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  1. Tan CH, Wong KY, Chong HP, Tan NH, Tan KY
    J Proteomics, 2019 08 30;206:103418.
    PMID: 31201947 DOI: 10.1016/j.jprot.2019.103418
    The Philippine cobra, Naja philippinensis, is a WHO Category 1 venomous snake of medical importance responsible for fatal envenomation in the northern Philippines. To elucidate the venom proteome and pathophysiology of envenomation, N. philippinensis venom proteins were decomplexed with reverse-phase high-performance liquid chromatography, and protein fractions were subsequently digested with trypsin, followed by nano-liquid chromatography-tandem mass spectrometry analysis and data mining. Three-finger toxins (3FTX, 66.64% of total venom proteins) and phospholipases A2 (PLA2, 22.88%) constitute the main bulk of venom proteome. Other proteins are present at low abundances (<4% each); these include metalloproteinase, serine protease, cobra venom factor, cysteine-rich secretory protein, vespryn, phosphodiesterase, 5' nucleotidase and nerve growth factor. In the three-finger toxin family, the alpha-neurotoxins comprise solely short neurotoxins (SNTX, 44.55%), supporting that SNTX is the principal toxin responsible for neuromuscular paralysis and lethality reported in clinical envenomation. Cytotoxins (CTX) are the second most abundant 3FTX proteins in the venom (21.31%). The presence of CTX correlates with the venom cytotoxic effect, which is more prominent in murine cells than in human cells. From the practical standpoint, SNTX-driven neuromuscular paralysis is significant in N. philippinensis envenomation. Antivenom production and treatment should be tailored accordingly to ensure effective neutralization of SNTX. BIOLOGICAL SIGNIFICANCE: The venom proteome of Naja philippinensis, the Philippine cobra, is unravelled for the first time. Approximately half the protein bulk of the venom is made up of short neurotoxins (44.55% of the total venom proteins). As the only alpha-neurotoxins present in the venom, short neurotoxins are the causative toxins of the post-synaptic blockade and fast-onset neuromuscular paralysis in N. philippinensis envenomation. A substantial amount of cytotoxins (21.31%) was also detected in N. philippinensis venom, supporting that the venom can be cytotoxic although the effect is much weaker in human cells compared to murine cells. The finding is consistent with the low incidence of local tissue necrosis in N. philippinensis envenomation, although this does not negate the need for monitoring and care of bite wound in the patients.
    Matched MeSH terms: Neurotoxicity Syndromes/etiology; Neurotoxicity Syndromes/epidemiology*; Neurotoxicity Syndromes/pathology; Neurotoxicity Syndromes/therapy
  2. Tan CH, Palasuberniam P, Blanco FB, Tan KY
    Trans R Soc Trop Med Hyg, 2021 01 07;115(1):78-84.
    PMID: 32945886 DOI: 10.1093/trstmh/traa087
    BACKGROUND: The Philippine cobra (Naja philippinensis) and Samar cobra (Naja samarensis) are two WHO Category 1 medically important venomous snakes in the Philippines. Philippine cobra antivenom (PCAV) is the only antivenom available in the country, but its neutralization capacity against the venoms of N. philippinensis and hetero-specific N. samarensis has not been reported. This knowledge gap greatly hinders the optimization of antivenom use in the region.

    METHODS: This study examined the immunological binding and neutralization capacity of PCAV against the two cobra venoms using WHO-recommended protocols.

    RESULTS: In mice, both venoms were highly neurotoxic and lethal with a median lethal dose of 0.18 and 0.20 µg/g, respectively. PCAV exhibited strong and comparable immunoreactivity toward the venoms, indicating conserved venom antigenicity between the two allopatric species. In in vivo assay, PCAV was only moderately effective in neutralizing the toxicity of both venoms. Its potency was even lower against the hetero-specific N. samarensis venom by approximately two-fold compared with its potency against N. philippinensis venom.

    CONCLUSION: The results indicated that PCAV could be used to treat N. samarensis envenomation but at a higher dose, which might increase the risk of hypersensitivity and worsen the shortage of antivenom supply in the field. Antivenom manufacturing should be improved by developing a low-dose, high-efficacy product against cobra envenomation.

