematic review of non-invasive wearable sensor-based studies

Seth EA, Watterson J, Xie J, Arulsamy A, Md Yusof HH, Ngadimon IW, et al.

Epilepsia Open, 2024 Feb;9(1):41-59.
PMID: 37881157 DOI: 10.1002/epi4.12854

A reliable seizure detection or prediction device can potentially reduce the morbidity and mortality associated with epileptic seizures. Previous findings indicating alterations in cardiac activity during seizures suggest the usefulness of cardiac parameters for seizure detection or prediction. This study aims to examine available studies on seizure detection and prediction based on cardiac parameters using non-invasive wearable devices. The Embase, PubMed, and Scopus databases were used to systematically search according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Human studies that evaluated seizure detection or prediction based on cardiac parameters collected using wearable devices were included. The QUADAS-2 tool and proposed standards for validation for seizure detection devices were used for quality assessment. Twenty-four articles were identified and included in the analysis. Twenty studies evaluated seizure detection algorithms, and four studies focused on seizure prediction. Most studies used either a wrist-worn or chest-worn device for data acquisition. Among the seizure detection studies, cardiac parameters utilized for the algorithms mainly included heart rate (HR) (n = 11) or a combination of HR and heart rate variability (HRV) (n = 6). HR-based seizure detection studies collectively reported a sensitivity range of 56%-100% and a false alarm rate (FAR) of 0.02-8/h, with most studies performing retrospective validation of the algorithms. Three of the seizure prediction studies retrospectively validated multimodal algorithms, combining cardiac features with other physiological signals. Only one study prospectively validated their seizure prediction algorithm using HRV extracted from ECG data collected from a custom wearable device. These studies have demonstrated the feasibility of using cardiac parameters for seizure detection and prediction with wearable devices, with varying algorithmic performance. Many studies are in the proof-of-principle stage, and evidence for real-time detection or prediction is currently limited. Future studies should prioritize further refinement of the algorithm performance with prospective validation using large-scale longitudinal data. PLAIN LANGUAGE SUMMARY: This systematic review highlights the potential use of wearable devices, like wristbands, for detecting and predicting seizures via the measurement of heart activity. By reviewing 24 articles, it was found that most studies focused on using heart rate and changes in heart rate for seizure detection. There was a lack of studies looking at seizure prediction. The results were promising but most studies were not conducted in real-time. Therefore, more real-time studies are needed to verify the usage of heart activity-related wearable devices to detect seizures and even predict them, which will be beneficial to people with epilepsy.
Fulltext An Expanded Narrative Review of Neurotransmitters on Alzheimer's Disease: The Role of Therapeutic Interventions on Neurotransmission

Akyuz E, Arulsamy A, Aslan FS, Sarisözen B, Guney B, Hekimoglu A, et al.

Mol Neurobiol, 2025 Feb;62(2):1631-1674.
PMID: 39012443 DOI: 10.1007/s12035-024-04333-y

Alzheimer's disease (AD) is a progressive neurodegenerative disease. The accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles are the key players responsible for the pathogenesis of the disease. The accumulation of Aβ plaques and tau affect the balance in chemical neurotransmitters in the brain. Thus, the current review examined the role of neurotransmitters in the pathogenesis of Alzheimer's disease and discusses the alterations in the neurochemical activity and cross talk with their receptors and transporters. In the presence of Aβ plaques and neurofibrillary tangles, changes may occur in the expression of neuronal receptors which in turn triggers excessive release of glutamate into the synaptic cleft contributing to cell death and neuronal damage. The GABAergic system may also be affected by AD pathology in a similar way. In addition, decreased receptors in the cholinergic system and dysfunction in the dopamine neurotransmission of AD pathology may also contribute to the damage to cognitive function. Moreover, the presence of deficiencies in noradrenergic neurons within the locus coeruleus in AD suggests that noradrenergic stimulation could be useful in addressing its pathophysiology. The regulation of melatonin, known for its effectiveness in enhancing cognitive function and preventing Aβ accumulation, along with the involvement of the serotonergic system and histaminergic system in cognition and memory, becomes remarkable for promoting neurotransmission in AD. Additionally, nitric oxide and adenosine-based therapeutic approaches play a protective role in AD by preventing neuroinflammation. Overall, neurotransmitter-based therapeutic strategies emerge as pivotal for addressing neurotransmitter homeostasis and neurotransmission in the context of AD. This review discussed the potential for neurotransmitter-based drugs to be effective in slowing and correcting the neurodegenerative processes in AD by targeting the neurochemical imbalance in the brain. Therefore, neurotransmitter-based drugs could serve as a future therapeutic strategy to tackle AD.
Fulltext Traumatic brain injury-induced peripheral damage: The dynamics of the inflammatory and autophagy pathway from acute to chronic stages

Doğanyiğit Z, Taheri S, Okan A, Yılmaz Z, Üner AK, Akyüz E, et al.

