Displaying publications 1 - 20 of 27 in total

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  1. Angelopoulou E, Paudel YN, Papageorgiou SG, Piperi C
    ACS Chem Neurosci, 2021 08 04;12(15):2749-2764.
    PMID: 34275270 DOI: 10.1021/acschemneuro.1c00295
    Alzheimer's disease (AD) is the most common neurodegenerative disorder with obscure pathogenesis and no disease-modifying therapy to date. AD is multifactorial disease that develops from the complex interplay of genetic factors and environmental exposures. The E4 allele of the gene encoding apolipoprotein E (APOE) is the most common genetic risk factor for AD, whereas the E2 allele acts in a protective manner. A growing amount of epidemiological evidence suggests that several lifestyle habits and environmental factors may interact with APOE alleles to synergistically affect the risk of AD development. Among them, physical exercise, dietary habits including fat intake and ketogenic diet, higher education, traumatic brain injury, cigarette smoking, coffee consumption, alcohol intake, and exposure to pesticides and sunlight have gained increasing attention. Although the current evidence is inconsistent, it seems that younger APOE4 carriers in preclinical stages may benefit mostly from preventive lifestyle interventions, whereas older APOE4 noncarriers with dementia may show the most pronounced effects. The large discrepancies between the epidemiological studies may be attributed to differences in the sample sizes, the demographic characteristics of the participants, including age and sex, the methodological design, and potential related exposures and comorbidities as possible cofounding factors. In this Review, we aim to discuss available evidence of the prominent APOE genotype-environment interactions in regard to cognitive decline with a focus on AD, providing an overview of the current landscape in this field and suggesting future directions.
  2. Li X, Gao D, Paudel YN, Li X, Zheng M, Liu G, et al.
    ACS Chem Neurosci, 2022 Feb 02;13(3):330-339.
    PMID: 35044760 DOI: 10.1021/acschemneuro.1c00656
    Parkinson's disease (PD) is a devastating disease of the central nervous system that occurs mainly in the elderly age group, affecting their quality of life. The PD pathogenesis is not yet fully understood and lacks the disease-modifying treatment strategies. Sanghuangprous vaninii (S. vaninii) is a perennial fungus with a plethora of pharmacological activities including anti-cancer and antioxidant activity and so on. However, no study till date has reported its neuroprotective effect against symptoms that are similar to PD in pre-clinical investigation. In the current study, we investigated anti-PD-like effects of S. vaninii mycelium extracts (SvMEs) on MPTP-induced PD in zebrafish. We observed that the loss of dopaminergic neurons and neurovascular reduction were reversed by using SvMEs in the zebrafish brain in a concentration-independent manner. Moreover, it also relieved locomotor impairments in MPTP-induced PD zebrafish. In addition, SvMEs exerted significant antioxidant activity in vitro, which was also demonstrated in vivo on ktr4:NTR-hKikGR zebrafish. Upon investigating the underlying mechanism, we found that SvMEs may alleviate oxidant stress and accelerate α-synuclein degradation and then alleviate PD-like symptoms. Antioxidant-related genes (sod1, gss, gpx4a, gclm, and cat) implied that the SvMEs exhibited anti-PD activity due to the antioxidation mechanism. Finally, upon analysis of chemical composition of SvMEs by liquid chromatography-mass spectrometry, we identified 10 compounds that are plausibly responsible for the anti-PD-like effect of SvMEs. On the limiting part, the finding of the study would have been more robust had we investigated the protein expression of genes related to PD and oxidative stress and compared the effects of SvMEs with any standard anti-PD therapy. Despite this, our results indicated that SvMEs possess anti-PD effects, indicating SvMEs as a potential candidate that is worth exploring further in this avenue.
  3. Mungroo MR, Shahbaz MS, Anwar A, Saad SM, Khan KM, Khan NA, et al.
    ACS Chem Neurosci, 2020 08 19;11(16):2438-2449.
