Publications by authors named "Gowhar Ali"

32 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

Distribution and molecular characterization of potato virus Y (PVY) strains infecting potato () crop in Kashmir (India).

Virusdisease 2021 Dec 31;32(4):784-788. Epub 2021 Jul 31.

Division of Plant Pathology, Sher-E-Kashmir University of Agricultural Sciences and Technology of Kashmir (SKUAST-K)- Shalimar, Srinagar, J&K 190025 India.

For breeding resistant cultivars, understanding the nature and distribution of PVY strains is indispensable. In present study, during the course of survey two hundred potato samples showing symptoms of vein clearing, mosaic, stunting, mottling, curling and vein banding were collected from 4 major potato growing districts of Kashmir valley. The disease incidence ranged from 16 to 27.33% with maximum in district Srinagar (27.33%). All the samples were serologically tested for PVY infection using DAS-ELISA and 74 tested positive for PVY infection. Out of 74 positive samples forty samples were re-confirmed by RT-PCR by amplifying 900 bp using coat protein (CP) gene specific primers. The PCR-positive samples were further characterized into different strains using strain specific primers. The strains NTN, N and O were reported and among them NTN strain was found to be most prevalent throughout the valley. The phylogenetic analysis of selected isolates carried out with known PVY strains also confirmed that the isolates belong to the N, NTN and O strains of PVY. The study will help in developing point of care strain specific diagnostics and also in devising the strategy for developing PVY resistant varieties, because when we have the complete information about the virus and its strains it will help us in screening the germplasm against each strain and, therefore, eventually development of a multi-strain resistant variety.

Supplementary Information: The online version contains supplementary material available at 10.1007/s13337-021-00722-2.
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http://dx.doi.org/10.1007/s13337-021-00722-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8630282PMC
December 2021

Cyclopentanone Derivative Attenuates Memory Impairment by Inhibiting Amyloid Plaques Formation in the 5xFAD Mice.

Int J Mol Sci 2021 Sep 3;22(17). Epub 2021 Sep 3.

Natural and Medical Sciences Research Center, University of Nizwa, Birkat-ul-Mouz 616, Nizwa, Oman.

Alzheimer's disease (AD) is a chronic neurodegenerative disorder. This study was designed to investigate the effects of cyclopentanone derivative i.e., 2-(hydroxyl-(3-nitrophenyl)methyl)cyclopentanone (3NCP) on behavior, amyloid β (Aβ) plaque deposition, and βAPP cleaving enzyme-1 (BACE-1) expression in the 5xFAD mouse brain. In this study, computational studies were conducted to predict the binding mode of the 3NCP with target sites of the β-secretase. In vivo studies were performed on the 5xFAD mice model of AD using different behavioral test models like light/dark box, elevated plus maze (EPM), and the Barnes maze tests for the assessment of anxiety, spatial learning and memory. The thioflavin-S staining, immunohistochemistry (IHC), and RT-PCR studies were carried out to find the effect of the 3NCP on the β-amyloid plaques formation and BACE-1 expression. The results of the computational studies showed that the 3NCP has excellent binding affinities for beta-secretase. The light/dark box study depicted that the 3NCP does not cause anxiety. The 3NCP treatment effects in the EPM and Barnes maze tests showed a significant effect on learning and memory. Furthermore, the results of the thioflavin staining and IHC revealed that the 3NCP significantly reduced the formation of the beta-amyloid plaques in brain tissues. Moreover, the RT-PCR study showed that 3NCP significantly reduced the BACE-1 expression in the brain. Conclusively, the results of the current study demonstrate that the 3NCP may be a potential candidate for AD treatment in the future.
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http://dx.doi.org/10.3390/ijms22179559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8430684PMC
September 2021

Attenuation of spatial memory in 5xFAD mice by targeting cholinesterases, oxidative stress and inflammatory signaling using 2-(hydroxyl-(2-nitrophenyl)methyl)cyclopentanone.

Int Immunopharmacol 2021 Nov 31;100:108083. Epub 2021 Aug 31.

Natural and Medical Sciences Research Center, University of Nizwa, Birkat-ul-Mouz 616, Nizwa, Sultanate of Oman.

