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Routinely used anti-inflammatory drugs are associated with off-target effects such as cyclooxygenase (COX)-1 inhibition and gastric ulcers. The aim of this study is to examine the anti-inflammatory potential and gastroprotective effects of synthetic amino acid derivatives of 2-mercaptobenzimidazole (MBAA1, MBAA2, MBAA3, MBAA4 and MBAA5). The results showed that compound MBAA5 possess a potential anti-inflammatory action by inhibition of 15-LOX and COX-2. MBAA5 also attenuated the pro-inflammatory cytokines and mediators (TNF-α, IL-1ß and COX-2) in rat hind paw in carrageenan-induced inflammatory model of rat. 2-mercaptobenzimidazole derivative, MBAA5 also inhibited gastric H+/K+ ATPase and demonstrated a better selectivity index for COX-2 (SI 27.17) in comparison to celecoxib (SI 41.43). Molecular docking studies predicted the binding interactions of the synthesized compounds with retrieved target proteins of H+/K+ ATPase, COX-1, COX-2, and 15-LOX. The results of in silico and molecular docking analysis of amino acid derivatives of 2-mercaptobenzimidazoles further explained their pharmacological activities. Moreover, these compounds presented better antimicrobial activity against three clinical isolates of Helicobacter pylori. Together, our findings suggested that these synthetic 2-mercaptobenzimidazole derivatives are safer therapeutic candidates for inflammation.
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Aminoácidos/farmacologia , Araquidonato 15-Lipoxigenase/efeitos dos fármacos , Benzimidazóis/farmacologia , Ciclo-Oxigenase 2/efeitos dos fármacos , Citocinas/efeitos dos fármacos , ATPase Trocadora de Hidrogênio-Potássio/efeitos dos fármacos , Aminoácidos/química , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Araquidonato 15-Lipoxigenase/metabolismo , Benzimidazóis/química , Carragenina , Simulação por Computador , Ciclo-Oxigenase 1/efeitos dos fármacos , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Citocinas/metabolismo , ATPase Trocadora de Hidrogênio-Potássio/metabolismo , Helicobacter pylori/efeitos dos fármacos , Inflamação/metabolismo , Interleucina-1beta/efeitos dos fármacos , Interleucina-1beta/metabolismo , Inibidores de Lipoxigenase/farmacologia , Simulação de Acoplamento Molecular , Ratos , Úlcera Gástrica/induzido quimicamente , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Benzimidazole is an important pharmacophore for clinically active drugs against inflammation and treatment of pain, however, it is associated with gastrointestinal side effects. Here we synthesized benzimidazole based agents with significant analgesic/anti-inflammatory potential but with less gastrointestinal adverse effects. In this study, we synthesized novel, orally bioavailable 2-mercaptobenzimidazole amino acid conjugates (4a-4o) and screened them for analgesic, anti-inflammatory and gastro-protective effects. The synthesized 2-mercaptbenzimidazole derivatives were characterized for their structure using FTIR, 1 H NMR and 13 C NMR spectroscopic techniques. The 2-mercaptobenzimidazole amino acid conjugates have found to possess potent analgesic, anti-inflammatory and gastroprotective activities, particularly with compound 4j and 4k. Most of the compounds exhibited remarkable anti-ulcer and antisecretory effects. Molecular docking studies were carried out to study the binding affinities and interactions of the synthesized compounds with target proteins COX-2 (PDB ID: 3LN1) and H+ /K+ -ATPase (PDB ID: 5Y0B). Our results support the clinical promise of these newly synthesized 2-mercaptobezimidazol conjugates as a component of therapeutic strategies for inflammation and analgesia, for which the gastric side effects are always a major limitation.
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Carbonic anhydrase (CA) is abundant in glial cells in the brain and CA type II isoform (CA II) activity in the hippocampus plays an important role in buffering extracellular pH transients produced by neural activity. Chronic ethanol exposure results in respiratory and metabolic acidosis, producing shifts in extracellular pH in the brain and body. These neurophysiological changes by ethanol are hypothesized to contribute to the continued drinking behavior and physical withdrawal behavior in subjects consuming ethanol chronically. We explored whether chronic ethanol self-administration (ethanol drinking, 10% v/v; ED) without or under the influence of chronic intermittent ethanol vapor (CIE-ED) experience alters the expression of CA II in the hippocampus. Postmortem hippocampal tissue analyses demonstrated that CA II levels were enhanced in the hilus region of the hippocampus in ED and CIE-ED rats. We used a novel molecule-4-fluoro-N-(4-sulfamoylphenyl) benzenesulfonamide (4-FS)-a selective CA II inhibitor, to determine whether CA II plays a role in ethanol self-administration in ED and CIE-ED rats and physical withdrawal behavior in CIE-ED rats. 4-FS (20 mg/kg, i.p.) reduced ethanol self-administration in ED rats and physical withdrawal behavior in CIE-ED rats. Postmortem hippocampal tissue analyses demonstrated that 4-FS reduced CA II expression in ED and CIE-ED rats to control levels. In parallel, 4-FS enhanced GABAA receptor expression, reduced ratio of glutamatergic GluN2A/2B receptors and enhanced the expression of Fos, a marker of neuronal activation in the ventral hippocampus in ED rats. These findings suggest that 4-FS enhanced GABAergic transmission and increased activity of neurons of inhibitory phenotypes. Taken together, these findings support the role of CA II in assisting with negative affective behaviors associated with moderate to severe alcohol use disorders (AUD) and that CA II inhibitors are a potential therapeutic target to reduce continued drinking and somatic withdrawal symptoms associated with moderate to severe AUD.
