Publications by authors named "Robert D E Sewell"

62 Publications

Selected Thiadiazine-Thione Derivatives Attenuate Neuroinflammation in Chronic Constriction Injury Induced Neuropathy.

Front Mol Neurosci 2021 16;14:728128. Epub 2021 Dec 16.

Department of Pharmacy, University of Peshawar, Peshawar, Pakistan.

Neuropathic pain refers to a lesion or disease of peripheral and/or central somatosensory neurons and is an important body response to actual or potential nerve damage. We investigated the therapeutic potential of two thiadiazine-thione [TDT] derivatives, 2-(5-propyl-6-thioxo-1, 3, 5-thiadiazinan-3-yl) acetic acid [TDT1] and 2-(5-propyl-2-thioxo-1, 3, 5-thiadiazinan-3-yl) acetic acid [TDT2] against CCI (chronic constriction injury)-induced neuroinflammation and neuropathic pain. Mice were used for assessment of acute toxicity of TDT derivatives and no major toxic/bizarre responses were observed. Anti-inflammatory activity was assessed using the carrageenan test, and both TDT1 and TDT2 significantly reduced carrageenan-induced inflammation. We also used rats for the induction of CCI and performed allodynia and hyperalgesia-related behavioral tests followed by biochemical and morphological analysis using RT-qPCR, immunoblotting, immunohistochemistry and immunofluorescence. Our findings revealed that CCI induced clear-cut allodynia and hyperalgesia which was reversed by TDT1 and TDT2. To determine the function of TDT1 and TDT2 in glia-mediated neuroinflammation, Iba1 mRNA and protein levels were measured in spinal cord tissue sections from various experimental groups. Interestingly, TDT1 and TDT2 substantially reduced the mRNA expression and protein level of Iba1, implying that TDT1 and TDT2 may mitigate CCI-induced astrogliosis. molecular docking studies predicted that both compounds had an effective binding affinity for TNF-α and COX-2. The compounds interactions with the proteins were dominated by both hydrogen bonding and van der Waals interactions. Overall, these results suggest that TDT1 and TDT2 exert their neuroprotective and analgesic potentials by ameliorating CCI-induced allodynia, hyperalgesia, neuroinflammation and neuronal degeneration in a dose-dependent manner.
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http://dx.doi.org/10.3389/fnmol.2021.728128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8716630PMC
December 2021

Pharmacological evaluation of the gabapentin salicylaldehyde derivative, gabapentsal, against tonic and phasic pain models, inflammation, and pyrexia.

Naunyn Schmiedebergs Arch Pharmacol 2021 10 12;394(10):2033-2047. Epub 2021 Jul 12.

Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, CF10 3NB, UK.

Gabapentinoids are effective drugs in most animal models of pain and inflammation with variable effects in humans. The current study evaluated the pharmacological activity of gabapentin (GBP) and its salicylaldehyde derivative (gabapentsal; [2-(1-(((2-hydroxybenzylidene) amino) methyl) cyclohexyl) acetic acid]; GPS) in well-established mouse models of nociceptive pain, inflammatory edema, and pyrexia at doses of 25-100 mg/kg. GPS allayed tonic visceral pain as reflected by acetic acid-induced nociception and it also diminished thermally induced nociception as a mimic of phasic thermal pain. Antagonism of GPS-induced antinociceptive activities by naloxone (NLX, 1.0 mg/kg, subcutaneously, s.c), beta-funaltrexamine (β-FNT, 5.0 mg/kg, s.c), naltrindole (NT, 1.0 mg/kg, s.c), and nor-binaltorphimine (NOR-BNI, 5.0 mg/kg, s.c), and pentylenetetrazole (PTZ-15 mg/kg, intraperitoneally, i.p) implicated an involvement of both opioidergic and GABAergic mechanisms. Tail immersion test was conducted in order to delineate the mechanistic insights of antinociceptive response. Inflammatory edema induced by carrageenan, histamine, or serotonin was also effectively reversed by GPS in a fashion analogous to aspirin (150 mg/kg, i.p), chlorpheniramine (1.0 mg/kg, i.p), and mianserin (1.0 mg/kg, i.p), respectively. Additionally, yeast-induced pyrexia was decreased by GPS in a comparable manner to acetaminophen (50 mg/kg, i.p). These observations suggest that GPS possesses ameliorative properties in tonic, phasic, and tail immersion tests of nociception via opioidergic and GABAergic mechanisms, curbs inflammatory edema, and is antipyretic in nature.
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http://dx.doi.org/10.1007/s00210-021-02118-xDOI Listing
October 2021

Effect of fennel on primary dysmenorrhea: a systematic review and meta-analysis.

J Complement Integr Med 2021 Jan 11;18(2):261-269. Epub 2021 Jan 11.

Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran.

Background: One of the most common complaints for women is dysmenorrhea. Several studies investigated the treatment effects of medicinal plants on primary dysmenorrhea.

Objectives: This systematic review and meta-analysis investigates the effect of (Fennel) on pain in primary dysmenorrhea in comparison to non-steroidal anti-inflammatory drugs such as mefenamic acid.

Methods: PubMed, EMBASE, EBSCO Web of Science, Scopus, Cochrane library, Cochrane Central Register of Controlled Trials (CENTRAL), Science Direct, ProQuest, ISI Web of Science, Google Scholar, Magiran, SID, Iran Medex, and Irandoc were searched up to January 2019. Quality assessment of clinical trials was conducted using Jadad scoring system. Totally, 12 studies were entered in the meta-analysis. was calculated to determine heterogeneity. Fixed effects and/or random effects models were applied.

Results: Meta-analysis of these trials showed that intake decreased significantly the intensity of dysmenorrhea compared to the placebo (SMD -0.632; CI: -0.827 to -0.436; p<0.001; heterogeneity p=0.807; =0%; fixed effect model; seven articles). However, the effect of Mefenamic acid with was not different from each other (SMD=-0.214; CI: -0.446 to 0.017; p=0.07; heterogeneity p=0.58; =0%; fixed effect model; six trials).

Conclusion: The alleviates dysmenorrhea. Regarding the same effect of with NSAIDs, it is highly recommend to the women suffered from dysmenorrhea specifically the ones who have high tendency toward herbal medicine.
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http://dx.doi.org/10.1515/jcim-2019-0212DOI Listing
January 2021

A novel gabapentin analogue assuages neuropathic pain response in chronic sciatic nerve constriction model in rats.