Folia Neuropathol, 2024 Aug 21.
PMID: 39165216 DOI: 10.5114/fn.2024.140788

INTRODUCTION: Traumatic brain injury (TBI) is one of the major causes of death and disability worldwide, and brings a huge burden on the quality of life of patients with TBI and the country's healthcare system. Peripheral organs, especially the kidney, and liver, may be affected by the onset of molecular responses following brain tissue damage. While secondary injury responses post TBI has been well studied in the brain, the effect/consequences of these responses in the peripheral organs have not yet been fully elucidated. Thus, our study aimed to investigate the immunoreactivity of these responses, particularly via proinflammatory cytokines and autophagy markers in the kidney and liver post-acute and chronic TBI.
MATERIAL AND METHODS: Mild TBI (mTBI) and repetitive mTBI (r-mTBI) were induced in male and female 2-month-old Balb/c mice via the Marmarou weight-drop model. Liver and kidney tissues were sampled at 24 hours (acute) and 30 days (chronic) post TBI and subjected to histopathological and immunoreactivity analysis.
RESULTS: Interleukin (IL)-6 levels were significantly increased in the male liver and kidney tissues in both TBI groups compared to the control group but were seen to be decreased in the female r-mTBI chronic liver and r-mTBI acute kidney. Tumor necrosis factor a (TNF-a) levels were found to increase only in the female r-mTBI chronic kidney tissue and mTBI chronic liver tissue. IL-1b levels were increased in the male and female r-mTBI liver tissues but decreased in the female mTBI kidney tissue. Inducible nitric oxide synthase (iNOS) levels were found to be significantly increased in the female mTBI acute and r-mTBI chronic kidney tissue and mTBI liver tissue, but decreased in the r-mTBI acute kidney and r-mTBI liver tissues. Beclin-1 levels were increased in male mTBI chronic and r-mTBI acute liver tissue but decreased in the r-mTBI chronic group. LC3A/B and P62/SQSTM1 levels were significantly increased in the female mTBI chronic and male r-mTBI chronic liver tissues but decreased in the male r-mTBI and female r-mTBI acute kidney tissues. Significant histopathological changes were also observed in the liver and kidney tissue which were dependent on the TBI severity, gender, and time post TBI.
CONCLUSIONS: The results showed that TBI may elicit peripheral molecular responses, particularly in terms of alteration in the levels of inflammatory cytokines and autophagy markers, which were gender- and time-dependent. This suggests that TBI may have a significant role in the cellular damage of the kidney and liver in both the acute and chronic phases post TBI, thus ensuring that the effects of TBI may not be confined to the brain.
Fulltext Neuroprotective potency of mangiferin against 3-nitropropionic acid induced Huntington's disease-like symptoms in rats: possible antioxidant and anti-inflammatory mechanisms

Lum PT, Sekar M, Seow LJ, Shaikh MF, Arulsamy A, Retinasamy T, et al.

Front Pharmacol, 2023;14:1189957.
PMID: 37521470 DOI: 10.3389/fphar.2023.1189957

Huntington's disease (HD), a neurodegenerative disease, normally starts in the prime of adult life, followed by a gradual occurrence of psychiatric disturbances, cognitive and motor dysfunction. The daily performances and life quality of HD patients have been severely interfered by these clinical signs and symptoms until the last stage of neuronal cell death. To the best of our knowledge, no treatment is available to completely mitigate the progression of HD. Mangiferin, a naturally occurring potent glucoxilxanthone, is mainly isolated from the Mangifera indica plant. Considerable studies have confirmed the medicinal benefits of mangiferin against memory and cognitive impairment in neurodegenerative experimental models such as Alzheimer's and Parkinson's diseases. Therefore, this study aims to evaluate the neuroprotective effect of mangiferin against 3-nitropropionic acid (3-NP) induced HD in rat models. Adult Wistar rats (n = 32) were randomly allocated equally into four groups of eight rats each: normal control (Group I), disease control (Group II) and two treatment groups (Group III and Group IV). Treatment with mangiferin (10 and 20 mg/kg, p. o.) was given for 14 days, whereas 3-NP (15 mg/kg, i. p.) was given for 7 days to induce HD-like symptoms in rats. Rats were assessed for cognitive functions and motor coordination using open field test (OFT), novel object recognition (NOR) test, neurological assessment, rotarod and grip strength tests. Biochemical parameters such as oxidative stress markers and pro-inflammatory markers in brain hippocampus, striatum and cortex regions were evaluated. Histopathological study on brain tissue was also conducted using hematoxylin and eosin (H&E) staining. 3-NP triggered anxiety, decreased recognition memory, reduced locomotor activity, lower neurological scoring, declined rotarod performance and grip strength were alleviated by mangiferin treatment. Further, a significant depletion in brain malondialdehyde (MDA) level, an increase in reduced glutathione (GSH) level, succinate dehydrogenase (SDH), superoxide dismutase (SOD) and catalase (CAT) activities, and a decrease in tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β) and interleukin-6 (IL-6) levels were observed in mangiferin treated groups. Mangiferin also mitigated 3-NP induced histopathological alteration in the brain hippocampus, striatum and cortex sections. It could be inferred that mangiferin protects the brain against oxidative damage and neuroinflammation, notably via antioxidant and anti-inflammatory activities. Mangiferin, which has a good safety profile, may be an alternate treatment option for treating HD and other neurodegenerative disorders. The results of the current research of mangiferin will open up new avenues for the development of safe and effective therapeutic agents in diminishing HD.
Fulltext A comprehensive phytochemical, biological, and toxicological studies of roots and aerial parts of Crotalaria burhia Buch.-Ham: An important medicinal plant