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Consumo de Bebidas Alcoólicas/tratamento farmacológico , Alcoolismo/tratamento farmacológico , Anidrase Carbônica II/antagonistas & inibidores , Inibidores da Anidrase Carbônica/uso terapêutico , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Sulfonamidas/uso terapêutico , Consumo de Bebidas Alcoólicas/metabolismo , Alcoolismo/metabolismo , Animais , Anidrase Carbônica II/metabolismo , Inibidores da Anidrase Carbônica/química , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Ratos , Ratos Long-Evans , Síndrome de Abstinência a Substâncias/metabolismo , Sulfonamidas/química , BenzenossulfonamidasRESUMO
Bacopa monnieri is a perennial herb with a world known image as a nootropic. We investigated the effect of Bacopa monnieri methanolic extract (Mt Ext BM) 10, 20, and 30 mg/kg body weight (b.w) on acquisition and expression of morphine withdrawal induced depression in mice. Locally available Bacopa monnieri (BM) was screened for contents of Bacoside A3, Bacopasaponin C, and Bacopaside II using HPLC with UV. Morphine dependence was induced in mice using twice daily escalating chronic morphine treatments (20-65 mg/kg b.w) for eight consecutive days. Morphine withdrawal induced depression was assayed in animals using forced swimming test (FST), three days after last morphine injection. The HPLC analysis revealed that Mt-ext BM contained Bacoside A3 as major component, i.e. 4 µg in each mg of extract. The chronic treatment with Met Ext BM 10, 20, and 30 mg/kg b.w. dosing significantly inhibited opioid withdrawal induced depression in mice. These findings imply a newer potential role of Bacopa monnieri in the clinical management of opioid withdrawal induced depression which can be attributed to Bacoside A3.
Assuntos
Bacopa/química , Depressão/tratamento farmacológico , Morfina/efeitos adversos , Extratos Vegetais/farmacologia , Síndrome de Abstinência a Substâncias , Animais , Depressão/induzido quimicamente , Feminino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fitoterapia , Saponinas/farmacologia , Triterpenos/farmacologiaRESUMO
CONTEXT: Hypericum perforatum Linn. (Hypericaceae) (St. John's wort) attenuates opium withdrawal signs. AIM: To explore the therapeutic potential of Hypericum perforatum in the management of opium-induced withdrawal syndrome. MATERIALS AND METHODS: The effect of the Hypericum perforatum hydro-ethanol extract was investigated for potential to reverse naloxone (0.25 mg/kg)-induced opium withdrawal physical signs. Rats received opium extract (80-650 mg/kg) twice daily for 8 days along with Hypericum perforatum (20 mg/kg, orally) twice daily in chronic treatment and the same single dose 1 h before induction of withdrawal syndrome in the acute treated group. RESULTS: Hypericum perforatum reduced stereotype jumps and wet dog shake number in the chronic treatment compared to the saline control group (F(2, 24) = 3.968, p < 0. 05) and (F(2, 24) = 3.689, p < 0.05), respectively. The plant extract in the acutely treated group reduced diarrhea (F(2, 24) = 4.850, p < 0. 05 vs. saline). It decreased rectal temperature by chronic treatment at 30 min (F(2, 24) = 4.88, p < 0.05), 60 min (F(2, 240 = 5.364, p < 0.01) and 120 min (F(2, 24) = 4.907, p < 0.05). DISCUSSION AND CONCLUSION: This study reveals that the extract of Hypericum perforatum attenuates some physical signs of opium withdrawal syndrome possibly through direct or indirect interaction with opioid receptors. Further study is needed to clarify its mechanism.