Behav Brain Res 2021 05 16;405:113190. Epub 2021 Feb 16.

Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, CF103NB, UK. Electronic address:

Gabapentin (GBP) is an established drug that has been used in the management of symptoms of neuropathy but it is associated with unwanted side effects such as sedation and motor incoordination. The goal of the study was to find out a drug with greater efficacy and safety for the treatment of neuropathic pain. Our previously synthesized GABA analogue (Gabapentsal, GPS) was tested (25-100 mg/kg, i.p) in chronic constriction injury (CCI) induced nociceptive model of static allodynia, dynamic allodynia, thermal hyperalgesia, mechanical hyperalgesia and cold allodynia in rats (Sprague Dawley). Open field and rotarod tests were performed to assess the impact of GPS on the motor performance of the animals. GBP (100 mg/kg, i.p) was used as a standard for comparison. GPS dose dependently reduced static (P <0.001) and dynamic allodynia (P <0.001), thermal hyperalgesia (P <0.001), mechanical hyperalgesia (P < 0.001) and cold allodynia (P < 0.001). In comparison to GBP, GPS failed to alter any significantly the motor performance of rats in both the open field and rotarod assays. These results suggest that GPS is effective in alleviating nociception in CCI neuropathic pain model but free from the side effect of motor discoordination seen in the treatment with GBP. In conclusion, GPS may prove to be a prospectively more effective and safer option in the management of neuropathic syndromes.
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http://dx.doi.org/10.1016/j.bbr.2021.113190DOI Listing
May 2021

Hydroalcoholic Extract of Anchusa Italica Protects Global Cerebral Ischemia-Reperfusion Injury Via a Nitrergic Mechanism.

Basic Clin Neurosci 2020 May-Jun;11(3):323-332. Epub 2020 May 1.

Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran.

Introduction: In stroke models, Inducible Nitric Oxide Synthase (iNOS) expression initiates cellular toxicity due to excessive Nitric Oxide (NO) generation. Anchusa italica is a medicinal herb with anti-inflammatory, antioxidant and neuroprotective properties. This study evaluated the antioxidant activity and NOS mRNA expression of the Hydroalcoholic Extract Of Anchusa Italica (HEAI) in an experimental stroke model in rats.

Methods: The stroke model was induced by bilateral occlusion of both common carotid arteries for 60 min. Twenty-four hours after surgery, HEAI (50 and 100 mg/kg i.p.) was injected daily for 10 consecutive days. mRNA expression levels of NOS subtypes and hippocampal Brain-Derived Neurotrophic Factor (BDNF) were studied using real-time PCR. Besides, hippocampal tissue plus serum concentrations of NO and Malondialdehyde (MDA) were measured.

Results: HEAI decreased MDA in both serum and hippocampal tissue and also reduced serum NO levels. Additionally, in the HEAI-treated groups, a down-regulation of iNOS mRNA expression, and an up-regulation of BDNF mRNA expression were observed.

Conclusion: The results indicated that the administration of HEAI even after the onset of ischemia protects the brain from free radical injury and inflammation via a down-regulation of iNOS expression inhibiting NO production and an up-regulation of BDNF mRNA.
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http://dx.doi.org/10.32598/bcn.11.2.1665.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502191PMC
May 2020

Inflammasome Signaling and Other Factors Implicated in Atherosclerosis Development and Progression.

Curr Pharm Des 2020 ;26(22):2583-2590

Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran.

Chronic inflammation plays an extensive role in the onset and progression of metabolic disorders such as atherosclerosis, type 2 diabetes, gout and obesity. Atherosclerosis accounts for up to 70% mortality in patients with type 2 diabetes and is also a chronic condition that causes atrial stenosis due to a lipometabolism imbalance. The purpose of this article is to consider the inflammatory factors implicated in atherosclerosis and their role in the development and progression of this vascular disease. The inflammasome signaling pathway is an important inflammatory mechanism involved in the development of atherosclerosis. The most important inflammasome pathway in this respect is the NLRP3 inflammasome (Nucleotide-binding oligomerization domain (NOD)-like receptor with a pyrin domain 3), whose activation leads to the generation of important inflammatory cytokines including interleukins 1β and 18 (IL-1β and 18). The activities of these mature cytokines and inflammatory factors produced by other inflammatory pathways lead to arterial inflammation and eventually arterial occlusion, which can result in life-threatening complications such as myocardial infarction and stroke. Therefore, it is essential to seek out more precise mechanisms for the activation of inflammasomes and other inflammatory pathways for the development of therapeutic strategies of atherosclerosis.
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http://dx.doi.org/10.2174/1381612826666200504115045DOI Listing
December 2020

Mechanisms of Medicinal Plant Activity on Nitric Oxide (NO) Bioavailability as Prospective Treatments for Atherosclerosis.

Curr Pharm Des 2020 ;26(22):2591-2601

Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran.

Background And Objective: Atherosclerosis is one of the leading causes of human morbidity globally and reduced bioavailability of vascular nitric oxide (NO) has a critical role in the progression and development of the atherosclerotic disease. Loss of NO bioavailability, for example via a deficiency of the substrate (L-arginine) or cofactors for endothelial nitric oxide synthase (eNOS), invariably leads to detrimental vascular effects such as impaired endothelial function and increased smooth muscle cell proliferation, deficiency of the substrate (Larginine) or cofactors for eNOS. Various medicinal plants and their bioactive compounds or secondary metabolites with fewer side effects are potentially implicated in preventing cardiovascular disease by increasing NO bioavailability, thereby ameliorating endothelial dysfunction. In this review, we describe the most notable medicinal plants and their bioactive compounds that may be appropriate for enhancing NO bioavailability, and treatment of atherosclerosis.

Methods: The material in this article was obtained from noteworthy scientific databases, including Web of Science, PubMed, Science Direct, Scopus and Google Scholar.

Results: Medicinal plants and their bioactive compounds influence NO production through diverse mechanisms including the activation of the nuclear factor kappa B (NF-κB) signaling pathway, activating protein kinase C (PKC)-α, stimulating protein tyrosine kinase (PTK), reducing the conversion of nitrite to NO via nitrate-nitrite reduction pathways, induction of eNOS, activating the phosphatidylinositol 3-kinase (PI3K)/serine threonine protein kinase B (AKT) (PI3K/AKT/eNOS/NO) pathway and decreasing oxidative stress.