    PMID: 31961126 DOI: 10.1021/acschemneuro.9b00596
    Naegleria fowleri and Balamuthia mandrillaris are protist pathogens that infect the central nervous system, causing primary amoebic meningoencephalitis and granulomatous amoebic encephalitis with mortality rates of over 95%. Quinazolinones and their derivatives possess a wide spectrum of biological properties, but their antiamoebic effects against brain-eating amoebae have never been tested before. In this study, we synthesized a variety of 34 novel arylquinazolinones derivatives (Q1-Q34) by altering both quinazolinone core and aryl substituents. To study the antiamoebic activity of these synthetic arylquinazolinones, amoebicidal and amoebistatic assays were performed against N. fowleri and B. mandrillaris. Moreover, amoebae-mediated host cells cytotopathogenicity and cytotoxicity assays were performed against human keratinocytes cells in vitro. The results revealed that selected arylquinazolinones derivatives decreased the viability of B. mandrillaris and N. fowleri significantly (P < 0.05) and reduced cytopathogenicity of both parasites. Furthermore, these compounds were also found to be least cytotoxic against HaCat cells. Considering that nanoparticle-based materials possess potent in vitro activity against brain-eating amoebae, we conjugated quinazolinones derivatives with silver nanoparticles and showed that activities of the drugs were enhanced successfully after conjugation. The current study suggests that quinazolinones alone as well as conjugated with silver nanoparticles may serve as potent therapeutics against brain-eating amoebae.
  4. Rajendran K, Anwar A, Khan NA, Siddiqui R
    ACS Chem Neurosci, 2017 12 20;8(12):2626-2630.
    PMID: 29206032 DOI: 10.1021/acschemneuro.7b00430
    The overall aim of this study was to determine whether conjugation with silver nanoparticles enhances effects of available drugs against primary amoebic meningoencephalitis due to Naegleria fowleri. Amphotericin B, Nystatin, and Fluconazole were conjugated with silver nanoparticles, and synthesis was confirmed using UV-visible spectrophotometry. Atomic force microscopy determined their size in range of 20-100 nm. To determine amoebicidal effects, N. fowleri were incubated with drugs-conjugated silver nanoparticles, silver nanoparticles alone, and drugs alone. The findings revealed that silver nanoparticles conjugation significantly enhanced antiamoebic effects of Nystatin and Amphotericin B but not Fluconazole at micromolar concentrations, compared with the drugs alone. For the first time, our findings showed that silver nanoparticle conjugation enhances efficacy of antiamoebic drugs against N. fowleri. Given the rarity of the disease and challenges in developing new drugs, it is hoped that modifying existing drugs to enhance their antiamoebic effects is a useful avenue that holds promise in improving the treatment of brain-eating amoebae infection due to N. fowleri.
  5. Anwar A, Rajendran K, Siddiqui R, Raza Shah M, Khan NA
    ACS Chem Neurosci, 2019 01 16;10(1):658-666.
    PMID: 30346711 DOI: 10.1021/acschemneuro.8b00484
    Central nervous system (CNS) infections caused by free-living amoebae such as Acanthamoeba species and Naegleria fowleri are rare but fatal. A major challenge in the treatment against the infections caused by these amoebae is the discovery of novel compounds that can effectively cross the blood-brain barrier to penetrate the CNS. It is logical to test clinically approved drugs against CNS diseases for their potential antiamoebic effects since they are known for effective blood-brain barrier penetration and affect eukaryotic cell targets. The antiamoebic effects of clinically available drugs for seizures targeting gamma-amino butyric acid (GABA) receptor and ion channels were tested against Acanthamoeba castellanii belonging to the T4 genotype and N. fowleri. Three such drugs, namely, diazepam (Valium), phenobarbitone (Luminal), phenytoin (Dilantin), and their silver nanoparticles (AgNPs) were evaluated against both trophozoites and cysts stage. Drugs alone and drug conjugated silver nanoparticles were tested for amoebicidal, cysticidal, and host-cell cytotoxicity assays. Nanoparticles were synthesized by sodium borohydride reduction of silver nitrate with drugs as capping agents. Drug conjugated nanoconjugates were characterized by ultraviolet-visible (UV-vis) and Fourier transform infrared (FT-IR) spectroscopies and atomic force microscopy (AFM). In vitro moebicidal assay showed potent amoebicidal effects for diazepam, phenobarbitone, and phenytoin-conjugated AgNPs as compared to drugs alone against A. castellanii and N. fowleri. Furthermore, both drugs and drug conjugated AgNPs showed compelling cysticidal effects. Drugs conjugations with silver nanoparticles enhanced their antiacanthamoebic activity. Interestingly, amoeba-mediated host-cell cytotoxicity was also significantly reduced by drugs alone as well as their nanoconjugates. Since, these drugs are being used to target CNS diseases, their evaluation against brain-eating amoebae seems feasible due to advantages such as permeability of the blood-brain barrier, established pharmacokinetics and dynamics, and United States Food and Drug Administration (FDA) approval. Given the limited availability of effective drugs against brain-eating amoebae, the clinically available drugs tested here present potential for further in vivo studies.