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Hypericum/química , Antagonistas de Entorpecentes/uso terapêutico , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Ópio/toxicidade , Fitoterapia , Extratos Vegetais/uso terapêutico , Síndrome de Abstinência a Substâncias/prevenção & controle , Animais , Modelos Animais de Doenças , Feminino , Masculino , Naloxona/farmacologia , Antagonistas de Entorpecentes/isolamento & purificação , Transtornos Relacionados ao Uso de Opioides/psicologia , Ópio/administração & dosagem , Componentes Aéreos da Planta/química , Extratos Vegetais/isolamento & purificação , Ratos Sprague-Dawley , Síndrome de Abstinência a Substâncias/psicologiaRESUMO
INTRODUCTION: Boswellic acids (BAs) are a group of pentacyclic triterpenoids of the ursane and oleanane type. They have shown very interesting biological properties that have led to the development of a number of synthesis protocols. Both natural BAs and their synthetic derivatives may be useful in the treatment of a variety of cancers, viral infections and inflammatory diseases. AREAS COVERED: This review covers patents relating to the therapeutic activities of natural BAs and their synthetic derivatives. The latest patented studies of boswellic acids (are summarized by using the keywords 'boswellic acid,' in SciFinder, PubMed, and Google Patents and databases in the year from 2016 to 2023. EXPERT OPINION: Boswellic acids have shown potent antiviral, anticancer and anti-inflammatory potential. Few BAs analogues have been prepared by modification at the C24-CO2H functional groups. In particular, the C-24 amide and amino analogues have shown enhanced anticancer effects compared to the parent AKBA. In addition, BAs have the ability to form conjugates with other antiviral, anti-inflammatory and anticancer drugs that synergistically enhance their biological efficacy. In addition, this conjugation strategy will increase the solubility and bioavailability of BAs, which is one of the most important issues in the development of BAs.
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Anti-Inflamatórios , Antivirais , Desenvolvimento de Medicamentos , Neoplasias , Patentes como Assunto , Triterpenos , Humanos , Triterpenos/farmacologia , Triterpenos/química , Animais , Antivirais/farmacologia , Anti-Inflamatórios/farmacologia , Neoplasias/tratamento farmacológico , Antineoplásicos/farmacologia , Inflamação/tratamento farmacológico , Viroses/tratamento farmacológico , Disponibilidade BiológicaRESUMO
Polygonatum verticillatum is commonly used for the treatment of asthma and inflammation. The current study was aimed to scrutinize the pharmacological profile of methanolic extract of the aerial parts (PA). Isolated tracheal preparations were used for the evaluation of bronchodilatory activity, whilst the in vivo carrageenan-induced paw oedema test and an in vitro lipoxygenase (LOX) inhibitory assay were used for the assessment of the anti-inflammatory profile of PA. When tested against carbachol and K⺠(80 mM)-induced contractions, PA caused complete inhibition of isolated rabbit tracheal preparations in a dose-dependent mode, similar to verapamil. While elucidating possible mechanism, PA shifted the Ca²âº concentration-response curves to the right, analogous to that produced by verapamil, confirming a Ca²âº channel blocker-like activity. PA provoked profound reduction in paw oedema with a maximum protection of 60.87% at 200 mg/kg i.p. in a dose-dependent manner which was augmented by its prominent LOX inhibitory activity (IC50 : 125 µg/mL). These findings authenticated its therapeutic potential in the treatment of asthmatic and inflammatory conditions.
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Anti-Inflamatórios/farmacologia , Broncodilatadores/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Inibidores de Lipoxigenase/farmacologia , Extratos Vegetais/farmacologia , Polygonatum/química , Animais , Carbacol/efeitos adversos , Carragenina/efeitos adversos , Edema/tratamento farmacológico , Feminino , Técnicas In Vitro , Inflamação/tratamento farmacológico , Masculino , Componentes Aéreos da Planta/química , Coelhos , Ratos , Ratos Wistar , Traqueia/efeitos dos fármacos , Verapamil/farmacologiaRESUMO
Background: Oil rents (OR) and natural gas rents (NGR) have significant contributions to the income of the Middle East and North Africa (MENA) economies and may increase emissions. Moreover, spatial autocorrelation is expected in carbon dioxide (CO2) emissions due to the geographically closed economies in the MENA region. Thus, we examine the impact of OR and NGR on CO2 emissions caring spatial dimensions and analyze the environmental Kuznets curve (EKC). Methods: We apply the spatial Durbin model technique on the effects of OR, NGR, and economic growth on CO2 emissions in 17 MENA nations from 2000-2019, i.e., Algeria, Bahrain, Egypt, Iran, Iraq, Israel, Jordan, Kuwait, Libya, Morocco, Oman, Qatar, Saudi Arabia, Syria, Tunisia, the United Arab Emirates (UAE), and Yemen. Moreover, diagnostic tests are applied to reach the most appropriate spatial specification and to have the most robust results. Results: The results disclose that CO2 emissions have spillovers and emissions of any country can damage the environment of neighboring countries. The EKC is corroborated with a turning point of 38,698 constant 2015 US dollars. Israel and Qatar are in 2nd phase of the EKC, and 15 MENA economies are in 1st stage. Thus, the economic expansion of most economies has ecological concerns. The effect of natural gas rents is found statistically insignificant. Oil rents have minute negative effects on emissions of local economies with an elasticity coefficient of -0.2117. Nevertheless, these have a positive indirect effect with an elasticity coefficient of 0.5328. Thus, the net effect of oil rents is positive. One percent increase in oil rents could accelerate 0.3211% of emissions. Thus, we suggest the MENA countries reduce reliance on oil rents in their income to avoid the negative environmental effects of the oil sector.