Conclusion: Medicinal plants and/or their constituent bioactive compounds may be considered as safe therapeutic options for enhancing NO bioavailability and prospective preventative therapy for atherosclerosis.
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http://dx.doi.org/10.2174/1381612826666200318152049DOI Listing
December 2020

Review of Phytochemical Compounds as Antiviral Agents Against Arboviruses from the Genera Flavivirus and Alphavirus.

Curr Drug Discov Technol 2020 ;17(4):484-497

Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, CF10 NB. Wales, United Kingdom.

Arboviruses are a diverse group of viruses that are among the major causes of emerging infectious diseases. Arboviruses from the genera flavivirus and alphavirus are the most important human arboviruses from a public health perspective. During recent decades, these viruses have been responsible for millions of infections and deaths around the world. Over the past few years, several investigations have been carried out to identify antiviral agents to treat these arbovirus infections. The use of synthetic antiviral compounds is often unsatisfactory since they may raise the risk of viral mutation; they are costly and possess either side effects or toxicity. One attractive strategy is the use of plants as promising sources of novel antiviral compounds that present significant inhibitory effects on these viruses. In this review, we describe advances in the exploitation of compounds and extracts from natural sources that target the vital proteins and enzymes involved in arbovirus replication.
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http://dx.doi.org/10.2174/1570163817666200122102443DOI Listing
September 2021

Neurotransmitter, Antioxidant and Anti-neuroinflammatory Mechanistic Potentials of Herbal Medicines in Ameliorating Autism Spectrum Disorder.

Curr Pharm Des 2019 ;25(41):4421-4429

Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran.

Background: Autism spectrum disorder (ASD) is a neurodevelopmental issue that disrupts behavior, nonverbal communication, and social interaction, impacting all aspects of an individual's social development. The underlying origin of autism is unclear, however, oxidative stress, as well as serotonergic, adrenergic and dopaminergic systems are thought to be implicated in ASD. Despite the fact that there is no effective medication for autism, current pharmacological treatments are utilized to ameliorate some of the symptoms such as selfmutilation, aggression, repetitive and stereotyped behaviors, inattention, hyperactivity, and sleep disorders.

Methods: In accord with the literature regarding the activity of herbal medicines on neurotransmitter function, we aimed to review the most worthy medicinal herbs possessing neuroprotective effects.

Results: Based on the outcome, medicinal herbs such as Zingiber officinale, Astragalus membranaceu, Ginkgo biloba, Centella asiatica and Acorus calamus, have antioxidant activity, which can influence neurotransmitter systems and are potentially neuroprotective.

Conclusion: Consequently, these herbs, in theory at least, appear to be suitable candidates within an overall management strategy for those on the autism spectrum.
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http://dx.doi.org/10.2174/1381612825666191112143940DOI Listing
June 2020

Efficacy of a topical gabapentin gel in a cisplatin paradigm of chemotherapy-induced peripheral neuropathy.

BMC Pharmacol Toxicol 2019 08 28;20(1):51. Epub 2019 Aug 28.

Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, CF10 3NU, UK.

Background: Chemotherapy induced peripheral neuropathy (CIPN) has been attributed to chemotherapeutic agents such as cisplatin which adversely affect disease outcome leading to increased cancer related morbidity. The clinical efficacy of systemic gabapentin in neuropathic pain management is limited by central side-effects in addition to a scarceness of conclusive evidence of its efficacy in CIPN management. The topical route therefore may provide a relatively safe alternative for neuropathic pain treatment in general and CIPN in particular.

Methods: Cisplatin induced neuropathic nociception was established in rats after a single weekly cisplatin injection (3.0 mg/kg, intraperitoneally) for 4 weeks. The evoked neuropathic sensation of allodynia was assessed by plantar application of von Frey monofilaments as the paw withdrawal threshold (PWT), whereas the expression of heat-hypoalgesia was determined on a hot-plate as paw withdrawal latency (PWL). Gabapentin gel (10% w/w) was applied three-times daily on the hind paws while in a concurrent systemic study, gabapentin was administered daily (75 mg/kg, intraperitoneally) for 4 weeks. To assess any evidence of neurological adverse symptoms of cisplatin and the central side-effect propensity of systemic or topical gabapentin, evaluation of motor coordination (rotarod test) and gait (footprint analysis) were performed.

Results: Cisplatin invoked a progressive development of neuropathic hind paw allodynia (decreased PWT, days 7-28) and heat hypoalgesia (increased PWL, days 21-28). Topical gabapentin significantly delayed the expression of both allodynia on protocol days 21 and 28 and heat-hypoalgesia (day 28). Systemic gabapentin displayed a comparative anti-neuropathic predisposition through a sustained suppression of tactile allodynia on days 14 and 21-28 as well as thermal hypoalgesia (days 21 and 28). Systemic gabapentin also impaired motor coordination and gait thus affirming its clinically documented central side effects, but these outcomes were not evident after topical treatment.

Conclusions: Both topical and systemic gabapentin exhibit a propensity to attenuate CIPN in a cisplatin paradigm. Gabapentin applied topically may therefore provide an adjunctive or alternative route for CIPN management upon cessation of systemic medications due to intolerable side-effects.
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http://dx.doi.org/10.1186/s40360-019-0329-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714310PMC
August 2019

Antioxidants and Atherosclerosis: Mechanistic Aspects.

Biomolecules 2019 07 25;9(8). Epub 2019 Jul 25.

Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord 8813833435, Iran.

