Publications by authors named "Muzaffar Abbas"

24 Publications

  • Page 1 of 1

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

Amino acid derivatives of 2-Mercaptobenzimidazoles suppress cytokines at the site of inflammation and block gastric H+/K+ ATPase.

Pak J Pharm Sci 2021 May;34(3(Supplementary)):1157-1163

Faculty of Pharmacy, Capital University of Science and Technology, Islamabad, Pakistan.

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-1β 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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May 2021

Thiazolidine Derivatives Attenuate Carrageenan-Induced Inflammatory Pain in Mice.

Drug Des Devel Ther 2021 4;15:369-384. Epub 2021 Feb 4.

State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen, People's Republic of China.

Background: Peripheral inflammation leads to the development of persistent thermal hyperalgesia and mechanical allodynia associated with increased expression of interleukin-1β (IL-1β) 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-1β 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-1β 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-1β 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-1β expression in the spinal cord.
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http://dx.doi.org/10.2147/DDDT.S281559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871178PMC
October 2021

Effects of α7 Nicotinic Acetylcholine Receptor Positive Allosteric Modulator on BDNF, NKCC1 and KCC2 Expression in the Hippocampus following Lipopolysaccharide-Induced Allodynia and Hyperalgesia in a Mouse Model of Inflammatory Pain.

CNS Neurol Disord Drug Targets 2021 ;20(4):366-377

Department of Pharmaceutical Sciences, College of Pharmacy, South Dakota State University, Brookings SD 57007, United States.

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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http://dx.doi.org/10.2174/1871527319666201230102616DOI Listing
January 2022

Effect of 4-Fluoro-N-(4-sulfamoylbenzyl) Benzene Sulfonamide on cognitive deficits and hippocampal plasticity during nicotine withdrawal in rats.

Biomed Pharmacother 2020 Nov 23;131:110783. Epub 2020 Sep 23.

Physiology Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran.

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.
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http://dx.doi.org/10.1016/j.biopha.2020.110783DOI Listing
November 2020

Analgesic and Antiallodynic Effects of 4-Fluoro-N-(4-Sulfamoylbenzyl) Benzene Sulfonamide in a Murine Model of Pain.

Drug Des Devel Ther 2020 27;14:4511-4518. Epub 2020 Oct 27.

Department of Pharmacy, COMSATS University Islamabad, Abbottabad Campus, Abbottabad, Pakistan.

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 5HT 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.
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http://dx.doi.org/10.2147/DDDT.S269777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602919PMC
August 2021

Effect of 4-Fluoro-N-(4-Sulfamoylbenzyl) Benzene Sulfonamide on Acquisition and Expression of Nicotine-Induced Behavioral Sensitization and Striatal Adenosine Levels.

Drug Des Devel Ther 2020 17;14:3777-3786. Epub 2020 Sep 17.

Department of Pharmacy, COMSATS University Islamabad, Abbottabad Campus, Islamabad, Pakistan.

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.
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http://dx.doi.org/10.2147/DDDT.S270025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505708PMC
July 2021

Benzimidazole Derivative Ameliorates Opioid-Mediated Tolerance during Anticancer- Induced Neuropathic Pain in Mice.

Anticancer Agents Med Chem 2021 ;21(3):365-371

Department of Basic Medical Sciences, Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan.

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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http://dx.doi.org/10.2174/1871520620999200818155031DOI Listing
October 2021

Amino acid conjugates of 2-mercaptobenzimidazole provide better anti-inflammatory pharmacology and improved toxicity profile.

Drug Dev Res 2020 Aug 11. Epub 2020 Aug 11.

ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash University, Parkville, Australia.

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, H NMR and 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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http://dx.doi.org/10.1002/ddr.21728DOI Listing
August 2020

A Novel Sulfonamide, 4-FS, Reduces Ethanol Drinking and Physical Withdrawal Associated With Ethanol Dependence.

Int J Mol Sci 2020 Jun 21;21(12). Epub 2020 Jun 21.

VA San Diego Healthcare System, San Diego, CA 92161, USA.

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% /; 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 GABA 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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http://dx.doi.org/10.3390/ijms21124411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352747PMC
June 2020

Benzimidazole Containing Acetamide Derivatives Attenuate Neuroinflammation and Oxidative Stress in Ethanol-Induced Neurodegeneration.