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Dióxido de Carbono , Gás Natural , Dióxido de Carbono/análise , Oriente Médio , Análise Espacial , TunísiaRESUMO
This study aimed to investigate the impact of entrepreneurial educational support (NEES), entrepreneurial activities support (NEAS), and entrepreneurial commercialization support (NECS) on the nascent entrepreneurial intention (NEI) by mediating roles of entrepreneurial self-efficacy (NESE), opportunity recognition (OR), and the moderating effect of meaning in life (MLI). Data were gathered using a survey questionnaire from the 868 management, engineering, technical, and vocational institute students of China. The NEI model was analyzed using the partial least squares structural equation modeling through Smart-PLS software. The findings of the study reveal that NEES, NEAS, and NECS have a positive effect on NEI. Meanwhile, results indicate that NESE and OR partially mediate the relationship between entrepreneurship support programs and nascent entrepreneurial intention. Furthermore, the relationship between NESE and the NEI was insignificantly influenced by MLI, and the relationship between OR and the NEI was significantly moderated by MLI. Lastly, implications and limitations are also discussed in this article.
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Nicotinic acetylcholine receptors (nAChRs), particularly the α7 nAChR, play a critical role in neuroinflammation and microglial activation associated with major depressive disorder (MDD). Microglial quinolinic acid (QUIN), which is synthesized by 3-hydroxyanthranilic acid dioxygenase (HAAO), is an N-methyl-D-aspartate (NMDA) receptor agonist and has been implicated in the development of MDD-related symptoms. In the present study, we assessed the effects of PNU120596, an α7 nAChR positive allosteric modulator (PAM), on HAAO expression and QUIN formation in the hippocampus and prefrontal cortex. We also investigated the effects of memantine, an NMDA receptor antagonist, alone and in combination with PNU120596 on cognitive deficit and depressive-like behaviors induced by lipopolysaccharide (LPS) in mice using the Y-maze and forced swim test, respectively. LPS (1 mg/kg, i.p.) elevated HAAO expression and QUIN formation in the hippocampus and prefrontal cortex, which were reduced with pretreatment with PNU120596 (4 mg/kg, i.p.). Furthermore, memantine (1 or 3 mg/kg, i.p.) prevented the cognitive deficit and depressive-like behaviors induced by LPS in mice. Together, these results suggest that the antidepressant-like effects of PNU120596 are mediated by attenuation of LPS-induced QUIN formation. Therefore, α7 nAChR PAM could be a potential therapeutic candidate for MDD associated with neurotoxic glutamatergic transmission.
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INTRODUCTION: Frankincense (Boswellia sp.) gum resins have been employed as an incense in cultural and religious ceremonies for many years. Frankincense resin has over the years been employed to treat depression, inflammation, and cancer in traditional medicines. AREAS COVERED: This inclusive review focuses on the significance of frankincense diterpenoids, and in particular, incensole derivatives for establishment future treatments of depression, neurological disorders, and cancer. The authors survey the available literature and furnish an overview of future perspectives of these intriguing molecules. EXPERT OPINION: Numerous diterpenoids including cembrane, prenylaromadendrane, and the verticillane-type have been isolated from various Boswellia resins. Cembrane-type diterpenoids occupy a crucial position in pharmaceutical chemistry and related industries because of their intriguing biological and encouraging pharmacological potentials. Several cembranes have been reported to possess anti-Alzheimer, anti-inflammatory, hepatoprotective, and antimalarial effects along with a good possibility to treat anxiety and depression. Although some slight drawbacks of these compounds have been noted, including the selectivity of these diterpenoids, there is a great need to address these in future research endeavors. Moreover, it is vitally important for medicinal chemists to prepare libraries of incensole-heterocyclic analogs as well as hybrid compounds between incensole or its acetate and anti-depressant or anti-inflammatory drugs.