Atherosclerosis is a chronic inflammatory disease which is a major cause of coronary heart disease and stroke in humans. It is characterized by intimal plaques and cholesterol accumulation in arterial walls. The side effects of currently prescribed synthetic drugs and their high cost in the treatment of atherosclerosis has prompted the use of alternative herbal medicines, dietary supplements, and antioxidants associated with fewer adverse effects for the treatment of atherosclerosis. This article aims to present the activity mechanisms of antioxidants on atherosclerosis along with a review of the most prevalent medicinal plants employed against this multifactorial disease. The wide-ranging information in this review article was obtained from scientific databases including PubMed, Web of Science, Scopus, Science Direct and Google Scholar. Natural and synthetic antioxidants have a crucial role in the prevention and treatment of atherosclerosis through different mechanisms. These include: The inhibition of low density lipoprotein (LDL) oxidation, the reduction of reactive oxygen species (ROS) generation, the inhibition of cytokine secretion, the prevention of atherosclerotic plaque formation and platelet aggregation, the preclusion of mononuclear cell infiltration, the improvement of endothelial dysfunction and vasodilation, the augmentation of nitric oxide (NO) bioavailability, the modulation of the expression of adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) on endothelial cells, and the suppression of foam cell formation.
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http://dx.doi.org/10.3390/biom9080301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722928PMC
July 2019

Effective Antiviral Medicinal Plants and Biological Compounds Against Central Nervous System Infections: A Mechanistic Review.

Curr Drug Discov Technol 2020 ;17(4):469-483

Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff CF10 3NB, Wales, United Kingdom.

Background And Objective: Infectious diseases are amongst the leading causes of death in the world and central nervous system infections produced by viruses may either be fatal or generate a wide range of symptoms that affect global human health. Most antiviral plants contain active phytoconstituents such as alkaloids, flavonoids, and polyphenols, some of which play an important antiviral role. Herein, we present a background to viral central nervous system (CNS) infections, followed by a review of medicinal plants and bioactive compounds that are effective against viral pathogens in CNS infections.

Methods: A comprehensive literature search was conducted on scientific databases including: PubMed, Scopus, Google Scholar, and Web of Science. The relevant keywords used as search terms were: "myelitis", "encephalitis", "meningitis", "meningoencephalitis", "encephalomyelitis", "central nervous system", "brain", "spinal cord", "infection", "virus", "medicinal plants", and "biological compounds".

Results: The most significant viruses involved in central nervous system infections are: Herpes Simplex Virus (HSV), Varicella Zoster Virus (VZV), West Nile Virus (WNV), Enterovirus 71 (EV71), Japanese Encephalitis Virus (JEV), and Dengue Virus (DENV). The inhibitory activity of medicinal plants against CNS viruses is mostly active through prevention of viral binding to cell membranes, blocking viral genome replication, prevention of viral protein expression, scavenging reactive Oxygen Species (ROS), and reduction of plaque formation.

Conclusion: Due to the increased resistance of microorganisms (bacteria, viruses, and parasites) to antimicrobial therapies, alternative treatments, especially using plant sources and their bioactive constituents, appear to be more fruitful.
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http://dx.doi.org/10.2174/1570163816666190715114741DOI Listing
September 2021

Depression and Treatment with Effective Herbs.

Curr Pharm Des 2019 ;25(6):738-745

Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran.

Depression is a common psychiatric disease and one of the main causes of disability worldwide. In spite of certain developments in this field, chemical and synthetic drugs used for the treatment of depression disrupt the treatment process due to numerous side effects and high cost. Today, the goal of using a potential method for treating depression involves the use of medicinal and phytochemical plants, which have many therapeutic benefits. Studies have shown that medicinal plants affect the nervous system and exert antidepressant effects in various ways, including synaptic regulation of serotonin, noradrenaline and dopamine, and inflammatory mediators. In this study, depression as well as the factors and mechanisms involved in its development are first addressed, and then medicinal plants effective in the treatment of depression along with their mechanisms of actions are reported.
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http://dx.doi.org/10.2174/1381612825666190402105803DOI Listing
February 2020

A Review on the Most Important Medicinal Plants Effective in Cardiac Ischemia-Reperfusion Injury.

Curr Pharm Des 2019 ;25(3):352-358

Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran.

Ischemia, referring to reduction and restriction of perfusion to myocardial tissue which involves coronary artery through the formation of misplaced clots and thrombosis, is one of the most important cardiovascular diseases. Plant-based compounds help to improve or prevent disease by affecting the factors involved in the disease. This review was conducted to report the medicinal plants and factors effective in cardiac ischemiareperfusion (I/R) injury to supplement the knowledge about this disease and its prevention and treatment using certain medicinal plants and their active compounds. For this purpose, medicinal plants and their potential antioxidant activities, effects on lipid levels and plaque formation, atherosclerosis and development of cardiovascular diseases and ischemia were reviewed.

Methods: To conduct this review, relevant articles published between 1983 and 2018 were retrieved from the Google Scholar, PubMed, Scientific Information Database, Web of Science, and Scopus using search terms antioxidant, ischemia, reperfusion, heart, infarct, inflammation, cholesterol and medicinal plants. Then, the eligible articles were reviewed.

Results: The active compounds of plants, including phenolic compounds, flavonoids, and antioxidant compounds, can be effective on certain pathogenic factors particularly in decreasing cholesterol and blood pressure, preventing an increase in free radicals and ultimately reducing blood clots and vascular resistance to reduce and prevent ischemic disease and its harmful effects.

Conclusion: Medicinal plants discussed in this article seem to be able to prevent cardiac damage and the disease progression via affecting the factors that are involved in ischemia.
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http://dx.doi.org/10.2174/1381612825666190329144016DOI Listing
February 2020

Neuropathic pain models and outcome measures: a dual translational challenge.

Ann Transl Med 2018 Nov;6(Suppl 1):S42

Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK.

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http://dx.doi.org/10.21037/atm.2018.09.58DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291563PMC
November 2018

Medicinal Plants and Atherosclerosis: A Review on Molecular Aspects.

Curr Pharm Des 2018 ;24(26):3123-3131

Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran.