    Matched MeSH terms: Neurotoxicity Syndromes
  3. Mustafa NS, Bakar NHA, Mohamad N, Adnan LHM, Fauzi NFAM, Thoarlim A, et al.
    Basic Clin Neurosci, 2020 07 01;11(4):381-388.
    PMID: 33613876 DOI: 10.32598/bcn.9.10.485
    N-Methyl-3, 4-methylenedioxyamphetamine (MDMA), or ecstasy is a recreational drug of abuse. It is a synthetic substance that affects the body's systems, which its mechanism of action and treatment should be more investigated. MDMA provides an immediate enjoyable feeling by stimulating the release of neurotransmitters, such as dopamine and serotonin in the brain. Unfortunately, abnormal regulation of the brain neurotransmitters, as well as the increased oxidative stress causes damage to the brain neurons after the MDMA exposure. Only a few studies have been done regarding its treatment. Thus, the treatment of MDMA complications should be further explored mainly by targeting its mechanism of action in the neurotransmitter systems. Hence, this study presents a short review regarding the recent findings on the role of neurotransmitters to cause MDMA neurotoxicity. The results will be useful for future research in elucidating the potential treatment based on the targeted mechanisms to treat the neurotoxic effects of MDMA.
    Matched MeSH terms: Neurotoxicity Syndromes
  4. Chang SH, Lim CS, Low TS, Chong HT, Tan SY
    Transplant Proc, 2001 12 26;33(7-8):3700-1.
    PMID: 11750577
    Matched MeSH terms: Neurotoxicity Syndromes/etiology*
  5. Swamy M, Suhaili D, Sirajudeen KN, Mustapha Z, Govindasamy C
    PMID: 25395704
    BACKGROUND: Increased nitric oxide (NO), neuronal inflammation and apoptosis have been proposed to be involved in excitotoxicity plays a part in many neurodegenerative diseases. To understand the neuro-protective effects of propolis, activities of Nitric oxide synthase (NOS) and caspase-3 along with NO and tumor necrosis factor-α (TNF-α) levels were studied in cerebral cortex (CC), cerebellum (CB) and brain stem (BS) in rats supplemented with propolis prior to excitotoxic injury with kainic acid (KA).

    MATERIALS AND METHODS: Male Sprague-Dawley rats were divided into four groups (n=6 rats per group) as Control, KA, Propolis and KA+Propolis. The control group and KA group have received vehicle and saline. Propolis group and propolis + KA group were orally administered with propolis (150 mg/kg body weight), five times every 12 hours. KA group and propolis +KA group were injected subcutaneously with kainic acid (15 mg/kg body weight) and were sacrificed after 2 hrs. CC, CB and BS were separated, homogenized and used for estimation of NOS, caspase-3, NO and TNF-α by commercial kits. Results were analyzed by one way ANOVA, reported as mean + SD (n=6 rats), and p<0.05 was considered statistically significant.

    RESULTS: The concentration of NO, TNF-α, NOS and caspase-3 activity were increased significantly (p<0.001) in all the three brain regions tested in KA group compared to the control. Propolis supplementation significantly (p<0.001) prevented the increase in NOS, NO, TNF-α and caspase-3 due to KA.

    CONCLUSION: Results of this study clearly demonstrated that the propolis supplementation attenuated the NOS, caspase-3 activities, NO, and TNF-α concentration and in KA mediated excitotoxicity. Hence propolis can be a possible potential protective agent against excitotoxicity and neurodegenerative disorders.

    Matched MeSH terms: Neurotoxicity Syndromes/metabolism; Neurotoxicity Syndromes/prevention & control*
  6. Tay CG, Lee VWM, Ong LC, Goh KJ, Ariffin H, Fong CY
    Pediatr Blood Cancer, 2017 Aug;64(8).
    PMID: 28139029 DOI: 10.1002/pbc.26471
    BACKGROUND: Vincristine, an essential component of childhood acute lymphoblastic leukaemia (ALL) therapeutic protocols, is associated with dose-dependent neurotoxicity, but its long-term morbidity in treated children has not been clearly elucidated. The aim of this study is to determine the prevalence of vincristine-induced peripheral neuropathy (VIPN) among Malaysian childhood ALL survivors and its impact on motor function and quality of life.