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Boswellia , Diterpenos , Franquincenso , Anti-Inflamatórios/farmacologia , Boswellia/química , Diterpenos/química , Diterpenos/farmacologia , Descoberta de Drogas , Franquincenso/química , HumanosRESUMO
BACKGROUND & OBJECTIVES: Hyperalgesia and allodynia are frequent symptoms of inflammatory pain. Neuronal excitability induced by the Brain-Derived Neurotrophic Factor (BDNF)-tyrosine receptor kinase B (TrkB) cascade has a role in the modulation of inflammatory pain. The effects of 3a,4,5,9b-tetrahydro-4-(1-naphthalenyl)-3H-cyclopentan[c]quinoline-8-sulfonamide (TQS), an α7 nicotinic Acetylcholine Receptor Positive Allosteric Modulator (nAChR PAM), on hippocampal BDNF, cation-chloride cotransporters, NKCC1 and KCC2, expression in inflammatory pain are not known. The objective of the study was to determine the effects of TQS on BDNF, NKCC1, and KCC2 expression in the hippocampus following lipopolysaccharide (LPS)-induced allodynia and hyperalgesia in a mouse model of inflammatory pain. METHODS: Mice were treated with TQS followed by LPS (1 mg/kg, ip) administration. The effects of TQS on mRNA and BDNF in the hippocampus were examined using qRT-PCR and Western blot, respectively. Immunoreactivity of BDNF, NKCC1, and KCC2 in the hippocampus was measured after LPS administration using immunofluorescence assay. Allodynia and hyperalgesia were determined using von Frey filaments and hot plate, respectively. RESULTS: The LPS (1 mg/kg) upregulates mRNA of BDNF and downregulates mRNA of KCC2 in the hippocampus and pretreatment of TQS (4 mg/kg) reversed the effects induced by LPS. In addition, the TQS decreased LPS-induced upregulation of BDNF and p-NKCC1 immunoreactivity in the dentate gyrus and CA1 region of the hippocampus. BDNF receptor (TrkB) antagonist, ANA12 (0.50 mg/kg), and NKCC1 inhibitor bumetanide (30 mg/kg) reduced LPS-induced allodynia and hyperalgesia. Blockade of TrkB with ANA12 (0.25 mg/kg) enhanced the effects of TQS (1 mg/kg) against LPS-induced allodynia and hyperalgesia. Similarly, bumetanide (10 mg/kg) enhanced the effects of TQS (1 mg/kg) against allodynia and hyperalgesia. CONCLUSION: These results suggest that antinociceptive effects of α7 nAChR PAM are associated with downregulation of hippocampal BDNF and p-NKCC1 and upregulation of KCC2 in a mouse model of inflammatory pain.
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Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hipocampo/efeitos dos fármacos , Hiperalgesia/metabolismo , Dor/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Regulação Alostérica/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Inflamação/metabolismo , Lipopolissacarídeos/metabolismo , Masculino , Camundongos , Microglia/metabolismoRESUMO
BACKGROUND: Cancer is known to be the second significant cause of death worldwide. Chemotherapeutic agents such as platinum-based compounds are frequently used single-handedly or accompanied by additional chemotherapies to treat cancer patients. Chemotherapy-induced peripheral painful neuropathy is seen in around 40% of patients who are treated with platinum-based compounds, including cisplatin. This not only decreases the quality of life of patients but also patients' compliance with cisplatin. OBJECTIVES: Nalbuphine, an opioid, is frequently used to treat acute and chronic pain, coupled with cisplatin in cancer patients. However, long term use of nalbuphine induces tolerance to its analgesic effects. We employed the same strategy to induce tolerance in mice. METHODS: Here, we investigated analgesic effects of 2-[(pyrrolidin-1-yl) methyl]-1H-benzimidazole (BNZ), a benzimidazole derivative, on nalbuphine-induced tolerance during cisplatin-induced neuropathic pain using hot plate test, tail-flick tests and von Frey filament in mouse models. Furthermore, we investigated the effects of BNZ on the expression of Tumor Necrosis Factor-alpha (TNF-α) in the spinal cord. RESULTS: The results showed that BNZ reduced tolerance to analgesic effects of nalbuphine and TNF-α expression in mice. CONCLUSION: BNZ could be a potential drug candidate for the management of nalbuphine-induced tolerance in cisplatin-induced neuropathic pain.