Atherosclerosis is an inflammatory vascular disease that is characterized by progressive accumulation of cholesterol in the arterial walls and it is a major cause of cardiovascular disease. Issues related to the side effects of synthetic drugs have in recent times, led to the misuse of drugs, a lack of patient consultations, and consequently, a disruption in meticulous disease control. Therefore, a new insight into medicinal plants has recently emerged and much research has been conducted on these herbs in an attempt to prepare novel naturally based drugs. The aim of this review article was to scrutinize the molecular mechanisms of medicinal plants possessing effectiveness against atherosclerosis. To conduct the review, electronic searches were performed to retrieve potentially relevant publications, indexed within internet databases and reference textbooks concerning the effects and underlying molecular mechanisms of plants or their constituents used to treat atherosclerosis. Overall, medicinal plants facilitate atherosclerosis treatment through a variety of mechanisms which include the regulation of expression of inflammatory factors, stimulation of peroxisome proliferator-activated receptors (PPARs), inhibition of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase), promotion of ATP-binding cassette transporter A1 (ABCA1) as well as ATP-binding cassette transporter G (ABCG), facilitation of adiponectin activity, reduction of sterol regulatory element-binding proteins (SREBPs) and antioxidant activity. An increased perception of these herbal mechanistic links is an important prelude to the design of novel plant based drugs.
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http://dx.doi.org/10.2174/1381612824666180911121525DOI Listing
October 2019

Immunosuppression-lipid Metabolism Interplay and Medicinal Plants in Atherosclerosis: A Review.

Curr Pharm Des 2018 ;24(24):2789-2793

Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran.

Atherosclerosis is a chronic arterial disease responsible for the majority of vascular-related deaths throughout the world. Immune cells and inflammation in conjunction with hyperlipidemia play a key role in atherosclerosis development. Regarding the low efficacy of the synthetic drugs and also the associated negative side effects which can adversely influence health-related quality of life, looking for natural, affordable and non-toxic substances seem necessary. Plant-derived natural products play a critical role in the prevention and treatment of atherosclerosis. In this review, we aimed to outline the most important medicinal herbs effective for atherosclerosis through the impact on immune system.
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http://dx.doi.org/10.2174/1381612824666180829105309DOI Listing
October 2019

Medicinal Plants with Multiple Effects on Diabetes Mellitus and Its Complications: a Systematic Review.

Curr Diab Rep 2018 08 13;18(10):72. Epub 2018 Aug 13.

Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran.

Purpose Of Review: This systematic review describes evidence concerning medicinal plants that, in addition to exerting hypoglycemic effects, decrease accompanying complications such as nephropathy, neuropathy, retinopathy, hypertension, and/or hyperlipidemia among individuals with diabetes mellitus (DM).

Recent Findings: Studies on the antidiabetic mechanisms of medicinal plants have shown that most of them produce hypoglycemic activity by stimulating insulin secretion, augmenting peroxisome proliferator-activated receptors (PPARs), inhibiting α-amylase or α-glucosidase, glucagon-like peptide-1 (GLP-1) secretion, advanced glycation end product (AGE) formation, free radical scavenging plus antioxidant activity (against reactive oxygen or nitrogen species (ROS/RNS)), up-regulating or elevating translocation of glucose transporter type 4 (GLUT-4), and preventing development of insulin resistance. Not only are medicinal plants effective in DM, but many of them also possess a variety of effects on other disease states, including the complications of DM. Such plants may be appropriate alternatives or adjuncts to available antidiabetic medications.
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http://dx.doi.org/10.1007/s11892-018-1042-0DOI Listing
August 2018

The Neurogenesis Actuator and NR2B/NMDA Receptor Antagonist Ro25-6981 Consistently Improves Spatial Memory Retraining Via Brain Region-Specific Gene Expression.

J Mol Neurosci 2018 Jun 22;65(2):167-178. Epub 2018 May 22.

Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Redwood Building, King Edward VII Ave., Cathays Park, Cardiff, CF10 3NB, UK.

NR2B-containing NMDA (NR2B/NMDA) receptors are important in controlling neurogenesis and are involved in generating spatial memory. Ro25-6981 is a selective antagonist at these receptors and actuates neurogenesis and spatial memory. Inter-structural neuroanatomical profiles of gene expression regulating adult neurogenesis and neuroapoptosis require examination in the context of memory retrieval and reversal learning. The aim was to investigate spatial memory retrieval and reversal learning in relation to gene expression-linked neurogenetic processes following blockade of NR2B/NMDA receptors by Ro25-6981. Rats were trained in Morris water maze (MWM) platform location for 5 days. Ro25-6981 was administered (protocol days 6-7) followed by retraining (days 15-18 or 29-32). Platform location was tested (on days 19 or 33) then post-mortem brain tissue sampling (on days 20 or 34). The expression of three genes known to regulate cell proliferation (S100a6), differentiation (Ascl1), and apoptosis (Casp-3) were concomitantly evaluated in the hippocampus, prefrontal cortex, and cerebellum in relation to the MWM performance protocol. Following initial training, Ro25-6981 enhanced visuospatial memory retrieval performance during further retraining (protocol days 29-32) but did not influence visuospatial reversal learning (day 33). Hippocampal Ascl1 and Casp-3 expressions were correspondingly increased and decreased while cerebellar S100a6 and Casp-3 activities were decreased and increased respectively 27 days after Ro25-6981 treatment. Chronological analysis indicated a possible involvement of new mature neurons in the reconfiguration of memory processes. This was attended by behavioral/gene correlations which revealed direct links between spatial memory retrieval enhancement and modified gene activity induced by NR2B/NMDA receptor blockade and upregulation.
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http://dx.doi.org/10.1007/s12031-018-1083-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6061165PMC
June 2018

Intranasally Administered S100A9 Amyloids Induced Cellular Stress, Amyloid Seeding, and Behavioral Impairment in Aged Mice.

ACS Chem Neurosci 2018 06 12;9(6):1338-1348. Epub 2018 Apr 12.

Department of Medical Biochemistry and Biophysics , Umeå University , Umeå SE-90187 , Sweden.

Amyloid formation and neuroinflammation are major features of Alzheimer's disease pathology. Proinflammatory mediator S100A9 was shown to act as a link between the amyloid and neuroinflammatory cascades in Alzheimer's disease, leading together with Aβ to plaque formation, neuronal loss and memory impairment. In order to examine if S100A9 alone in its native and amyloid states can induce neuronal stress and memory impairment, we have administered S100A9 species intranasally to aged mice. Single and sequential immunohistochemistry and passive avoidance behavioral test were conducted to evaluate the consequences. Administered S100A9 species induced widespread cellular stress responses in cerebral structures, including frontal lobe, hippocampus and cerebellum. These were manifested by increased levels of S100A9, Bax, and to a lesser extent activated caspase-3 immunopositive cells. Upon administration of S100A9 fibrils, the amyloid oligomerization was observed in the brain tissues, which can further exacerbate cellular stress. The cellular stress responses correlated with significantly increased training and decreased retention latencies measured in the passive avoidance test for the S100A9 treated animal groups. Remarkably, the effect size in the behavioral tests was moderate already in the group treated with native S100A9, while the effect sizes were large in the groups administered S100A9 amyloid oligomers or fibrils. The findings demonstrate the brain susceptibility to neurotoxic damage of S100A9 species leading to behavioral and memory impairments. Intranasal administration of S100A9 species proved to be an effective method to study amyloid induced brain dysfunctions, and S100A9 itself may be postulated as a target to allay early stage neurodegenerative and neuroinflammatory processes.
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http://dx.doi.org/10.1021/acschemneuro.7b00512DOI Listing
June 2018

COMT and GAD1 gene polymorphisms are associated with impaired antisaccade task performance in schizophrenic patients.