Alzheimer's disease (AD) is classified pathologically as a progressive neurological disorder associated with memory decline. The study was designed to assess the underlying molecular signaling involved in the neuroprotective effect of the 2-(hydroxyl-(2-nitrophenyl)methyl)cyclopentanone (2NCP) as a novel therapeutic agent for AD. In this connection, in vitro cholinesterases inhibitory and antioxidant activities were investigated. In vivo studies were carried out on a well-known 5xFAD mice model in different behavioural models such as light/dark box,balance beam, rotarod, elevated plus maze (EPM),novel object recognition (NOR), paddling Y-maze, and Morris water maze (MWM) tests. Hippocampus (HC) and frontal cortex (FC) homogenates were examined for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities, 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radicals, glutathione S-transferase (GST), glutathione (GSH), and catalase. Further, we examined the expression of inflammatory cytokines and Nrf2 in the HC and FC through RT-PCR. Computational studies were conducted to predict the binding mode of the 2NCP with target sites of nuclear factor-κB (NF-κB) and cholinesterases. The findings of in vitro assays revealed that the IC values of the 2NCP against AChE and BChE were 17 and 23 µg/ml respectively. DPPH antioxidant assay displayed an IC value for the 2NCP was 62 µg/ml. Whereas, theex vivo study depicted that the activities of AChE and BChEwere significantly reduced. Moreover, free radicals load, GSH level, catalase and GST activities were significantly declined. Furthermore, in vivostudies showed that the 2NCP treated animals exhibited gradual memory improvement and improved motor functions. RT-PCR study revealed that mRNA levels of the inflammatory mediators (IL-1β, IL-6, TNF-α) were significantly reduced, while the expression of antioxidant Nrf2 was significantly increased.The molecular docking studies further confirmed that the 2NCP showed excellent binding affinities for NF-κB and cholinesterases. Taken together, the 2NCP improves spatial memory and learning, short- and long-term memory,markedly inhibits cholinesterases, reduced neuroinflammation, and mitigated oxidative stress in the 5xFAD mice; hence the 2NCP may be a potential candidate for the management of AD.
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http://dx.doi.org/10.1016/j.intimp.2021.108083DOI Listing
November 2021

Alleviation of Memory Deficit by Bergenin via the Regulation of Reelin and Nrf-2/NF-κB Pathway in Transgenic Mouse Model.

Int J Mol Sci 2021 Jun 20;22(12). Epub 2021 Jun 20.

Pharmacological Sciences Research Lab, Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad 45320, Pakistan.

The present study aims to determine the neuroprotective effect of Bergenin against spatial memory deficit associated with neurodegeneration. Preliminarily, the protective effect of Bergenin was observed against HO-induced oxidative stress in HT-22 and PC-12 cells. Further studies were performed in 5xFAD Tg mouse model by administering Bergenin (1, 30 and 60 mg/kg; orally), whereas Bergenin (60 mg/kg) significantly attenuated the memory deficit observed in the Y-maze and Morris water maze (MWM) test. Fourier transform-infrared (FT-IR) spectroscopy displayed restoration of lipids, proteins and their derivatives compared to the 5xFAD Tg mice group. The differential scanning calorimeter (DSC) suggested an absence of amyloid beta (Aβ) aggregation in Bergenin-treated mice. The immunohistochemistry (IHC) analysis suggested the neuroprotective effect of Bergenin by increasing Reelin signaling (Reelin/Dab-1) and attenuated Aβ (1-42) aggregation in hippocampal regions of mouse brains. Furthermore, IHC and western blot results suggested antioxidant (Keap-1/Nrf-2/HO-1), anti-inflammatory (TLR-4/NF-kB) and anti-apoptotic (Bcl-2/Bax/Caspase-3) effect of Bergenin. Moreover, a decrease in Annexin V/PI-stained hippocampal cells suggested its effect against neurodegeneration. The histopathological changes were reversed significantly by Bergenin. In addition, a remarkable increase in antioxidant level with suppression of pro-inflammatory cytokines, oxidative stress and nitric oxide production were observed in specific regions of the mouse brains.
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http://dx.doi.org/10.3390/ijms22126603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234641PMC
June 2021

Toxicological Evaluation of Novel Cyclohexenone Derivative in an Animal Model through Histopathological and Biochemical Techniques.