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Analgésicos Opioides/uso terapêutico , Benzimidazóis/farmacologia , Neuralgia/tratamento farmacológico , Analgésicos Opioides/síntese química , Analgésicos Opioides/química , Animais , Antineoplásicos/efeitos adversos , Benzimidazóis/síntese química , Benzimidazóis/química , Cisplatino/efeitos adversos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Tolerância a Medicamentos , Masculino , Camundongos , Estrutura Molecular , Nalbufina , Neuralgia/induzido quimicamente , Neuralgia/patologia , Relação Estrutura-AtividadeRESUMO
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. In silico 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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BACKGROUND: Peripheral inflammation leads to the development of persistent thermal hyperalgesia and mechanical allodynia associated with increased expression of interleukin-1ß (IL-1ß) in the spinal cord. The aim of the present study was to investigate the effects of thiazolidine derivatives, 1b ([2-(2-hydroxyphenyl)-1,3-thiazolidin-4-yl](morpholin-4-yl)methanone) and 1d (2-hydroxy-4-{[2-(2-hydroxyphenyl)-1,3-thiazolidine-4-carbonyl]amino}benzoic acid), on thermal hyperalgesia, mechanical allodynia and on IL-1ß expression during carrageenan-induced inflammation in the spinal cord in mice. Inflammatory pain was induced by injecting 1% carrageenan into the right hind paw of the mice. METHODS: The animals were administered thiazolidine derivatives, 1b and 1d (1 mg/kg, 3 mg/kg, or 10 mg/kg), intraperitoneally 30 minutes before carrageenan administration. The animals' behavior was evaluated by measuring thermal hyperalgesia, mechanical allodynia, and motor coordination. The IL-1ß expression was measured by enzyme-linked immunosorbent assay. Acute and sub-acute toxicity studies were conducted to evaluate the toxicity profile of compounds. RESULTS: Treatment with the thiazolidine derivative, 1b and 1d, attenuated carrageenan-induced thermal hyperalgesia and mechanical allodynia at doses of 1 mg/kg, 3 mg/kg, and 10 mg/kg. No motor coordination deficits were observed in animals. The compounds also reduced IL-1ß expression in the spinal cord of mice. Acute and sub-acute toxicity studies revealed that both compounds were safe. CONCLUSION: The compounds exhibit promising activity against inflammatory pain due to their ability to produce anti-hyperalgesic and anti-allodynic effects and to inhibit IL-1ß expression in the spinal cord.
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Hiperalgesia/tratamento farmacológico , Inflamação/tratamento farmacológico , Dor/tratamento farmacológico , Tiazolidinas/uso terapêutico , Animais , Carragenina/administração & dosagem , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Hiperalgesia/induzido quimicamente , Hiperalgesia/metabolismo , Inflamação/induzido quimicamente , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Dor/induzido quimicamente , Dor/metabolismo , Relação Estrutura-AtividadeRESUMO
INTRODUCTION: Physical, chemical, thermal injuries along with infectious diseases lead to acute pain with associated inflammation, being the primary cause of hospital visits. Moreover, neuropathic pain associated with diabetes is a serious chronic disease leading to high morbidity and poor quality of life. OBJECTIVE: Earlier multiple sulphonamides have been reported to have an antinociceptive and antiallodynic profile. 4-Fluoro-N-(4-sulfamoylbenzyl) Benzene Sulfonamide (4-FBS), a synthetic sulfonamide with reported carbonic anhydrase inhibitory activity, was investigated for its potential effects in mice model of acute and diabetic neuropathic pain. METHODS AND RESULTS: 4-FBS was given orally (p.o.) one hour before the test and then mice were screened for antinociceptive activity by using the tail immersion test, which showed significant antinociceptive effect at both 20 and 40 mg/kg doses. To explore the possible mechanisms, thermal analgesia of 4-FBS was reversed by the 5HT3 antagonist ondansetron 1mg/kg intraperitoneally (i.p.) and by the µ receptor antagonist naloxone (1 mg/kg i.p.), implying possible involvement of serotonergic and opioidergic pathways in the analgesic effect of 4-FBS. Diabetes was induced in mice by a single dose of streptozotocin (STZ) 200 mg/kg i.p. After two weeks, animals first became hyperalgesic and progressively allodynic in the fourth week, which was evaluated through behavioral parameters like thermal and mechanical tests. 4-FBS at 20 and 40 mg/kg p.o. significantly reversed diabetes-induced hyperalgesia and allodynia at 30, 60, 90, and 120 minutes. CONCLUSION: These findings are significant and promising while further studies are warranted to explore the exact molecular mechanism and the potential of 4-FBS in diabetic neuropathic pain.