Eur Arch Psychiatry Clin Neurosci 2018 Sep 10;268(6):571-584. Epub 2018 Feb 10.

Cardiff School of Pharmacy and Pharmaceutical Sciences, Redwood Building, Cardiff University, Cardiff, CF10 3NB, UK.

Genetic influences modulating executive functions engaging prefrontal cortical brain systems were investigated in 141 male subjects. The effects of variations in two genes implicated in dopamine and GABA activities in the prefrontal cortex: rs4680 (Val158/Met polymorphism of the catechol-o-methyltransferase gene-COMT) and rs3749034 (C/T) substitution in the promoter region of the glutamic acid decarboxylase gene (GAD1) were studied on antisaccade (AS) performance in healthy subjects and schizophrenic patients. Genotyping revealed a trend towards a reduced proportion of COMT Val/Met heterozygotes and a significantly increased frequency of the GAD1 rs3749034 C allele in schizophrenic patients relative to controls. Patients had elevated error rates, increased AS latencies and increased latency variability (coefficient of variation) compared to controls. The influence of polymorphisms was observed only in patients but not in controls. A substantial effect of the COMT genotype was noted on the coefficient of variation in latency, and this measure was higher in Val homozygotes compared to Met allele carriers (p < 0.05) in the patient group. The outcome from rs3749034 was also disclosed on the error rate (higher in T carriers relative to C homozygotes, p < 0.01) and latency (increased in C homozygotes relative to T carriers, p < 0.01). Binary logistic regression showed that inclusion of the genotype factor (i.e., selective estimation of antisaccade measures in CC carriers) considerably increased the validity of the diagnostic model based on the AS measures. These findings may well be derived from specific genetic associations with prefrontal cortex functioning in schizophrenia.
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http://dx.doi.org/10.1007/s00406-018-0881-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6096577PMC
September 2018

S100A9 Protein Aggregates Boost Hippocampal Glutamate Modifying Monoaminergic Neurochemistry: A Glutamate Antibody Sensitive Outcome on Alzheimer-like Memory Decline.

ACS Chem Neurosci 2018 03 4;9(3):568-577. Epub 2017 Dec 4.

Cardiff School of Pharmacy and Pharmaceutical Sciences , Cardiff University , Cardiff CF10 3NB , United Kingdom.

Alzheimer's disease (AD) involves dementia conceivably arising from integrated inflammatory processes, amyloidogenesis, and neuronal apoptosis. Glutamate can also cause neuronal death via excitotoxicity, and this is similarly implicated in some neurological diseases. The aim was to examine treatment with in vitro generated proinflammatory protein S100A9 aggregate species alone or with glutamate antibodies (Glu-Abs) on Morris water maze (MWM) spatial learning and memory performance in 12 month old mice. Amino acid and monoamine cerebral neurotransmitter metabolic changes were concurrently monitored. Initially, S100A9 fibrils were morphologically verified by atomic force microscopy and Thioflavin T assay. They were then administered intranasally alone or with Glu-Abs for 14 days followed by a 5 day MWM protocol before hippocampal and prefrontal cortical neurochemical analysis. S100A9 aggregates evoked spatial amnesia which correlated with disrupted glutamate and dopaminergic neurochemistry. Hippocampal glutamate release, elevation of DOPAC and HVA, as well as DOPAC/DA and HVA/DA ratios were subsequently reduced by Glu-Abs which simultaneously prevented the spatial memory deficit. The present outcomes emphasized the pathogenic nature of S100A9 fibrillar aggregates in causing spatial memory amnesia associated with enhanced hippocampal glutamate release and DA-ergic disruption in the aging brain. This finding might be exploited during dementia management through a neuroprotective strategy.
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http://dx.doi.org/10.1021/acschemneuro.7b00379DOI Listing
March 2018

The flavonoid 6-methoxyflavone allays cisplatin-induced neuropathic allodynia and hypoalgesia.

Biomed Pharmacother 2017 Nov 6;95:1725-1733. Epub 2017 Oct 6.

Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, CF10 3NB, UK. Electronic address:

Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose limiting side-effect of several commonly used chemotherapeutic agents (such as cisplatin) that profoundly impairs patient quality of life. Unfortunately, neither prophylactic strategies nor symptomatic treatments have proven useful in this condition. Flavonoids are found ubiquitously in fruits and vegetables and exert a multiplicity of beneficial effects. In this study, the antinociceptive activity of 6-methoxyflavone (6-MF) was investigated and evaluated in comparison with gabapentin in a rat model of CIPN. The effect on motor balance was also assessed using the rotarod and footprint analysis paradigms. 6-MF possessed both peripheral and central antinociceptive activities against tonic and phasic nociceptive stimuli. Cisplatin administration (3.0mg/kg/week, i.p.) for four consecutive weeks generated temporal mechanical allodynia (decreased paw withdrawal threshold; PWT) and thermal hypoalgesia (increased paw thermal threshold; PTT) in the bilateral hindpaws. Daily treatment with 6-MF (25, 50 and 75mg/kg/day, i.p) for four weeks attenuated the cisplatin-induced expression of nocifensive behaviors observed as a significant increase in PWT and alleviation of PTT during the third and fourth weeks of cisplatin administration. Accordingly, daily gabapentin (75mg/kg, i.p) suppressed the expression of CIPN by normalizing the PWT and hotplate response latency. However, these antinociceptive actions were associated with motor impairment exemplified by a significant decrease in rotarod endurance latency and a deficit in the uniformity of step alternation. In contrast, 6-MF was devoid of these adverse side-effects. These findings suggested that 6-MF afforded desirable neuropathic pain alleviating effects in CIPN and it was devoid of gabapentin-like unwanted motor side-effects.
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http://dx.doi.org/10.1016/j.biopha.2017.09.108DOI Listing
November 2017

Gabapentin and its salicylaldehyde derivative alleviate allodynia and hypoalgesia in a cisplatin-induced neuropathic pain model.