  6. Bhaskaran M, Devegowda VG, Gupta VK, Shivachar A, Bhosale RR, Arunachalam M, et al.
    ACS Chem Neurosci, 2020 10 07;11(19):2962-2977.
    PMID: 32945654 DOI: 10.1021/acschemneuro.0c00555
    Glioblastoma multiforme (GBM), a standout among the most dangerous class of central nervous system (CNS) cancer, is most common and is an aggressive malignant brain tumor in adults. In spite of developments in modality therapy, it remains mostly incurable. Consequently, the need for novel systems, strategies, or therapeutic approaches for enhancing the assortment of active agents meant for GBM becomes an important criterion. Currently, cancer research focuses mainly on improving the treatment of GBM via diverse novel drug delivery systems. The treatment options at diagnosis are multimodal and include radiation therapy. Moreover, significant advances in understanding the molecular pathology of GBM and associated cell signaling pathways have opened opportunities for new therapies. Innovative treatment such as immunotherapy also gives hope for enhanced survival. The objective of this work was to collect and report the recent research findings to manage GBM. The present review includes existing novel drug delivery systems and therapies intended for managing GBM. Reported novel drug delivery systems and diverse therapies seem to be precise, secure, and relatively effective, which could lead to a new track for the obliteration of GBM.
  7. Han C, Schmitt J, Gilliland KM
    ACS Chem Neurosci, 2020 Jan 13.
    PMID: 31841631 DOI: 10.1021/acschemneuro.9b00535
    The psychoactive plant kratom is a native plant to Southeast Asia, and its major bioactive alkaloid is mitragynine. Mitragynine exerts its analgesic properties by acting on the opioid receptors. One of its active metabolites, 7-hydroxymytraginine, is found to be 40 times more potent than mitragynine and 10 times more potent than morphine. Interestingly, current research suggests that mitragynine behaves as an atypical opioid agonist, possessing analgesic activity with less severe side effects than those of typical opioids. Although Thailand and Malaysia have criminalized the use, possession, growing, or selling of kratom due to its abuse potential, kratom still remains unregulated in the United States. The U.S. Drug Enforcement Agency (DEA) listed kratom as a "drug of concern" in 2008 with the intent to temporarily place mitragynine and 7-hydroxymitragynine onto Schedule I of the Controlled Substances Act. However, responses from the general public, U.S. Congress, and Kratom Alliances had the DEA retract their intent. Kratom is currently marketed in the United States as a dietary or herbal supplement used to treat chronic pain, anxiety, and depression with over $207 million in annual sales in the United States alone. Here, we will review the traditional and medicinal uses of kratom along with the synthesis of its bioactive ingredients and their pharmacology, metabolism, and structure-activity relationships. The importance in society of this currently controversial substance will also be discussed.
  8. Khan NA, Anwar A, Siddiqui R
    ACS Chem Neurosci, 2017 11 15;8(11):2355.