Assuntos
Analgésicos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Neuropatias Diabéticas/tratamento farmacológico , Hiperalgesia/tratamento farmacológico , Dor/tratamento farmacológico , Administração Oral , Analgésicos/administração & dosagem , Analgésicos/química , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/química , Diabetes Mellitus Experimental/induzido quimicamente , Neuropatias Diabéticas/induzido quimicamente , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Hiperalgesia/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Estreptozocina , Relação Estrutura-AtividadeRESUMO
Withdrawal from chronic nicotine has damaging effects on a variety of learning and memory tasks. Various Sulfonamides that act as carbonic anhydrase inhibitors have documented role in modulation of various cognitive, learning, and memory processing. We investigated the effects of 4-Fluoro-N-(4-sulfamoylbenzyl) Benzene Sulfonamide (4-FBS) on nicotine withdrawal impairments in rats using Morris water maze (MWM), Novel object recognition, Passive avoidance, and open field tasks. Also, Brain-derived neurotrophic factor (BDNF) profiling and in vivo field potential recording were assessed. Rats were exposed to saline or chronic nicotine 3.8 mg/kg subcutaneously for 14 days in four divided doses, spontaneous nicotine withdrawal was induced by quitting nicotine for 72 h (hrs). Animals received 4-FBS at 20, 40, and 60 mg/kg after 72 h of withdrawal in various behavioral and electrophysiological paradigms. Nicotine withdrawal causes a deficit in learning and long-term memory in the MWM task. No significant difference was found in novel object recognition tasks among all groups while in passive avoidance task nicotine withdrawal resulted in a deficit of hippocampus-dependent fear learning. Anxiety like behavior was observed during nicotine withdrawal. Plasma BDNF level was reduced during nicotine withdrawal as compared to the saline group reflecting mild cognitive impairment, stress, and depression. Withdrawal from chronic nicotine altered hippocampal plasticity, caused suppression of long-term potentiation (LTP) in the CA1 area of the hippocampus. Our results showed that 4-FBS at 40 and 60 mg/kg significantly prevented nicotine withdrawal-induced cognitive deficits in behavioral as well as electrophysiological studies. 4-FBS at 60 mg/kg upsurge nicotine withdrawal-induced decrease in plasma BDNF. We conclude that 4-FBS at 40 and 60 mg /kg effectively prevented chronic nicotine withdrawal-induced impairment in long term potentiation and cognitive performance.
Assuntos
Transtornos Cognitivos/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Animais , Ansiedade/tratamento farmacológico , Ansiedade/etiologia , Aprendizagem da Esquiva/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/sangue , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/fisiopatologia , Relação Dose-Resposta a Droga , Medo/efeitos dos fármacos , Hipocampo/patologia , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Nicotina/efeitos adversos , Ratos , Ratos Wistar , Síndrome de Abstinência a Substâncias/complicações , Tabagismo/psicologiaRESUMO
Oxidative stress-induced neuroinflammation is the prominent feature of neurodegenerative disorders, and is characterized by a gradual decline of structure and function of neurons. Many biochemical events emerge thanks to the result of this neurodegeneration, and ultimately provoke neuroinflammation, activation of microglia, and oxidative stress, leading to neuronal death. This cascade not only explains the complexity of events taking place across different stages, but also depicts the need for more effective therapeutic agents. The present study was designed to investigate the neuroprotective effects of newly synthesized benzimidazole containing acetamide derivatives, 3a (2-(4-methoxyanilino)-N-[1-(4-methylbenzene-1-sulfonyl)-1H-benzimidazol-2-yl] acetamide) and 3b (2-(Dodecylamino)-N-[1-(4-methylbenzene-1-sulfonyl)-1H-benzimidazol-2-yl] acetamide) against ethanol-induced neurodegeneration in the rat model. Both derivatives were characterized spectroscopically by proton NMR (1H-NMR) and carbon-13 NMR (13C-NMR) and evaluated for neuroprotective potential using different pharmacological approaches. In vivo experiments demonstrated that ethanol triggered neurodegeneration characterized by impaired antioxidant enzymes and elevated oxidative stress. Furthermore, ethanol administration induced neuroinflammation, as demonstrated by elevated expression of tumor necrotic factor (TNF-α), nuclear factor κB (NF-κB), cyclooxygenase-2 (COX2), and ionized calcium-binding adapter molecule-1 (Iba-1), which was further validated by enzyme-linked immunosorbent assay (ELISA). Treatment with 3a and 3b ameliorated the ethanol-induced oxidative stress, neuroinflammation, and memory impairment. The affinity of synthesized derivatives towards various receptors involved in neurodegeneration was assessed through docking analysis. The versatile nature of benzimidazole nucleus and its affinity toward several receptors suggested that it could be a multistep targeting neuroprotectant. As repetitive clinical trials of neuroprotectants targeting a single step of the pathological process have failed previously, our results suggested that a neuroprotective strategy of acting at different stages may be more advantageous to intervene in the vicious cycles of neuroinflammation.