Toxics 2021 May 25;9(6). Epub 2021 May 25.

Faculty of Medicine, Transilvania University of Brasov, 500019 Brasov, Romania.

Toxicity studies were conducted to provide safety data of potential drug candidates by determining lethal and toxic doses. This study was designed for pre-clinical evaluation of novel cyclohexenone derivative with respect to the acute and sub-acute toxicity along with the diabetogenic potential. Acute and sub-acute toxicity were assessed after intraperitoneal (i.p) injection of the investigational compound through selected doses for 21 days. This was followed by assessment of isolated body organs (liver, kidney, heart and pancreas) via biochemical indicators and histopathological techniques. No signs of toxicity were revealed in the study of acute toxicity. Similarly, a sub-acute toxicity study showed no significant difference in biochemical indicators on 11th and 21st days between treated and control groups. However, in blood urea nitrogen (BUN) and random blood glucose/sugar (RBS) values, significant differences were recorded. Histopathological evaluation of liver, kidney, pancreas and heart tissues revealed mild to severe changes in the form of steatosis, inflammation, fibrosis, necrosis and myofibrillary damages on 11th and 21st days of treatment. In conclusion, the median lethal dose of the tested compound was expected to be greater than 500 mg/kg. No significant change occurred in selected biomarkers, except BUN and RBS levels, but a histopathological study showed moderate toxic effect on liver, kidney, pancreas and heart tissues by the cyclohexenone derivative.
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http://dx.doi.org/10.3390/toxics9060119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8227666PMC
May 2021

Mechanistic evaluation of a novel cyclohexenone derivative's functionality against nociception and inflammation: An in-vitro, in-vivo and in-silico approach.

Eur J Pharmacol 2021 Jul 16;902:174091. Epub 2021 Apr 16.

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

The synthesis of a novel cyclohexanone derivative (CHD; Ethyl 6-(4-metohxyphenyl)-2-oxo-4-phenylcyclohexe-3-enecarboxylate) was described and the subsequent aim was to perform an in vitro, in vivo and in silico pharmacological evaluation as a putative anti-nociceptive and anti-inflammatory agent in mice. Initial in vitro studies revealed that CHD inhibited both cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) enzymes and it also reduced mRNA expression of COX-2 and the pro-inflammatory cytokines TNF-α and IL-1β. It was then shown that CHD dose dependently inhibited chemically induced tonic nociception in the abdominal constriction assay and also phasic thermal nociception (i.e. anti-nociception) in the hot plate and tail immersion tests in comparison with aspirin and tramadol respectively. The thermal test outcomes indicated a possible moderate centrally mediated anti-nociception which, in the case of the hot plate test, was pentylenetetrazole (PTZ) and naloxone reversible, implicating GABAergic and opioidergic mechanisms. CHD was also effective against both the neurogenic and inflammatory mediator phases induced in the formalin test and it also disclosed anti-inflammatory activity against the phlogistic agents, carrageenan, serotonin, histamine and xylene compared with standard drugs in edema volume tests. In silico studies indicated that CHD possessed preferential affinity for GABA, opioid and COX-2 target sites and this was supported by molecular dynamic simulations where computation of free energy of binding also favored the formation of stable complexes with these sites. These findings suggest that CHD has prospective anti-nociceptive and anti-inflammatory properties, probably mediated through GABAergic and opioidergic interactions supplemented by COX-2 and 5-LOX enzyme inhibition in addition to reducing pro-inflammatory cytokine expression. CHD may therefore possess potentially beneficial therapeutic effectiveness in the management of inflammation and pain.
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http://dx.doi.org/10.1016/j.ejphar.2021.174091DOI Listing
July 2021

Attenuation of nociceptive and paclitaxel-induced neuropathic pain by targeting inflammatory, CGRP and substance P signaling using 3-Hydroxyflavone.

Neurochem Int 2021 03 5;144:104981. Epub 2021 Feb 5.