    PMID: 28933530 DOI: 10.1021/acschemneuro.7b00343
    Brain-eating amoebae (Acanthamoeba spp., Balamuthia mandrillaris, and Naegleria fowleri) can cause opportunistic infections involving the central nervous system. It is troubling that the mortality rate is more than 90% despite advances in antimicrobial chemotherapy over the last few decades. Here, we describe urgent key priorities for improving outcomes from infections due to brain-eating amoebae.
  9. 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.
  10. Anwar A, Siddiqui R, Khan NA
    ACS Chem Neurosci, 2019 01 16;10(1):6-12.
    PMID: 30149693 DOI: 10.1021/acschemneuro.8b00321
    Pathogenic free-living amoebae including Acanthamoeba spp., Balamuthia mandrillaris, and Naegleria fowleri cause infections of the central nervous system (CNS), which almost always prove fatal. The mortality rate is high with the CNS infections caused by these microbes despite modern developments in healthcare and antimicrobial chemotherapy. The low awareness, delayed diagnosis, and lack of effective drugs are major hurdles to overcome these challenges. Nanomaterials have emerged as vital tools for concurrent diagnosis and therapy, which are commonly referred to as theranostics. Nanomaterials offer highly sensitive diagnostic systems and viable therapeutic effects as a single modality. There has been good progress to develop nanomaterials based efficient theranostic systems against numerous kinds of tumors, but this field is yet immature in the context of infectious diseases, particularly parasitic infections. Herein, we describe the potential value of theranostic applications of nanomaterials against brain infections due to pathogenic amoebae.
  11. Akyuz E, Kullu I, Arulsamy A, Shaikh MF
    ACS Chem Neurosci, 2021 04 21;12(8):1281-1292.
    PMID: 33813829 DOI: 10.1021/acschemneuro.1c00083
    Epilepsy is a result of unprovoked, uncontrollable, and repetitive outburst of abnormal and excessive electrical discharges, known as seizures, in the neurons. Epilepsy is a devastating neurological condition that affects 70 million people globally. Unfortunately, only two-thirds of epilepsy patients respond to antiepileptic drugs while others become drug resistant and may be more prone to epilepsy comorbidities such as SUDEP. Oxidative stress, mitochondrial dysfunction, imbalance in the excitatory and inhibitory neurotransmitters, and neuroinflammation are some of the common pathologies of neurological disorders and epilepsy. Studies suggests that melatonin, a pineal hormone that governs sleep-wake cycles, may be neuroprotective against neurological disorders and thus may be translated as an antiepileptic as well. Melatonin has been shown to be an antioxidant, antiexcitotoxic, and anti-inflammatory hormone/molecule in neurodegenerative diseases, which may contribute to its antiepileptic and neuroprotective properties in epilepsy as well. In addition, melatonin has evidently been shown to play a regulatory role in the cardiorespiratory system and sleep-wake cycles, which may have positive implications toward epilepsy associated comorbidities, such as SUDEP. However, studies investigating the changes in melatonin release due to epilepsy and melatonin's antiepileptic role have been inconclusive and scarce, respectively. Thus, this comprehensive review aims to summarize and elucidate the potential role of melatonin in the pathogenesis of epilepsy and its comorbidities, in hopes to develop new diagnostic and therapeutic approaches that will improve the lives of epileptic patients, particularly those who are drug resistant.
  12. Rajendran K, Ahmed U, Meunier AC, Shaikh MF, Siddiqui R, Anwar A
    ACS Chem Neurosci, 2023 Dec 06;14(23):4105-4114.