Eur J Pharmacol 2017 Nov 1;814:302-312. Epub 2017 Sep 1.

Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff CF10 3NB, UK. Electronic address:

Cisplatin is an effective chemotherapeutic agent indicated in cancer chemotherapy. However, its clinical use is associated with peripheral neuropathy that invariably impairs patient quality of life. Gabapentin (GBP) is an effective analgesic for neuropathic pain conditions but its clinical efficacy in cisplatin-induced neuropathic pain (CINP) is limited, in addition to generating unwanted side-effects. In this study, a gabapentin-salicylaldehyde derivative [gabapentsal (GPS)] was synthesized and evaluated to explore any potential benefit in comparison with GBP in a rat model of CIPN. Administration of cisplatin (3.0mg/kg/week, i.p.) for five consecutive weeks generated reproducible mechanical-allodynia (decreased paw withdrawal threshold to von Frey filament application; PWT, g) and thermal hypoalgesia (increased nociceptive reaction latency in the hot plate paradigm; s). Treatment with GBP or its derivative on the 37th day of the experimental protocol, dose dependently attenuated cisplatin-induced nocifensive behaviors. Accordingly, doses of GBP (50-100mg/kg, i.p.) and GPS (25-100mg/kg, i.p.) suppressed the expression of CINP by normalizing the PWT and hot plate response latency 1h and 3h post administration. In the rotarod paradigm, GBP at all doses markedly impaired motor performance, whilst GPS was devoid of motor incoordination except at the highest dose, when a mild impairment occurred. Salicylaldehyde alone had no effect on CINP or rotarod performance and neither was there any synergism when coadministered with GBP. These findings suggest that both GBP and GPS have beneficial effects in the neuropathic pain model though GPS may be potentially more useful in the management of CINP.
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http://dx.doi.org/10.1016/j.ejphar.2017.08.040DOI Listing
November 2017

Characterization of 6-methoxyflavanone as a novel anxiolytic agent: A behavioral and pharmacokinetic approach.

Eur J Pharmacol 2017 Apr 28;801:19-27. Epub 2017 Feb 28.

Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff CF10 3NB, UK. Electronic address:

Benzodiazepines are regularly prescribed for treatment of anxiety though there are side effects. Flavonoids have selective affinity for GABA receptors implicated in anxiolytic-like activity in rodents, but are devoid of the unwanted side effects of benzodiazepines. In this study, 6-methoxyflavanone (6-MeOF), a positive allosteric modulator of γ-amino butyric acid (GABA) responses at human recombinant GABA receptors, was evaluated for its behavioral profile in the elevated plus-maze as well as the staircase- plus and open-field tests in mice. In addition, the distribution of 6-MeOF in selected brain areas involved in anxiety (amygdala and cerebral cortex) was also examined using a validated high performance liquid chromatography ultraviolet detection (HPLC/UV) method. 6-MeOF (10, 30 and 50mg/kg) exerted an anxiolytic-like effect, increasing entries and time spent in the open arm and the central platform, as well as head-dipping frequency in the mouse elevated plus-maze assay. It also decreased rearing incidence without suppressing the number of steps ascended in the staircase test. Whereas, in the open-field anxiety test, 6-MeOF had no effect on locomotor activity at lower doses, a decrease was observed at the highest dose (100mg/kg). 6-MeOF additionally produced an anxiolytic-like increase in the time spent at the center of the open-field apparatus. These effects were preferentially antagonized by pentylenetetrazole (15mg/kg). Furthermore, pharmacokinetic studies disclosed a rapid appearance of 6-MeOF in the plasma and discrete brain areas. Taken together, our findings suggest that 6-MeOF readily crosses the blood brain barrier (BBB) generating anxiolytic activity, mediated through the GABAergic system.
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http://dx.doi.org/10.1016/j.ejphar.2017.02.047DOI Listing
April 2017

Erratum to: Synthetic and natural antioxidants attenuate cisplatin-induced vomiting.

BMC Pharmacol Toxicol 2017 02 1;18(1). Epub 2017 Feb 1.

Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, CF103NB, UK.

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http://dx.doi.org/10.1186/s40360-017-0117-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5288848PMC
February 2017

Synthetic and natural antioxidants attenuate cisplatin-induced vomiting.

BMC Pharmacol Toxicol 2017 01 13;18(1). Epub 2017 Jan 13.

Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, CF103NB, UK.

Background: Synthetic and natural antioxidants including Bacopa monnieri (L.) Pennell (Scrophulariaceae) which also possess anti-dopaminergic properties, have been proposed to be useful for emetogenic chemotherapy. In this study, synthetic [N-(2-mercaptopropionyl) glycine (MPG), vitamin C (Vit-C)] and natural [grape seed proanthocyanidin (GP), B. monnieri n-butanolic fraction (BM-ButFr)] antioxidants and their combinations were evaluated against cisplatin-induced emesis in pigeons during a 24 h observation period.

Methods: Emesis was induced using cisplatin (7.0 mg/kg, i.v). MPG (10, 20, 30 mg/kg), Vit-C (100, 200, 300 mg/kg), GP (50, 100, 150 mg/kg) and BM-ButFr (5, 10, 20 mg/kg) and their combinations were administered i.m., 15 min before cisplatin administration. The number of vomiting bouts, retching, emetic latency and % weight loss were recorded to assess antiemetic potential. Antioxidant activity was evaluated by the DPPH free radical scavenging assay (FRSA).

Results: Significant attenuation of vomiting bouts, retching, % weight loss along with an increase in latency was produced by all the antioxidants and their combinations compared to cisplatin alone and this is the first report of this activity of GP in pigeons. Low EC values in the FRSA for MPG (67.66 μg/mL), Vit-C (69.42 μg/mL), GP (6.498 μg/mL) and BM-ButFr (55.61 μg/mL) compared to BHT standard (98.17 μg/mL) demonstrated their radical scavenging capacity. Correlation between the antioxidant activity and antiemetic efficacy disclosed a high degree of correlation for the tested antioxidants.