Biomolecules 2020 01 8;10(1). Epub 2020 Jan 8.

State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, China.

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 (H-NMR) and carbon-13 NMR (C-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.
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http://dx.doi.org/10.3390/biom10010108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7023260PMC
January 2020

The α7 nicotinic acetylcholine receptor positive allosteric modulator prevents lipopolysaccharide-induced allodynia, hyperalgesia and TNF-α in the hippocampus in mice.

Pharmacol Rep 2019 Dec 3;71(6):1168-1176. Epub 2019 Jul 3.

Department of Pharmaceutical Sciences, College of Pharmacy, South Dakota State University, Brookings, SD, USA. Electronic address:

Background: Previous studies have shown that α7 nicotinic acetylcholine receptor (nAChR) has a critical role in the regulation of pain sensitivity and neuroinflammation. However, pharmacological effects of α7 nAChR activation in the hippocampus on neuroinflammatory mechanisms associated with allodynia and hyperalgesia remain unknown. We have determined the effects of 3a,4,5,9b-tetrahydro-4-(1-naphthalenyl)-3H-cyclopentan[c]quinoline-8-sulfonamide (TQS), an α7 nAChR positive allosteric modulator, on lipopolysaccharide (LPS)-induced allodynia and hyperalgesia in mice. We also evaluated the effects of TQS on immunoreactivity of microglial marker ionized-calcium binding adaptor molecule 1 (Iba-1), phospho-nuclear factor-κB (p-NF-κB p), tumor necrosis factor-alpha (TNF-α), and norepinephrine (NE) level.

Methods: Mice were treated with (0.25, 1 or 4 mg/kg, ip) followed by LPS (1 mg/kg, ip) administration. Allodynia and hyperalgesia were determined using von Frey filaments and hot plate respectively. Immunoreactivity of Iba-1, p-NF-κB p, and TNF-α, were measured in the hippocampus using immunofluorescence assay. Hippocampal NE level was evaluated using high performance liquid chromatography.

Results: LPS administration resulted in allodynia and hyperalgesia in mice after six h. Systemic administration of TQS prevented LPS-induced allodynia and hyperalgesia. TQS pretreatment significantly decreased the immunoreactivity of Iba-1, p-NF-κB, and TNF-α in CA1 and DG regions of the hippocampus. In addition, TQS reversed LPS-induced NE reduction in the hippocampus.

Conclusions: Taken together, our results suggest that TQS prevented LPS-induced allodynia and hyperalgesia, upregulation of TNF-α expression and NE level reduction involving microglial α7 nAChR in part in the hippocampus. Therefore, these findings highlight the important effects of α7 nAChR allosteric modulator against symptoms of inflammatory pain.
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http://dx.doi.org/10.1016/j.pharep.2019.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745232PMC
December 2019

Synthesis and anti-nociceptive potential of isoxazole carboxamide derivatives.

BMC Chem 2019 Dec 29;13(1). Epub 2019 Jan 29.

1Department of Pharmaceutical Chemistry, Riphah Institute of Pharmaceutical Science, Riphah International University, Islamabad, Pakistan.

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, HNMR, CNMR 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 (OCH) 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.
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http://dx.doi.org/10.1186/s13065-019-0518-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6659567PMC
December 2019

Corrigendum: Melatonin Protects MCAO-Induced Neuronal Loss NR2A Mediated Prosurvival Pathways.

Front Pharmacol 2019 21;10:702. Epub 2019 Jun 21.

State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China.

[This corrects the article DOI: 10.3389/fphar.2019.00297.].
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http://dx.doi.org/10.3389/fphar.2019.00702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6598544PMC
June 2019

Melatonin Protects MCAO-Induced Neuronal Loss via NR2A Mediated Prosurvival Pathways.

Front Pharmacol 2019 29;10:297. Epub 2019 Mar 29.

State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China.