    PROCEDURE: Survivors of childhood ALL aged 4-18 years who had completed chemotherapy for 2 years or more were evaluated for VIPN using both the clinical Total Neuropathy Score (cTNS) and nerve conduction studies. Motor function and quality of life of the survivors were assessed via the Bruininks-Oseretsky Test of Motor Proficiency Brief Form, Second Edition (BOT-2 Brief Form) and the Paediatric Quality of Life version 4.0 Generic Core Scales (PedsQL4.0) questionnaire, respectively.

    RESULTS: One hundred and one survivors with a duration of follow-up ranging from 2.0 to 10.3 years were recruited. Twenty-seven (26.7%) had abnormal cTNS scores and 69 (68.3%) had electrophysiological evidence of neuropathy. Of these, 16 (15.8%) had combined clinical and electrophysiological neuropathy (VIPN). Those previously treated on the intermediate- or high-risk treatment stratification arms had a higher risk of developing VIPN (67.3 vs. 32.7%; odds ratio [OR]: 9.06, 95% confidence interval [CI]: 1.14-71.86; P = 0.014). Survivors with VIPN had significantly lower quality of life scores in the physical (P = 0.024) and social domains (P = 0.039) compared with peers without VIPN, but no association with poorer motor function was observed.

    CONCLUSIONS: Sixteen percent of ALL survivors had VIPN. VIPN should be increasingly recognised as a late effect of chemotherapy, as it significantly affects physical and social function quality of life.