    PMID: 37983556 DOI: 10.1021/acschemneuro.3c00258
    Naegleria fowleri is one of the free-living amoebae and is a causative agent of a lethal and rare central nervous system infection called primary amoebic meningoencephalitis. Despite the advancement in antimicrobial chemotherapy, the fatality rate in the reported cases is more than 95%. Most of the treatment drugs used against N. fowleri infection are repurposed drugs. Therefore, a large number of compounds have been tested against N. fowleri in vitro, but most of the compounds showed high toxicity. To overcome this, we evaluated the effectiveness of naturally occurring terpene compounds against N. fowleri. In this study, we evaluated the antiamoebic potential of natural compounds including Thymol, Borneol, Andrographolide, and Forskolin againstN. fowleri. Thymol showed the highest amoebicidal activity with IC50/24 h at 153.601 ± 19.6 μM. Two combinations of compounds Forskolin + Thymol and Forskolin + Borneol showed a higher effect on the viability of trophozoites as compared to compounds alone and hence showed a synergistic effect. The IC50 reported for Forskolin + Thymol was 81.30 ± 6.86 μM. Borneol showed maximum cysticidal activity with IC50/24 h at 192.605 ± 3.01 μM. Importantly, lactate dehydrogenase release testing revealed that all compounds displayed minimal cytotoxicity to human HaCaT, HeLa, and SH-SY5Y cell lines. The cytopathogenicity assay showed that Thymol and Borneol also significantly reduced the host cell cytotoxicity of pretreated amoeba toward the human HaCaT cell line. So, these terpene compounds hold potential as therapeutic agents against infections caused by N. fowleri and are potentially a step forward in drug development against this deadly pathogen as these compounds have also been reported to cross the blood-brain barrier. Therefore, an in vivo study using animal models is necessary to assess the efficacy of these compounds and the need for further research into the intranasal route of delivery for the treatment of these life-threatening infections.
  13. Paudel YN, Khan SU, Othman I, Shaikh MF
    ACS Chem Neurosci, 2021 09 15;12(18):3288-3302.
    PMID: 34463468 DOI: 10.1021/acschemneuro.0c00825
    Glycyrrhizin (GL) is a well-known pharmacological inhibitor of high mobility group box 1 (HMGB1) and is abundantly present in the licorice root (Glycyrrhiza radix). HMGB1 protein, a key mediator of neuroinflammation, has been implicated in several neurological disorders, including epilepsy. Epilepsy is a devastating neurological disorder with no effective disease-modifying treatment strategies yet, suggesting a pressing need for exploring novel therapeutic options. In the current investigation, using a second hit pentylenetetrazol (PTZ) induced chronic seizure model in adult zebrafish, regulated mRNA expression of HMGB1 was inhibited by pretreatment with GL (25, 50, and 100 mg/kg, ip). A molecular docking study suggests that GL establishes different binding interactions with the various amino acid chains of HMGB1 and Toll-like receptor-4 (TLR4). Our finding suggests that GL pretreatment reduces/suppresses second hit PTZ induced seizure, as shown by the reduction in the seizure score. GL also regulates the second hit PTZ induced behavioral impairment and rescued second hit PTZ related memory impairment as demonstrated by an increase in the inflection ratio (IR) at the 3 h and 24 h T-maze trial. GL inhibited seizure-induced neuronal activity as demonstrated by reduced C-fos mRNA expression. GL also modulated mRNA expression of BDNF, CREB-1, and NPY. The possible mechanism underlying the anticonvulsive effect of GL could be attributed to its anti-inflammatory activity, as demonstrated by the downregulated mRNA expression level of HMGB1, TLR4, NF-kB, and TNF-α. Overall, our finding suggests that GL exerts an anticonvulsive effect and ameliorates seizure-related memory disruption plausibly through regulating of the HMGB1-TLR4-NF-kB axis.
  14. Yong SJ, Veerakumarasivam A, Lim WL, Chew J
    ACS Chem Neurosci, 2023 Mar 30.
    PMID: 36995304 DOI: 10.1021/acschemneuro.2c00679
    Recent advancements in lactoferrin research have uncovered that lactoferrin does function not only as an antimicrobial protein but also as an immunomodulatory, anticancer, and neuroprotective agent. Focusing on neuroprotection, this literature review delineates how lactoferrin interacts in the brain, specifically its neuroprotective effects and mechanisms against Alzheimer's and Parkinson's diseases (AD and PD), the two most common neurodegenerative diseases. The neuroprotective pathways involving surface receptors (heparan sulfate proteoglycan (HSPG) and lactoferrin receptor (LfR)), signaling pathways (extracellular regulated protein kinase-cAMP response element-binding protein (ERK-CREB) and phosphoinositide 3-kinase/Akt (PI3K/Akt)), and effector proteins (A disintegrin and metalloprotease10 (ADAM10) and hypoxia-inducible factor 1α (HIF-1α)) in cortical/hippocampal and dopaminergic neurons are described. These cellular effects of lactoferrin are likely responsible for attenuating cognitive and motor deficits, amyloid-β and α-synuclein accumulation, and neurodegeneration in animal and cellular models of AD and PD. This review also discusses the inconsistent findings related to the neuroprotective effects of lactoferrin against AD. Overall, this review contributes to the existing literature by clarifying the potential neuroprotective effects and mechanisms of lactoferrin in the context of AD and PD neuropathology.