Stroke is the significant cause of human mortality and sufferings depending upon race and demographic location. Melatonin is a potent antioxidant that exerts protective effects in differential experimental stroke models. Several mechanisms have been previously suggested for the neuroprotective effects of melatonin in ischemic brain injury. The aim of this study is to investigate whether melatonin treatment affects the glutamate N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor signaling in cerebral cortex and striatum 24 h after permanent middle cerebral artery occlusion (MCAO). Melatonin (5 mg/kg) attenuated ischemia-induced down regulation of NMDA receptor 2 (NR2a), postsynaptic density-95 (PSD95) and increases NR2a/PSD95 complex association, which further activates the pro-survival PI3K/Akt/GSK3β pathway with mitigated collapsin response mediator protein 2 (CRMP2) phosphorylation. Furthermore, melatonin increases the expression of γ-enolase, a neurotrophic factor in ischemic cortex and striatum, and preserve the expression of presynaptic (synaptophysin and SNAP25) and postsynaptic (p-GluR1845) protein. Our study demonstrated a novel neuroprotective mechanism for melatonin in ischemic brain injury which could be a promising neuroprotective agent for the treatment of ischemic stroke.
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http://dx.doi.org/10.3389/fphar.2019.00297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461025PMC
March 2019

The Benzimidazole Derivatives, B1 (-[(1-Benzimidazol-2-yl)Methyl]-4-Methoxyaniline) and B8 (-{4-[(1-Benzimidazol-2-yl)Methoxy]Phenyl}Acetamide) Attenuate Morphine-Induced Paradoxical Pain in Mice.

Front Neurosci 2019 12;13:101. Epub 2019 Feb 12.

Department of Basic Medical Sciences, Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan.

Despite being routinely used for pain management, opioid use is limited due to adverse effects such as development of tolerance and paradoxical pain, including thermal hyperalgesia and mechanical allodynia. Evidence indicates that continued morphine administration causes increased expression of proinflammatory mediators such as tumor necrosis factor-alpha (TNF-α). The objectives of the present study were to determine the effects of B1 (-[(1-benzimidazol-2-yl)methyl]-4-methoxyaniline) and B8 (-{4-[(1-benzimidazol-2-yl)methoxy]phenyl}acetamide), benzimidazole derivatives, on thermal nociception and mechanical allodynia during repeated morphine (intraperitoneal; 5 mg/kg twice daily for 6 days)-induced paradoxical pain and TNF-α expression in the spinal cord in mice. Our data indicate that administration of benzimidazole derivatives attenuated morphine-induced thermal hyperalgesia and mechanical allodynia. Benzimidazole derivatives also reduced TNF-α expression in mice. Taken together, these results suggest that benzimidazole derivatives might be useful for the treatment of neuroinflammatory consequences of continued morphine administration and could be potential drug candidates for the management of opioid-induced paradoxical pain.
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http://dx.doi.org/10.3389/fnins.2019.00101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6379466PMC
February 2019

The α7 nicotinic acetylcholine receptor positive allosteric modulator attenuates lipopolysaccharide-induced activation of hippocampal IκB and CD11b gene expression in mice.

Drug Discov Ther 2017;11(4):206-211

Department of Pharmaceutical Sciences, College of Pharmacy, South Dakota State University.

We have reported that 3a,4,5,9b-tetrahydro-4-(1-naphthalenyl)-3H-cyclopentan[c]quinoline-8-sulfonamide (TQS), α7 nicotinic acetylcholine receptor (nAChR) positive allosteric modulator (PAM) reduces lipopolysaccharide (LPS)-induced hyperalgesia and allodynia in mice. The objective of the present study was to determine the effects of TQS on LPS-induced activation of hippocampal inhibitor of κB (IκB) and cluster of differentiation 11b (CD11b) gene expression involving hyperalgesia and allodynia in mice. We also examined the effects of TQS on microglial phenotype following LPS administration. Pretreatment of TQS (4 mg/kg) reduced the expressions of IκB and CD11b mRNA. Pretreatment of methyllycaconitine (3 mg/kg), an α7 nAChR antagonist, reversed TQS-induced decrease in IκB and CD11b mRNA expressions in the hippocampus indicating the involvement of α7 nAChR. In addition, TQS (4 mg/kg) reversed the LPS-induced microglial morphological changes. These results suggest that TQS reduces LPS-induced IκB and CD11b gene expression and microglial activation associated with hyperalgesia and allodynia by targeting microglial α7 nAChR in the hippocampus.
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http://dx.doi.org/10.5582/ddt.2017.01038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369585PMC
July 2019

Neuropathic Pain and Lung Delivery of Nanoparticulate Drugs: An Emerging Novel Therapeutic Strategy.