Natural and Medical Sciences Research Center, University of Nizwa, Birkat-ul-Mouz 616, Nizwa, Oman. Electronic address:

Paclitaxel is an anti-microtubule agent, most widely used chemotherapeutic agent for the treatment of malignant solid tumors. However, it is associated with some severe side effects including painful neurotoxicity with reporting of neuropathic pain and sensory abnormalities by patients during and after paclitaxel therapy. Peripheral neuropathy was induced by the administration of paclitaxel (4 mg/kg on days 1, 3, 5, and 7). In this study, the anti-nociceptive and anti-inflammatory propensity of 3-Hydroxyflavone (3HF) in mice and the preventive effect of 3HF against paclitaxel-induced peripheral neuropathy in Sprague Dawley (SD) rats were investigated. Moreover, tactile and cold allodynia, thermal and tail immersion hyperalgesia, and effects on motor-coordination were also evaluated. Furthermore, the expression of proinflammatory cytokines i.e. Calcitonin gene-related peptide (CGRP), and Substance P from the spinal cord was examined through RT-PCR. Additionally, a computational structural biology approach was applied to search the potential therapeutic targets and to predict the binding mechanism of 3HF. Treatment of 3HF alleviated the nociceptive pain, paw edema, development of tactile and cold allodynia, and hyperalgesia. Similarly, treatment with 3HF suppressed the paclitaxel-induced increase in mRNA expression of several inflammatory cytokines including tumor necrosis factor -α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6), CGRP, and Substance P. However, the daily treatment of 3HF did not affect the motor behaviors of rats. The inhibitory mechanism of 3HF in neuropathic pain is predicted with extensive computational bioinformatics approach which indicates that the 3HF effectively interacts with the binding domains of Nuclear factor-kappa B (NF-κB), CGRP receptor and the receptor of Substance P to exert its inhibitory activities. However, the computationally predicted binding affinities revealed that the potential of binding of the compound with Substance P receptor (Neurokinin 1 receptor) is higher than the other receptors; there NK1R could be the most possible binding target of 3HF. These findings indicate that 3HF has anti-nociceptive, anti-inflammatory, and anti-neuropathic pain effects against paclitaxel-induced neuropathic pain.
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http://dx.doi.org/10.1016/j.neuint.2021.104981DOI Listing
March 2021

Synthetic β-hydroxy ketone derivative inhibits cholinesterases, rescues oxidative stress and ameliorates cognitive deficits in 5XFAD mice model of AD.

Mol Biol Rep 2020 Dec 19;47(12):9553-9566. Epub 2020 Nov 19.

Translational Genomics Laboratory, COMSATS University Islamabad, Park Road, Tarlai Kalan, Islamabad, 45600, Pakistan.

Alzheimer's disease (AD) is a progressive, chronic and age-related neurodegenerative disorder that affects millions of people across the world. In pursuit of new anti-AD remedies, 2-[Hydroxy-(4-nitrophenyl)methyl]-cyclopentanone (NMC), a β hydroxyl ketone derivative was studied to explore its neuroprotective potentials against AD. The in-vitro AChE and BuChE enzymes inhibition were evaluated by Ellman protocol and antioxidant potentials of NMC by DPPH free radical scavenging assay. In-vivo behavioral studies were performed in the transgenic 5xFAD mice model of AD using shallow water maze (SWM), Paddling Y-Maze (PYM), elevated plus maze (EPM) and balance beam (BB) tests. Also, the ex-vivo cholinesterase inhibitory effects of NMC and histopathological analysis of amyloid-β plaques were determined in the frontal cortex and hippocampal regions of the mice brain. NMC exhibited significant in vitro anti-cholinesterase enzyme potentials with an IC value of 67 μg/ml against AChE and 96 μg/ml against BuChE respectively. Interestingly, the activities of AChE and BuChE enzymes were also significantly lower in the cortex and hippocampus of NMC-treated groups. Also, in the DPPH assessment, NMC displayed substantial antioxidant properties with an IC value observed as 171 μg/ml. Moreover, histopathological analysis via thioflavin-s staining displayed significantly lower plaques depositions in the cortex and hippocampus region of NMC-treated mice groups. Furthermore, SWM, PYM, EPM, and BB behavioral analysis indicated that NMC enhanced spatial learning, memory consolidation and improved balance performance. Altogether, to the best of our knowledge, we believe that NMC may serve as a potential and promising anti-cholinesterase, antioxidant and neuroprotective agent against AD.
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http://dx.doi.org/10.1007/s11033-020-05997-0DOI Listing
December 2020

Attenuation of Spatial Memory in 5xFAD Mice by Halting Cholinesterases, Oxidative Stress and Neuroinflammation Using a Cyclopentanone Derivative.