  15. Rajendran K, Anwar A, Khan NA, Aslam Z, Raza Shah M, Siddiqui R
    ACS Chem Neurosci, 2020 08 19;11(16):2431-2437.
    PMID: 31347828 DOI: 10.1021/acschemneuro.9b00289
    Naegleria fowleri (N. fowleri) causes primary amoebic meningoencephalitis (PAM) which almost always results in death. N. fowleri is also known as "brain-eating amoeba" due to its literal infestation of the brain leading to an inflammatory response in the brain tissues. Currently, there is no single drug that is available to treat PAM, and most treatments are combinations of antifungal, anticancer, and anti-inflammatory drugs. Recently nanotechnology has gained attention in chemotherapeutic research converging on drug delivery, while oleic acid (OA) has shown positive effects on the human immune system and inflammatory processes. In continuation of our recent research in which we reported the effects of oleic acid conjugated with silver nanoparticles (OA-AgNPs) against free-living amoeba Acanthamoeba castellanii, in this report, we show their antiamoebic effects against N. fowleri. OA alone and its nanoconjugates were tested against the amoeba by using amoebicidal and host cell cytopathogenicity assays. Trypan blue exclusion assay was used to determine cell viability. The results revealed that OA-AgNPs exhibited significantly enhanced antiamoebic effects (P < 0.05) against N. fowleri as compared to OA alone. Evidently, lactate dehydrogenase release shows reduced N. fowleri-mediated host cell cytotoxicity. Based on our study, we anticipate that further studies on OA-AgNPs could potentially provide an alternative treatment of PAM.
  16. Yong SJ
    ACS Chem Neurosci, 2021 Feb 17;12(4):573-580.
    PMID: 33538586 DOI: 10.1021/acschemneuro.0c00793
    Long-COVID is a postviral illness that can affect survivors of COVID-19, regardless of initial disease severity or age. Symptoms of long-COVID include fatigue, dyspnea, gastrointestinal and cardiac problems, cognitive impairments, myalgia, and others. While the possible causes of long-COVID include long-term tissue damage, viral persistence, and chronic inflammation, the review proposes, perhaps for the first time, that persistent brainstem dysfunction may also be involved. This hypothesis can be split into two parts. The first is the brainstem tropism and damage in COVID-19. As the brainstem has a relatively high expression of ACE2 receptor compared with other brain regions, SARS-CoV-2 may exhibit tropism therein. Evidence also exists that neuropilin-1, a co-receptor of SARS-CoV-2, may be expressed in the brainstem. Indeed, autopsy studies have found SARS-CoV-2 RNA and proteins in the brainstem. The brainstem is also highly prone to damage from pathological immune or vascular activation, which has also been observed in autopsy of COVID-19 cases. The second part concerns functions of the brainstem that overlap with symptoms of long-COVID. The brainstem contains numerous distinct nuclei and subparts that regulate the respiratory, cardiovascular, gastrointestinal, and neurological processes, which can be linked to long-COVID. As neurons do not readily regenerate, brainstem dysfunction may be long-lasting and, thus, is long-COVID. Indeed, brainstem dysfunction has been implicated in other similar disorders, such as chronic pain and migraine and myalgic encephalomyelitis or chronic fatigue syndrome.
  17. Abdelnasir S, Mungroo MR, Shahabuddin S, Siddiqui R, Khan NA, Anwar A
    ACS Chem Neurosci, 2021 Oct 06;12(19):3579-3587.