CNS Neurol Disord Drug Targets 2017 ;16(3):303-310

Department of Pharmaceutical Sciences, South Dakota State University, 1055 Campanile Avenue, Avera Health and Science Center, SAV 265, Brookings, SD 57007. United States.

Neuropathic pain is a chronic neurological disorder affecting millions of people around the world. The currently available pharmacologic agents for the treatment of neuropathic pain have limited efficacy and are associated with dose related unwanted adverse effects. Due to the limited access of drug molecules across blood-brain barrier, a small percentage of drug that is administered systematically, reaches the central nervous system in active form. These therapeutic agents also require daily treatment regimen that is inconvenient and potentially impact patient compliance. Application of nanoparticulate drugs for enhanced delivery system has been explored extensively in the last decades. Pulmonary delivery of nanomedicines for the management of various diseases has become an emerging treatment strategy that ensures the targeted delivery of drugs both for systemic and local effects with low dose and limited adverse effects. To the best of our knowledge, there are no inhaled drug products available on market for the treatment of neuropathic pain. The advantages of delivering therapeutics into deep lungs include non-invasive drug delivery, higher bioavailability with low dose, lower systemic toxicity, and potentially greater blood-brain barrier penetration. This review discusses and highlights the important issues on the application of emerging nanoparticulate lung delivery of drugs for the effective treatment of neuropathic pain.
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http://dx.doi.org/10.2174/1871527315666161213104417DOI Listing
May 2018

Effects of alpha-7 nicotinic acetylcholine receptor positive allosteric modulator on lipopolysaccharide-induced neuroinflammatory pain in mice.

Eur J Pharmacol 2016 Jul 3;783:85-91. Epub 2016 May 3.

Department of Pharmaceutical Sciences, College of Pharmacy, South Dakota State University, Brookings, SD 57007, USA. Electronic address:

Evidence indicates that microglial activation contributes to the pathophysiology and maintenance of neuroinflammatory pain involving central nervous system alpha-7 nicotinic acetylcholine receptors. The objective of the present study was to determine the effects of 3a,4,5,9b-Tetrahydro-4-(1-naphthalenyl)-3H-cyclopentan[c]quinoline-8-sulfonamide (TQS), an alpha-7 nicotinic acetylcholine receptor positive allosteric modulator (PAM), on tactile allodynia and thermal hyperalgesia following lipopolysaccharide (LPS)-induced microglial activation in hippocampus, a neuroinflammatory pain model in mice. In addition, we examined the effects of TQS on microglial activation marker, an ionized calcium-binding adapter molecule 1 (Iba-1), in the hippocampus may be associated with neuroinflammatory pain. Pretreatment of TQS (4mg/kg) significantly reduced LPS (1mg/kg)-induced tactile allodynia and thermal hyperalgesia. Moreover, pretreatment of methyllycaconitine (3mg/kg) significantly reversed TQS-induced antiallodynic and antihyperalgesic responses indicating the involvement of alpha-7 nicotinic acetylcholine receptor. Pretreatment of TQS significantly decreased LPS-induced increased in hippocampal Iba-1 expression. Overall, these results suggest that TQS reduces LPS-induced neuroinflammatory pain like symptoms via modulating microglial activation likely in the hippocampus and/or other brain region by targeting alpha-7 nicotinic acetylcholine receptor. Therefore, alpha-7 nicotinic acetylcholine receptor PAM such as TQS could be a potential drug candidate for the treatment of neuroinflammatory pain.
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http://dx.doi.org/10.1016/j.ejphar.2016.05.003DOI Listing
July 2016

A streptozotocin-induced diabetic neuropathic pain model for static or dynamic mechanical allodynia and vulvodynia: validation using topical and systemic gabapentin.

Naunyn Schmiedebergs Arch Pharmacol 2015 Nov 3;388(11):1129-40. Epub 2015 Jul 3.