Pharmaceuticals (Basel) 2020 Oct 19;13(10). Epub 2020 Oct 19.

Department of Chemistry, University of Malakand, Chakdara 18000, Dir (L), KPK, Pakistan.

Alzheimer's disease (AD) is an irreversible and chronic neurological disorder that gradually destroys memory and thinking skills. The research study was designed to investigate the underlying molecular signaling involved in the neuroprotective effects of cyclopentanone derivative i.e., 2-(hydroxyl-(3-nitrophenyl)methyl)cyclopentanone (3NCP) as a therapeutic agent for AD. In this study, In vivo studies were carried out on a well-known 5xFAD mice model using different behavioural test models such as open field, rotarod, Morris water maze (MWM), and Y-maze tests. Furthermore, in vitro cholinesterase inhibition activity assays were carried out. The frontal cortex (FC) and hippocampus (HC) homogenates were tested for the levels/activities of cholinesterases, glutathione (GSH), glutathione S-transferase (GST), and catalase. Furthermore, the hippocampal expression of inflammatory cytokines was observed via RT-PCR and western blot. The results of in vivo studies show an enhancement in the learning behavior. The 3NCP treatment reduced latency time in MWM and Y-maze tests, also increase spontaneous alternation indicate significant effect of 3NCP on memory. Furthermore, open field and rotarod studies revealed that 3NCP does not cause motor coordination deficit. The results of the in vitro studies revealed that the IC values of the 3NCP against acetylcholinesterase () and butyrylcholinesterase () were 16.17 and 20.51 µg/mL, respectively. This decline in and was further supported by ex vivo studies. Further, the 3NCP mitigates the GSH level, GST, and catalase activities in HC and FC. The mRNA and protein expression of inflammatory cytokines (IL-1β, IL-6, TNF-α) markedly declined in RT-PCR and western blotting. The results of the current study conclusively demonstrate that 3NCP reduces oxidative stress and mitigates neuroinflammation in 5xFAD mice, implying that 3NCP may be a potential therapeutic candidate for AD treatment in the future.
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http://dx.doi.org/10.3390/ph13100318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603158PMC
October 2020

Synthesis, in-vitro, in-vivo anti-inflammatory activities and molecular docking studies of acyl and salicylic acid hydrazide derivatives.

Bioorg Chem 2020 11 28;104:104168. Epub 2020 Aug 28.

Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, Pakistan. Electronic address:

Over the course of time several drugs have been synthesized and are available in market for the treatment of inflammation. However, they were unable to cure effectively and associated with side effects. To effectively deal with such diseases, heterocycles and their derivatives have gained their special position. For this reason 1,3,4-oxadiazole (15-16), 1,2,4-triazole (17-18), Schiff base (19-24) and 3,5-disubstituted pyrazole (25) derivatives were synthesized starting from salicylic acid and acyl acid hydrazides (12-14) as COX-1 and COX-2 inhibitors. In vivo anti-inflammatory activities were also tested by carrageenan-induced mice paw edema against albino mice of any sex. Structures of all the synthesized compounds were confirmed by FT-IR and H NMR analysis. Schiff base derivative of 4-amiontirazole (24) with IC value of 1.76 ± 0.05 (COX-2) and 117.8 ± 2.59 emerged as potent COX-2 inhibitor. Furthermore, we also performed in-vivo anti-inflammatory investigations by using carrageenan induced paw edema test. From in-vivo anti-inflammatory activities, it was found that after 1 h the maximum percentage inhibition 15.8% was observed by compound 14 which is comparable with that of the standard drug followed by the compound 18 with percentage inhibition of 10.5%. After 3 h, the maximum percentage inhibition was observed by compound 18 with 22.2% and compound 14 with 16.7%. After 5 h the maximum percentage inhibition was observed by compound 18 with 29.4% followed by compound 16 with 23.5%. We further explore the mechanism of the inhibition by using docking simulations. Docking studies revealed that the selective COX-2 inhibitors established interactions with additional COX-2 enzyme pocket residues.
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http://dx.doi.org/10.1016/j.bioorg.2020.104168DOI Listing
November 2020