Anwar S, Faisal Nadeem M, Pervaiz I, Khurshid U, Akmal N, Aamir K, et al.

Front Plant Sci, 2022;13:988352.
PMID: 36212347 DOI: 10.3389/fpls.2022.988352

This study was designed to seek the phytochemical analysis, antioxidant, enzyme inhibition, and toxicity potentials of methanol and dichloromethane (DCM) extracts of aerial and root parts of Crotalaria burhia. Total bioactive content, high-performance liquid chromatography-photodiode array detector (HPLC-PDA) polyphenolic quantification, and ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS) analysis were utilized to evaluate the phytochemical composition. Antioxidant [including 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH)], 2,2'-azino-bis[3-ethylbenzothiazoline-6-sulfonic acid (ABTS), ferric reducing antioxidant power assay (FRAP), cupric reducing antioxidant capacity CUPRAC, phosphomolybdenum, and metal chelation assays] and enzyme inhibition [against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), α-glucosidase, α-amylase, and tyrosinase] assays were carried out for biological evaluation. The cytotoxicity was tested against MCF-7 and MDA-MB-231 breast cell lines. The root-methanol extract contained the highest levels of phenolics (37.69 mg gallic acid equivalent/g extract) and flavonoids (83.0 mg quercetin equivalent/g extract) contents, and was also the most active for DPPH (50.04 mg Trolox equivalent/g extract) and CUPRAC (139.96 mg Trolox equivalent /g extract) antioxidant assays. Likewise, the aerial-methanol extract exhibited maximum activity for ABTS (94.05 mg Trolox equivalent/g extract) and FRAP (64.23 mg Trolox equivalent/g extract) assays. The aerial-DCM extract was noted to be a convincing cholinesterase (AChE; 4.01 and BChE; 4.28 mg galantamine equivalent/g extract), and α-glucosidase inhibitor (1.92 mmol acarbose equivalent/g extract). All of the extracts exhibited weak to modest toxicity against the tested cell lines. A considerable quantities of gallic acid, catechin, 4-OH benzoic acid, syringic acid, vanillic acid, 3-OH-4-MeO benzaldehyde, epicatechin, p-coumaric acid, rutin, naringenin, and carvacrol were quantified via HPLC-PDA analysis. UHPLC-MS analysis of methanolic extracts from roots and aerial parts revealed the tentative identification of important phytoconstituents such as polyphenols, saponins, flavonoids, and glycoside derivatives. To conclude, this plant could be considered a promising source of origin for bioactive compounds with several therapeutic uses.
Incidence and predictors of posttraumatic epilepsy and cognitive impairment in patients with traumatic brain injury: A retrospective cohort study in Malaysia

Ngadimon IW, Mohan D, Shaikh MF, Khoo CS, Tan HJ, Chamhuri NS, et al.