    Matched MeSH terms: Neurotoxicity Syndromes/etiology; Neurotoxicity Syndromes/epidemiology*
  7. Rusmili MRA, Othman I, Abidin SAZ, Yusof FA, Ratanabanangkoon K, Chanhome L, et al.
    PLoS One, 2019;14(12):e0227122.
    PMID: 31887191 DOI: 10.1371/journal.pone.0227122
    Malayan krait (Bungarus candidus) is a medically important snake species found in Southeast Asia. The neurotoxic effects of envenoming present as flaccid paralysis of skeletal muscles. It is unclear whether geographical variation in venom composition plays a significant role in the degree of clinical neurotoxicity. In this study, the effects of geographical variation on neurotoxicity and venom composition of B. candidus venoms from Indonesia, Malaysia and Thailand were examined. In the chick biventer cervicis nerve-muscle preparation, all venoms abolished indirect twitches and attenuated contractile responses to nicotinic receptor agonists, with venom from Indonesia displaying the most rapid neurotoxicity. A proteomic analysis indicated that three finger toxins (3FTx), phospholipase A2 (PLA2) and Kunitz-type serine protease inhibitors were common toxin groups in the venoms. In addition, venom from Thailand contained L-amino acid oxidase (LAAO), cysteine rich secretory protein (CRISP), thrombin-like enzyme (TLE) and snake venom metalloproteinase (SVMP). Short-chain post-synaptic neurotoxins were not detected in any of the venoms. The largest quantity of long-chain post-synaptic neurotoxins and non-conventional toxins was found in the venom from Thailand. Analysis of PLA2 activity did not show any correlation between the amount of PLA2 and the degree of neurotoxicity of the venoms. Our study shows that variation in venom composition is not limited to the degree of neurotoxicity. This investigation provides additional insights into the geographical differences in venom composition and provides information that could be used to improve the management of Malayan krait envenoming in Southeast Asia.
    Matched MeSH terms: Neurotoxicity Syndromes/diagnosis; Neurotoxicity Syndromes/etiology
  8. Yokoyama K
    Neurotoxicology, 2007 Mar;28(2):364-73.
    PMID: 16730798
    Attention has been paid to neurobehavioral effects of occupational and environmental exposures to chemicals such as pesticides, heavy metals and organic solvents. The area of research that includes neurobehavioral methods and effects in occupational and environmental health has been called "Occupational and Environmental Neurology and Behavioral Medicine." The methods, by which early changes in neurological, cognitive and behavioral function can be assessed, include neurobehavioral test battery, neurophysiological methods, questionnaires and structured interview, biochemical markers and imaging techniques. The author presents his observations of neurobehavioral and neurophysiological effects in Tokyo subway sarin poisoning cases as well as in pesticide users (tobacco farmers) in Malaysia in relation to Green Tobacco Sickness (GTS). In sarin cases, a variety effects were observed 6-8 months after exposure, suggesting delayed neurological effects. Studies on pesticide users revealed that organophosphorus and dithiocarbamate affected peripheral nerve conduction and postural balance; subjective symptoms related to GTS were also observed, indicating the effects of nicotine absorbed from wet tobacco leaves. In addition, non-neurological effects of pesticides and other chemicals are presented, in relation to genetic polymorphism and oxidative stress.
    Matched MeSH terms: Neurotoxicity Syndromes/etiology*; Neurotoxicity Syndromes/genetics; Neurotoxicity Syndromes/physiopathology; Neurotoxicity Syndromes/psychology
  9. Gonzalez-Carter DA, Leo BF, Ruenraroengsak P, Chen S, Goode AE, Theodorou IG, et al.
    Sci Rep, 2017 03 02;7:42871.
    PMID: 28251989 DOI: 10.1038/srep42871
    Silver nanoparticles (AgNP) are known to penetrate into the brain and cause neuronal death. However, there is a paucity in studies examining the effect of AgNP on the resident immune cells of the brain, microglia. Given microglia are implicated in neurodegenerative disorders such as Parkinson's disease (PD), it is important to examine how AgNPs affect microglial inflammation to fully assess AgNP neurotoxicity. In addition, understanding AgNP processing by microglia will allow better prediction of their long term bioreactivity. In the present study, the in vitro uptake and intracellular transformation of citrate-capped AgNPs by microglia, as well as their effects on microglial inflammation and related neurotoxicity were examined. Analytical microscopy demonstrated internalization and dissolution of AgNPs within microglia and formation of non-reactive silver sulphide (Ag2S) on the surface of AgNPs. Furthermore, AgNP-treatment up-regulated microglial expression of the hydrogen sulphide (H2S)-synthesizing enzyme cystathionine-γ-lyase (CSE). In addition, AgNPs showed significant anti-inflammatory effects, reducing lipopolysaccharide (LPS)-stimulated ROS, nitric oxide and TNFα production, which translated into reduced microglial toxicity towards dopaminergic neurons. Hence, the present results indicate that intracellular Ag2S formation, resulting from CSE-mediated H2S production in microglia, sequesters Ag+ ions released from AgNPs, significantly limiting their toxicity, concomitantly reducing microglial inflammation and related neurotoxicity.
    Matched MeSH terms: Neurotoxicity Syndromes/drug therapy; Neurotoxicity Syndromes/metabolism
  10. Bhatti S, Ali Shah SA, Ahmed T, Zahid S