Efficacy assessment of salicylidene salicylhydrazide in chemotherapy associated peripheral neuropathy.

Eur J Pharmacol 2020 Dec 10;888:173481. Epub 2020 Aug 10.

Department of Pharmacy, Sarhad University of Science and Information Technology, Peshawar, Khyber Pakhtunkhwa, Pakistan. Electronic address:

Chemotherapy-induced peripheral neuropathy (CIPN) is an increasingly important problem for cancer survivors and is the foremost cause of drug-induced morbidity. In this study, the antinociceptive efficacy of salicylidene salicylhydrazide (SSH) in CIPN was investigated. SSH was evaluated for acute toxicity, antinociceptive effectiveness against tonic and phasic pain modalities, anti-inflammatory propensity, and effect on motoric balance. SSH was tested in the mouse models of oxaliplatin, paclitaxel, and vincristine associated established neuropathic nociceptive paradigms. The tested doses of SSH (10-75 mg/kg) strongly suppressed the expression of acetic acid-induced tonic visceral nociception, formalin-induced biphasic nociception, and acute phasic thermal nociception. SSH selectively antagonized the capsaicin-elicited nociceptive behavior. SSH produced a significant reduction in the phlogistic agents-induced temporal inflammatory escalation involving prostaglandins, serotonin, and histamine. SSH was devoid of any adverse-effects that impair the neurological processes involved in the arousal and coordination of movements. The neuropathic nociception inflicted by chemotherapeutic agents were expressed as reduced sensitivity to non-noxious mechanical stimuli (mechanical allodynia), increased nociceptive response to cold (cold allodynia), and decreased nociceptive latency to heat (heat hyperalgesia). SSH (50 and 75 mg/kg) significantly suppressed the expression of CIPN-induced established neuropathic allodynia and hyperalgesia and the anti-neuropathic effects were equipotent to gabapentin. These findings concluded that SSH is a novel analgesic that can be useful for treating peripheral neuropathic pain conditions linked with chemotherapy with the advantage of being free of neurological adverse-effects encountered with gabapentinoids.
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http://dx.doi.org/10.1016/j.ejphar.2020.173481DOI Listing
December 2020

The effect of gender and ABCB1 gene polymorphism on the pharmacokinetics of azithromycin in healthy male and female Pakistani subjects.

Can J Physiol Pharmacol 2020 Aug 3;98(8):506-510. Epub 2020 Mar 3.

Department of Pharmacy, Kohat University of Science and Technology, Kohat, Pakistan.

In the current study, the possible outcome of gender difference and genotypic polymorphism of the ABCB1 gene encoding P-glycoprotein on the pharmacokinetics of azithromycin has been evaluated. An open-label, comparative pharmacokinetic study was done in healthy Pakistani volunteers (females ( = 8) and males ( = 8)). They were administered a single 500 mg oral dose of azithromycin. Blood samples (≈5 mL) were collected in heparinized tubes and the HPLC/MS/MS method was used to determine azithromycin plasma levels. ABCB1 polymorphism (single nucleotide polymorphisms) at C3435T, G26SST was performed using the RFLP-PCR method. The Student test was applied to compare pharmacokinetic parameters of azithromycin between male and female human subjects (at 95% CI) using GraphPad Prism-8. A significant difference was observed in pharmacokinetic parameters between males and females, as in males (230 ± 80.2 ng/mL) was significantly higher than in females (224.9 ± 75.5 ng/mL), while [Formula: see text] was also significantly higher ( < 0.05) in males (2102 ± 200.3 ng·h·mL) compared to females (1825.7 ± 225.4 ng·h·mL). There was a significant variation in and AUC in three ABCB1 genotyping groups as well. Gender difference and ABCB1 gene polymorphisms have a significant impact on the pharmacokinetics of azithromycin, as they contribute to interindividual variability in therapeutic response.
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http://dx.doi.org/10.1139/cjpp-2019-0569DOI Listing
August 2020

Mini-Review: Drug-food interactions of commonly available juices of Pakistan.