Epilepsia, 2024 Jul;65(7):1962-1974.
PMID: 38752783 DOI: 10.1111/epi.18007

OBJECTIVE: Posttraumatic epilepsy (PTE) significantly impacts morbidity and mortality, yet local PTE data remain scarce. In addition, there is a lack of evidence on cognitive comorbidity in individuals with PTE in the literature. We sought to identify potential PTE predictors and evaluate cognitive comorbidity in patients with PTE.
METHODS: A 2-year retrospective cohort study was employed, in which adults with a history of admission for traumatic brain injury (TBI) in 2019 and 2020 were contacted. Three hundred one individuals agreed to participate, with a median follow-up time of 30.75 months. The development of epilepsy was ascertained using a validated tool and confirmed by our neurologists during visits. Clinical psychologists assessed the patients' cognitive performance.
RESULTS: The 2-year cumulative incidence of PTE was 9.3% (95% confidence interval [CI] 5.9-12.7). The significant predictors of PTE were identified as a previous history of brain injury [hazard ratio [HR] 4.025, p = .021], and intraparenchymal hemorrhage (HR: 2.291, p = .036), after adjusting for other confounders. TBI patients with PTE performed significantly worse on the total ACE-III cognitive test (73.5 vs 87.0, p = .018), CTMT (27.5 vs 33.0, p = .044), and PSI (74.0 vs 86.0, p = .006) than TBI patients without PTE. A significantly higher percentage of individuals in the PTE group had cognitive impairment, compared to the non-PTE group based on ACE-III (53.6% vs 46.4%, p = .001) and PSI (70% vs 31.7%, p = .005) scores at 2 years post-TBI follow-up.
SIGNIFICANCE: This study emphasizes the link between TBI and PTE and the chance of developing cognitive impairment in the future. Clinicians can target interventions to prevent PTE by identifying specific predictors, which helps them make care decisions and develop therapies to improve patients' quality of life.
Fulltext HMGB1 blood levels and neurological outcomes after traumatic brain injury: Insights from an exploratory study

Ngadimon IW, Mohan D, Shaikh MF, Khoo CS, Tan HJ, Lee YM, et al.

Epilepsia Open, 2025 Feb 12.
PMID: 39937590 DOI: 10.1002/epi4.70001

OBJECTIVE: Posttraumatic epilepsy (PTE) and cognitive impairment are severe complications following traumatic brain injury (TBI). Neuroinflammation likely contributes, but the role of specific inflammatory mediators requires clarification. High-mobility group box 1 (HMGB1) is an inflammatory cytokine released after brain injury that may be involved. This prospective longitudinal study investigated whether serum HMGB1 levels are associated with PTE development and cognitive decline over 12 months post-TBI.
METHODS: Serum samples were collected from 41 TBI patients, including mild and moderate to severe, at baseline, 6, and 12 months following TBI. HMGB1 was quantified by ELISA alongside interleukin-1β (IL-1β) and tumor necrosis factor (TNF). Cognitive assessments using validated neuropsychological assessments were performed at 6 and 12 months. The occurrence of PTE was also tracked.
RESULTS: HMGB1 remained elevated at 12 months post-TBI only in the subgroup (n = 6) that developed PTE (p = 0.026). PTE was associated with moderate to severe TBI cases. Higher HMGB1 levels at 12 months correlated with a greater decline in Addenbrooke's Cognitive Examination scores (p
Management of status epilepticus in Malaysia: A national survey of current practice and treatment gap

Lim KS, Khoo CS, Fong SL, Tan HJ, Fong CY, Mohamed AR, et al.

J Clin Neurosci, 2023 Aug;114:25-31.
PMID: 37279626 DOI: 10.1016/j.jocn.2023.05.006

INTRODUCTION: Early and effective treatment is fundamental in status epilepticus (SE) management. At the initiative of the Epilepsy Council of Malaysia, this study aimed to determine the treatment gap in SE across different healthcare settings in Malaysia.
METHODS: A web-based survey was sent to clinicians involved in the management of SE, across all states and at all levels of healthcare services.
RESULTS: A total of 158 responses were received from 104 health facilities, including 23 tertiary government hospitals (95.8% of all government tertiary hospitals in Malaysia), 4 (80.0%) universities, 14 (6.7%) private, 15 (11.5%) district hospitals and 21 clinics. Intravenous (IV) diazepam was available in 14 (93.3%) district and 33 (80.5%) tertiary hospitals for prehospital management. Non-IV benzodiazepine (rectal diazepam and intramuscular midazolam) was not widely available in prehospital services (75.8% and 51.5%). Intramuscular midazolam was underutilised (60.0% in district and 65.9% in tertiary hospitals). IV sodium valproate and levetiracetam were only available in 66.7% and 53.3% of the district hospitals, respectively. Electroencephalogram (EEG) services were available in only 26.7% of the district hospitals. Non-pharmacological therapies such as ketogenic diet, electroconvulsive therapy, and therapeutic hypothermia were not available in most district and tertiary hospitals for refractory and super-refractory SE.
CONCLUSIONS: We identified several gaps in the current practice of SE management, including limited availability and underutilization of non-IV midazolam in prehospital services, underutilization of non-IV midazolam and other second-line ASMs, and lack of EEG monitoring in district hospitals and limited treatment options for refractory and super-refractory SE in tertiary hospitals.

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