    Drug Chem Toxicol, 2018 Oct;41(4):399-407.
    PMID: 29742941 DOI: 10.1080/01480545.2018.1459669
    The present study investigates the neuroprotective effects of Foeniculum vulgare seeds in a lead (Pb)-induced brain neurotoxicity mice model. The dried seeds extract of Foeniculum vulgare was prepared with different concentrations of organic solvents (ethanol, methanol, n-hexane). The in vitro antioxidant activity of Foeniculum vulgare seed extracts was assessed through DPPH assay and the chemical composition of the extracts was determined by high-resolution 1H NMR spectroscopy. The age-matched male Balb/c mice (divided into 9 groups) were administered with 0.1% Pb and 75% and 100% ethanol extracts of Foeniculum vulgare seeds at a dose of 200 mg/kg/day and 20 mg/kg/day. The maximum antioxidant activity was found for 75% ethanol extract, followed by 100% ethanol extract. Gene expression levels of oxidative stress markers (SOD1 and Prdx6) and the three isoforms of APP (APP common, 770 and 695), in the cortex and hippocampus of the treated and the control groups were measured. Significant increase in APP 770 expression level while a substantial decrease was observed for SOD1, Prdx6 and APP 695 expression in Pb-treated groups. Interestingly, the deranged expression levels were significantly normalized by the treatment with ethanol extracts of Foeniculum vulgare seeds (specifically at dose of 200 mg/kg/day). Furthermore, the Pb-induced morphological deterioration of cortical neurons was significantly improved by the ethanol extracts of Foeniculum vulgare seeds. In conclusion, the present findings highlight the promising therapeutic potential of Foeniculum vulgare to minimize neuronal toxicity by normalizing the expression levels of APP isoforms and oxidative stress markers.
    Matched MeSH terms: Neurotoxicity Syndromes/prevention & control*
  11. Ooi TC, Ahmad Munawar M, Mohd Rosli NH, Abdul Malek SNA, Rosli H, Ibrahim FW, et al.
    PMID: 32382294 DOI: 10.1155/2020/5126457
    This study aimed to determine the effects of tropical fruit juice mixture (pomegranate, white guava, and Roselle) on biochemical, behavioral, and histopathological changes of β-amyloid- (Aβ-) induced rats. Formulation 8 (F8) of tropical fruit juice mixture was chosen for this present study due to its high phenolic content and antioxidant capacity. Forty Wistar male rats were divided into five groups: dPBS (sham-operated control), dAβ (Aβ control), JPBS (F8 and PBS), JAβ (F8 and Aβ), and IBFAβ (ibuprofen and Aβ). F8 (5 ml/kg BW), and ibuprofen (10 ml/kg BW) was given orally daily for four weeks before the intracerebroventricular infusion of Aβ for two weeks. Histological analysis and neuronal count of hippocampus tissue in the Cornu Ammonis (CA1) region showed that supplementation with F8 was able to prevent Aβ-induced tissue damage and neuronal shrinkage. However, no significant difference in locomotor activity and novel object recognition (NOR) percentage was detected among different groups at day 7 and day 14 following Aβ infusion. Only effect of time differences (main effect of day) was observed at day 7 as compared to day 14, where reduction in locomotor activity and NOR percentage was observed in all groups, with F (1, 7) = 6.940, p < 0.05 and F (1, 7) = 7.152, p < 0.05, respectively. Besides, the MDA level of the JAβ group was significantly lower (p < 0.01) than that of the dPBS group. However, no significant changes in SOD activity were detected among different groups. Significant reduction in plasma CRH level (p < 0.05) and iNOS expression (p < 0.01) in the brain was detected in the JAβ group as compared to the dAβ group. Hence, our current findings suggest that the tropical fruit juice mixture (F8) has the potential to protect the rats from Aβ-induced neurotoxicity in brain hippocampus tissue possibly via its antioxidant properties and the suppression of iNOS expression and CRH production.
    Matched MeSH terms: Neurotoxicity Syndromes
  12. Nurul Farhana Ramlan, Noraini Abu Bakar, Albert, Emmellie Laura, Syaizwan Zahmir Zulkifli, Syahida Ahmad, Mohammad Noor Amal Azmai, et al.
    MyJurnal
    An ideal model organism for neurotoxicology research should meet several characteristics, such as low cost and amenable for high throughput testing. Javanese medaka (JM) has been widely used in the ecotoxicological studies related to the marine and freshwater environment, but rarely utilized for biomedical research. Therefore, in this study, the applicability of using JM in the neurotoxicology research was assessed using biochemical comparison with an established model organism, the zebrafish. Identification of biochemical changes due to the neurotoxic effects of ethanol and endosulfan was assessed using Fourier Transform Infrared (FTIR) analysis. Treatment with ethanol affected the level of lipids, proteins, glycogens and nucleic acids in the brain of JM. Meanwhile, treatment with endosulfan showed alteration in the level of lipids and nucleic acids. For the zebrafish, exposure to ethanol affected the level of protein, fatty acid and amino acid, and exposure to endosulfan induced alteration in the fatty acids, amino acids, nucleic acids and protein in the brain of zebrafish. The sensitive response of the JM toward chemicals exposure proved that it was a valuable model for neurotoxicology research. More studies need to be conducted to further develop JM as an ideal model organism for neurotoxicology research.
    Matched MeSH terms: Neurotoxicity Syndromes
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