Pak J Pharm Sci 2019 Sep;32(5):2189-2196

Retail Pharmacist, Sharjah, United Arab Emirates.

Medicines are often consumed concurrently with food; sometimes to improve its absorption and efficacy. However, certain foods may modify the function of drug metabolizing enzymes or transport mechanisms that are crucial determinants of systemic drug availability. Extensive work has been reported on certain juices like grapefruit that affects the bioavailability of more than 60 medications. However, relatively less work has been reported on certain other commonly used fruit juices, especially in Pakistan, such as mango, strawberry, apple, banana, pomegranate and grape etc. Present review has taken an account of the current work done in this area.
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September 2019

Attenuation of vincristine-induced neuropathy by synthetic cyclohexenone-functionalized derivative in mice model.

Neurol Sci 2019 Sep 30;40(9):1799-1811. Epub 2019 Apr 30.

Institute of Chemical Sciences, University of Peshawar, Peshawar, 25120, Pakistan.

Vincristine (VCR) is a well-known anticancer drug which frequently induced painful neuropathy and impairs the quality of life of patients. The present study was designed to investigate the alleviative potential of a novel cyclohexenone derivative (CHD), i.e., ethyl 6-(4-methoxyphenyl)-2-oxo-4-phenylcyclohexe-3-enecarboxylate, against VCR-induced neuropathic pain in mice model. VCR was administered intraperitoneally for 10 days in two cycles to induce neuropathic pain. Static and dynamic mechanical allodynia was evaluated using von Frey hair filaments and cotton buds, respectively. Paw thermal hyperalgesia was determined through a hot plate analgesiometer. The tail cold immersion hyperalgesia and paw cold allodynia were determined by available standard protocols. The formalin nociception was induced via subplantar injection of formalin. The antioxidant potential was evaluated via 2,2-diphenyl-1-picrylhydrazyl free radical scavenging activity. The outcome of this study revealed that CHD (30-45 mg/kg) and gabapentin (75 mg/kg) significantly enhanced the paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) in static and dynamic allodynia, respectively, and increased the PWL in thermal hyperalgesia and tail withdrawal latency (TWL) as compared to the VCR-treated group. CHD significantly augmented the paw withdrawal duration (PWD) in paw cold allodynia, while the same compound only increased the paw elevation and paw licking in the delayed phase of formalin nociception. Moreover, CHD significantly inhibited the DPPH free radical scavenging action (IC = 56), butylated hydroxytoluene (BHT) (IC = 39), and ascorbic acid (IC = 2.93). In conclusion, CHD exhibited a profile of potential attenuative effect against the VCR-induced neuropathic pain which might be attributed to its possible antinociceptive and antioxidant effect.
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http://dx.doi.org/10.1007/s10072-019-03884-6DOI Listing
September 2019

Neuroprotective effect of Bacopa monnieri against morphine-induced histopathological changes in the cerebellum of rats.

Pak J Pharm Sci 2017 Nov;30(6):2067-2074

Department of Pharmacy, COMSATS Institute of information Technology, Abbottabad, Pakistan.