Conclusion: The selected synthetic and natural antioxidants and their combinations were able to attenuate cisplatin-induced vomiting, which correlated with their potent in vitro antioxidant activity.
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http://dx.doi.org/10.1186/s40360-016-0110-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5234122PMC
January 2017

Cellular efflux transporters and the potential role of natural products in combating efflux mediated drug resistance.

Front Biosci (Landmark Ed) 2017 01 1;22:732-756. Epub 2017 Jan 1.

Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff CF10 3NU, U.K.

Efflux mediated multidrug resistance (MDR) is a major problem in the treatment of bacterial, fungal and protozoal infections in addition to cancer chemotherapy. Among other well known mechanisms, efflux pumps are significant contributors to chemo-resistance. Efflux mediated resistance generally occurs through up-regulation of genes responsible for the expression of transporter proteins extruding drugs from the cell to create intracellular sub-therapeutic concentrations leading to resistance. The rapid expansion of MDR pathogens necessitates the discovery of resistance modifying drugs, which in combination with antimicrobial or chemotherapeutic agents would tend to reinstate the action of these drugs and avert the emergence of acquired resistance. This review describes the existence of efflux pumps in prokaryotes and eukaryotes as well as their role in chemo-resistance with a special focus on natural product-derived efflux pump inhibitors.
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http://dx.doi.org/10.2741/4513DOI Listing
January 2017

The misfolded pro-inflammatory protein S100A9 disrupts memory via neurochemical remodelling instigating an Alzheimer's disease-like cognitive deficit.

Behav Brain Res 2016 06 8;306:106-16. Epub 2016 Mar 8.

Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff CF10 3NB, UK. Electronic address:

Memory deficits may develop from a variety of neuropathologies including Alzheimer's disease dementia. During neurodegenerative conditions there are contributory factors such as neuroinflammation and amyloidogenesis involved in memory impairment. In the present study, dual properties of S100A9 protein as a pro-inflammatory and amyloidogenic agent were explored in the passive avoidance memory task along with neurochemical assays in the prefrontal cortex and hippocampus of aged mice. S100A9 oligomers and fibrils were generated in vitro and verified by AFM, Thioflavin T and A11 antibody binding. Native S100A9 as well as S100A9 oligomers and fibrils or their combination were administered intranasally over 14 days followed by behavioral and neurochemical analysis. Both oligomers and fibrils evoked amnestic activity which correlated with disrupted prefrontal cortical and hippocampal dopaminergic neurochemistry. The oligomer-fibril combination produced similar but weaker neurochemistry to the fibrils administered alone but without passive avoidance amnesia. Native S100A9 did not modify memory task performance even though it generated a general and consistent decrease in monoamine levels (DA, 5-HT and NA) and increased metabolic marker ratios of DA and 5-HT turnover (DOPAC/DA, HVA/DA and 5-HIAA) in the prefrontal cortex. These results provide insight into a novel pathogenetic mechanism underlying amnesia in a fear-aggravated memory task based on amyloidogenesis of a pro-inflammatory factor leading to disrupted brain neurochemistry in the aged brain. The data further suggests that amyloid species of S100A9 create deleterious effects principally on the dopaminergic system and this novel finding might be potentially exploited during dementia management through a neuroprotective strategy.
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http://dx.doi.org/10.1016/j.bbr.2016.03.016DOI Listing
June 2016

Passiflora incarnata attenuation of neuropathic allodynia and vulvodynia apropos GABA-ergic and opioidergic antinociceptive and behavioural mechanisms.

BMC Complement Altern Med 2016 Feb 24;16:77. Epub 2016 Feb 24.

Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, CF10 3NU, UK.

Background: Passiflora incarnata is widely used as an anxiolytic and sedative due to its putative GABAergic properties. Passiflora incarnata L. methanolic extract (PI-ME) was evaluated in an animal model of streptozotocin-induced diabetic neuropathic allodynia and vulvodynia in rats along with antinociceptive, anxiolytic and sedative activities in mice in order to examine possible underlying mechanisms.

Methods: PI-ME was tested preliminary for qualitative phytochemical analysis and then quantitatively by proximate and GC-MS analysis. The antinociceptive property was evaluated using the abdominal constriction assay and hot plate test. The anxiolytic activity was performed in a stair case model and sedative activity in an open field test. The antagonistic activities were evaluated using naloxone and/or pentylenetetrazole (PTZ). PI-ME was evaluated for prospective anti-allodynic and anti-vulvodynic properties in a rat model of streptozotocin induced neuropathic pain using the static and dynamic testing paradigms of mechanical allodynia and vulvodynia.

Results: GC-MS analysis revealed that PI-ME contained predominant quantities of oleamide (9-octadecenamide), palmitic acid (hexadecanoic acid) and 3-hydroxy-dodecanoic acid, among other active constituents. In the abdominal constriction assay and hot plate test, PI-ME produced dose dependant, naloxone and pentylenetetrazole reversible antinociception suggesting an involvement of opioidergic and GABAergic mechanisms. In the stair case test, PI-ME at 200 mg/kg increased the number of steps climbed while at 600 mg/kg a significant decrease was observed. The rearing incidence was diminished by PI-ME at all tested doses and in the open field test, PI-ME decreased locomotor activity to an extent that was analagous to diazepam. The effects of PI-ME were antagonized by PTZ in both the staircase and open field tests implicating GABAergic mechanisms in its anxiolytic and sedative activities. In the streptozotocin-induced neuropathic nociceptive model, PI-ME (200 and 300 mg/kg) exhibited static and dynamic anti-allodynic effects exemplified by an increase in paw withdrawal threshold and paw withdrawal latency. PI-ME relieved only the dynamic component of vulvodynia by increasing flinching response latency.

Conclusions: These findings suggest that Passiflora incarnata might be useful for treating neuropathic pain. The antinociceptive and behavioural findings inferring that its activity may stem from underlying opioidergic and GABAergic mechanisms though a potential oleamide-sourced cannabimimetic involvement is also discussed.
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http://dx.doi.org/10.1186/s12906-016-1048-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4765057PMC
February 2016
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