    PMID: 34545742 DOI: 10.1021/acschemneuro.1c00179
    Free-living amoebae include Acanthamoeba castellanii and Naegleria fowleri that are opportunistic protozoa responsible for life-threatening central nervous system infections with mortality rates over 90%. The rising number of cases and high mortality rates are indicative of the critical unmet need for the development of efficient drugs in order to avert future deaths. In this study, we assess the anti-amoebic capacity of a conducting polymer nanocomposite comprising polyaniline (PANI) and hexagonal boron nitride (hBN) against A. castellanii and N. fowleri. We observed significant amoebicidal and cysticidal effects using 100 μg/mL PANI/hBN (P < 0.05). Further, the nanocomposite demonstrated negligible cytotoxicity toward HaCaT and primary human corneal epithelial cells (pHCECs). In evaluating the mode of inhibition of A. castellanii due to treatment with PANI/hBN, increased intracellular reactive oxygen species (ROS) was measured and scanning microscopy visualized the formation of pores in the amoebae. Overall, this study is suggestive of the potential of the PANI/hBN nanocomposite as a promising therapy for amoeba infections.
  18. 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.
  19. Lum PT, Sekar M, Gan SH, Bonam SR, Shaikh MF
    ACS Chem Neurosci, 2021 Feb 03;12(3):391-418.
    PMID: 33475334 DOI: 10.1021/acschemneuro.0c00824
    Huntington's disease (HD), a neurodegenerative disease, normally starts in the prime of adult life, followed by a gradual occurrence of characteristic psychiatric disturbances and cognitive and motor dysfunction. To the best of our knowledge, there is no treatment available to completely mitigate the progression of HD. Among various therapeutic approaches, exhaustive literature reports have confirmed the medicinal benefits of natural products in HD experimental models. Building on this information, this review presents a brief overview of the neuroprotective mechanism(s) of natural products against in vitro/in vivo models of HD. Relevant studies were identified from several scientific databases, including PubMed, ScienceDirect, Scopus, and Google Scholar. After screening through literature from 2005 to the present, a total of 14 medicinal plant species and 30 naturally isolated compounds investigated against HD based on either in vitro or in vivo models were included in the present review. Behavioral outcomes in the HD in vivo model showed that natural compounds significantly attenuated 3-nitropropionic acid (3-NP) induced memory loss and motor incoordination. The biochemical alteration has been markedly alleviated with reduced lipid peroxidation, increased endogenous enzymatic antioxidants, reduced acetylcholinesterase activity, and increased mitochondrial energy production. Interestingly, following treatment with certain natural products, 3-NP-induced damage in the striatum was ameliorated, as seen histologically. Overall, natural products afforded varying degrees of neuroprotection in preclinical studies of HD via antioxidant and anti-inflammatory properties, preservation of mitochondrial function, inhibition of apoptosis, and induction of autophagy.
  20. Anwar A, Khan NA, Siddiqui R
    ACS Chem Neurosci, 2020 08 19;11(16):2378-2384.
    PMID: 32073257 DOI: 10.1021/acschemneuro.9b00613
    Brain-eating amoebae including Acanthamoeba spp., Naegleria fowleri, and Balamuthia mandrillaris cause rare infections of the central nervous system that almost always result in death. The high mortality rate, lack of interest for drug development from pharmaceutical industries, and no available effective drugs present an alarming challenge. The current drugs employed in the management and therapy of these devastating diseases are amphotericin B, miltefosine, chlorhexidine, pentamidine, and voriconazole which are generally used in combination. However, clinical evidence shows that these drugs have limited efficacy and high host cell cytotoxicity. Repurposing of drugs is a practical approach to utilize commercially available, U.S. Food and Drug Administration approved drugs for one disease against rare diseases caused by brain-eating amoebae. In this Perspective, we highlight some of the success stories of drugs repositioned against neglected parasitic diseases and identify future potential for effective and sustainable drug development against brain-eating amoebae infections.
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