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

Neuropathic vulvodynia is a state of vulval discomfort characterized by a burning sensation, diffuse pain, pruritus or rawness with an acute or chronic onset. Diabetes mellitus may cause this type of vulvar pain in several ways, so this study was conducted to evaluate streptozotocin-induced diabetes as a neuropathic pain model for vulvodynia in female rats. The presence of streptozotocin (50 mg/kg i.p.)-induced diabetes was initially verified by disclosure of pancreatic tissue degeneration, blood glucose elevation and body weight loss 5-29 days after a single treatment. Dynamic (shortened paw withdrawal latency to light brushing) and static (diminished von Frey filament threshold pressure) mechanical allodynia was then confirmed on the plantar foot surface. Subsequently, both static and dynamic vulvodynia was detected by application of the paradigm to the vulval region. Systemic gabapentin (75 mg/kg, i.p.) and topical gabapentin (10 % gel) were finally tested against allodynia and vulvodynia. Topical gabapentin and the control gel vehicle significantly increased paw withdrawal threshold in the case of the static allodynia model and also paw withdrawal latency in the model for dynamic allodynia when compared with the streptozotocin-pretreated group. Likewise, in the case of static and dynamic vulvodynia, there was a significant antivulvodynia effect of systemic and topical gabapentin treatment. These outcomes substantiate the value of this model not only for allodynia but also for vulvodynia, and this was corroborated by the findings not only with systemic but also with topical gabapentin.
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http://dx.doi.org/10.1007/s00210-015-1145-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4619463PMC
November 2015

Nature cures nature: Hypericum perforatum attenuates physical withdrawal signs in opium dependent rats.

Pharm Biol 2014 May 21;52(5):586-90. Epub 2013 Nov 21.

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

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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http://dx.doi.org/10.3109/13880209.2013.854811DOI Listing
May 2014

Inhibitory effect of bacopasides on spontaneous morphine withdrawal induced depression in mice.

Phytother Res 2014 Jun 14;28(6):937-9. Epub 2013 Nov 14.

Department of Pharmaceutical Sciences, COMSATS Institute of Information Technology, Abbottabad, 22060, Pakistan.

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.
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http://dx.doi.org/10.1002/ptr.5081DOI Listing
June 2014

Bronchodilator activity of aerial parts of Polygonatum verticillatum augmented by anti-inflammatory activity: attenuation of Ca²⁺ channels and lipoxygenase.

Phytother Res 2013 Sep 29;27(9):1288-92. Epub 2012 Oct 29.

Department of Pharmacy, University of Peshawar, Peshawar 25120, Pakistan.

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⁺ (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 Ca²⁺ concentration-response curves to the right, analogous to that produced by verapamil, confirming a Ca²⁺ 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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http://dx.doi.org/10.1002/ptr.4860DOI Listing
September 2013

Effect of Bacopasides on acquisition and expression of morphine tolerance.

Phytomedicine 2011 Jul 5;18(10):836-42. Epub 2011 Mar 5.

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

Opioids are extensively used for the management of both chronic malignant and non malignant pains. One major serious limitation associated with chronic use of opioids is the development of tolerance to its analgesic effect. The effect of Bacopa monnieri, a renowned ayurvedic medicine for acquisition and expression of morphine tolerance in mice, was investigated. Bacopa monnieri, n-Butanol fraction was analyzed on High performance liquid chromatography (HPLC), for Bacopaside A major components i.e. Bacoside A(3), Bacopaside ll and Bacosaponin C. Antinociceptive effect of n-Butanol extract of Bacopa monnieri (n Bt-ext BM) (5, 10 and 15 mg/kg) was assessed on hot plate. Effect of different doses of n Bt-ext BM on morphine antinociception was also assessed. n Bt-ext BM was also screened for development of tolerance to antinociceptive effect of Bacopa monnieri by administering 15 mg/kg n Bt-ext BM for seven days. Tolerance to morphine analgesia was induced in mice by administering intraperitoneally (I.P.) 20 mg/kg morphine twice daily for five days. Acute and Chronic administration of 5, 10 and 15 mg/kg n Bt-ext BM significantly reduced both expression and development of tolerance to morphine analgesia in mice. Additionally, Bacopa monnieri was found to enhance antinociceptive effect of morphine in intolerant animals. However, no tolerance to Bacopa monnieri antinociceptive effect was observed in seven days treatment schedule. These findings indicate effectiveness of Bacopa monnieri for management of morphine tolerance.
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http://dx.doi.org/10.1016/j.phymed.2011.01.023DOI Listing
July 2011
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