Assuntos
Acetamidas/farmacologia , Benzimidazóis/farmacologia , Acetamidas/síntese química , Acetamidas/metabolismo , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Benzimidazóis/síntese química , Benzimidazóis/metabolismo , Encéfalo/metabolismo , Etanol/efeitos adversos , Hipocampo/metabolismo , Masculino , Microglia/metabolismo , Simulação de Acoplamento Molecular/métodos , Doenças Neurodegenerativas/metabolismo , Neuroimunomodulação/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismoRESUMO
INTRODUCTION: Behavioral sensitization is a phenomenon that develops from intermittent exposure to nicotine and other psychostimulants, which often leads to heightened locomotor activity and then relapse. Sulfonamides that act as carbonic anhydrase inhibitors have a documented role in enhancing dopaminergic tone and normalizing neuroplasticity by stabilizing glutamate release. OBJECTIVE: The aim of the current study was to explore synthetic sulfonamides derivative 4-fluoro-N-(4-sulfamoylbenzyl) benzene-sulfonamide (4-FBS) (with documented carbonic anhydrase inhibitory activity) on acquisition and expression of nicotine-induced behavioral sensitization. METHODS: In the acquisition phase, selected 5 groups of mice were exposed to saline or nicotine 0.5mg/kg intraperitoneal (i.p) for 7 consecutive days. Selected 3 groups were administered with 4-FBS 20, 40, and 60 mg/kg p.o. along with nicotine. After 3 days of the drug-free period, ie, day 11, a challenge dose of nicotine was injected to all groups except saline and locomotor activity was recorded for 30 minutes. In the expression phase, mice were exposed to saline and nicotine only 0.5 mg/kg i.p for 7 consecutive days. After 3 days of the drug-free period, ie, day 11, 4-FBS at 20, 40, and 60 mg/kg were administered to the selected groups, one hour after drug a nicotine challenge dose was administered, and locomotion was recorded. At the end of behavioral experiments, all animals were decapitated and the striatum was excised and screened for changes in adenosine levels, using HPLC-UV. RESULTS: Taken together, our findings showed that 4-FBS in all 3 doses, in both sets of experiments significantly attenuated nicotine-induced behavioral sensitization in mice. Additionally, 4-FBS at 60mg/kg significantly lowered the adenosine level in the striatum. CONCLUSION: The behavioral and adenosine modulation is promising, and more receptors level studies are warranted to explore the exact mechanism of action of 4-FBS.
Assuntos
Adenosina/antagonistas & inibidores , Comportamento Animal/efeitos dos fármacos , Derivados de Benzeno/farmacologia , Nicotina/antagonistas & inibidores , Antagonistas Nicotínicos/farmacologia , Sulfonamidas/farmacologia , Adenosina/metabolismo , Administração Oral , Animais , Derivados de Benzeno/administração & dosagem , Derivados de Benzeno/síntese química , Relação Dose-Resposta a Droga , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Nicotina/administração & dosagem , Antagonistas Nicotínicos/administração & dosagem , Antagonistas Nicotínicos/síntese química , Sulfonamidas/administração & dosagem , Sulfonamidas/síntese químicaRESUMO
BACKGROUND: Isoxazole is an important pharmacophore in medicinal chemistry with a wide range of pharmacological activities. The present study deals with the synthesis and evaluation of antinociceptive potential of nine novel 3-substituted-isoxazole-4-carboxamide derivatives. SYNTHESIS: In the first step, respective oxime was prepared and further treated with ethylacetoacetate and anhydrous zinc chloride followed by hydrolysis of ester to furnish 3-substituted isoxazole-4-carboxylic acid. The respective carboxylic acids were converted to acid chlorides and condensed with aromatic amines to get the target carboxamide derivatives (A1-A5 and B1-B5). These compounds were characterized by FTIR, 1HNMR, 13CNMR and elemental analysis data and screened for their analgesic activity using acetic acid-induced writhing assay and hot plat test in mice and compared with the standard centrally acting analgesic, tramadol. RESULTS: All the synthesized carboxamide derivatives showed low to moderate analgesic activity. Among the synthesized derivatives B2 having methoxy (OCH3) showed high analgesic activity as compared to tramadol both in acetic acid-induced writhing assay and hot plate assay at dose of 6 mg/kg. To examine the involvement of opioidergic mechanism in the mediation of analgesic effects of isoxazole derivatives animals were further treated with non-selective opioid analgesic, naloxone (0.5 mg/kg). The results showed that compounds A3 and B2 follow a non-opioid receptor pathway in the mediation of analgesic effects. Synthesized compounds A3 and B2 were docked against non-opioid receptors COX-1 (3N8X), COX-2 (1PXX) and human capsaicin receptor (HCR, 3J9J) to analyze their binding interactions. They showed binding energies in the range of - 7.5 to - 9.7 kcal/mol. CONCLUSIONS: The results indicated that isoxazole carboxamide derivatives possess moderate analgesic potential especially compounds A3 and B2 can be considered as lead molecules and explored further for pain management with fewer side effects.