Opioid addiction is associated with oxidative cell injury in neuronal cells. In this study, Bacopa monnieri (L.), a reputed nootropic plant, was evaluated against morphine-induced histopathological changes in the cerebellum of rats. B. monnieri methanolic extract (mBME) (40 mg/kg, p.o) and ascorbic acid (50 mg/kg, i.p) were administered two hours before morphine (20 mg/kg, i.p) for 14 and 21 days. The in vitro antioxidant activity of mBME was determined by 2,2-diphenyl-1-picrylhydrazyl (DPPH) free-radical scavenging assay. Morphine produced vacuolization of basket and stellate cells and reduced the size of Purkinje cells in the cerebellum after 14 days. However, treatment for 21 days was associated with severe shrinkage of Purkinje cells with loss of their characteristic flask-shaped appearance as well as degeneration of basket, stellate and granule cells. Pretreatment with mBME and ascorbic acid for 14 and 21 days attenuated the morphine-induced histopathological changes in the cerebellum. The EC50 for the DPPH free-radical scavenging assay of mBME (39.06 μ/mL) as compared to ascorbic acid (30.25 μ/mL) and BHT (34.34 μ/mL) revealed that mBME strongly scavenged the free-radicals and thus possessed an efficient antioxidant propensity. These results concluded that B. monnieri having strong antioxidant activity exerted a protective effect against morphineinduced cerebellar toxicity.
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November 2017

Anti-Alzheimer's Studies on β-Sitosterol Isolated from L.

Front Pharmacol 2017 6;8:697. Epub 2017 Oct 6.

Department of Pharmacy, University of Malakand, Chakdara, Pakistan.

The family Polygonaceae is known for its traditional use in the management of various neurological disorders including Alzheimer's disease (AD). In search of new anti-AD drugs, β-sitosterol isolated from was subjected to , behavioral and molecular docking studies to confirm its possibility as a potential anti-Alzheimer's agent. The AChE, BChE inhibitory potentials of β-sitosterol were investigated following Ellman's assay. The antioxidant activity was tested using DPPH, ABTS and HO assays. Behavioral studies were performed on a sub-strain of transgenic mice using shallow water maze (SWM), Y-maze and balance beam tests. β-sitosterol was tested for inhibitory potentials against cholinesterase's and free radicals in the frontal cortex (FC) and hippocampus (HC). The molecular docking study was performed to predict the binding mode of β-sitosterol in the active sites of AChE and BChE as inhibitor. Considerable and cholinesterase inhibitory effects were observed in the β-sitosterol treated groups. β-sitosterol exhibited an IC value of 55 and 50 μg/ml against AChE and BChE respectively. Whereas, the activity of these enzymes were significantly low in FC and HC homogenates of transgenic animals. Molecular docking studies also support the binding of β-sitosterol with the target enzyme and further support the and results. In the antioxidant assays, the IC values were observed as 140, 120, and 280 μg/ml in the DPPH, ABTS and HO assays respectively. The free radicals load in the brain tissues was significantly declined in the β-sitosterol treated animals as compared to the transgenic-saline treated groups. In the memory assessment and coordination tasks including SWM, Y-maze and balance beam tests, β-sitosterol treated transgenic animals showed gradual improvement in working memory, spontaneous alternation behavior and motor coordination. These results conclude that β-sitosterol is a potential compound for the management of memory deficit disorders like AD.
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http://dx.doi.org/10.3389/fphar.2017.00697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5635809PMC
October 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

Olanzapine induced biochemical and histopathological changes after its chronic administration in rats.

Saudi Pharm J 2016 Nov 18;24(6):698-704. Epub 2015 Jun 18.

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

Olanzapine is a second generation antipsychotic acting mainly as a dopamine D and serotonine 5-HT receptors antagonist prescribed in the treatment of schizophrenia and various other psychiatric illnesses. Even though olanzapine is widely used in psychiatry, its effects on the architecture of pancreas, liver and kidneys are little known. The histology of pancreas especially has never been studied. For these reasons, the current study was designed to elucidate the toxic effects of chronic administration of olanzapine on pancreas, liver and kidneys and the enzymes released by these tissues in an escalating dose manner. Fourteen male rats were divided into two groups equally, the olanzapine group and the controls. Olanzapine was administered in a dose of 5 mg/kg/d for the first eight weeks, 10 mg/kg/d for next four weeks and 15 mg/kg/d through the last two week period of 14 weeks experiment. The controls received acidified saline only. Both the groups received restricted diet (20 g/12 h). The body weight and level of random blood sugar (RBS) were measured on a weekly basis. The levels of lipase, amylase, alanine transaminase (ALT) and aspartate transaminase (AST) were determined terminally. At the end of the experiment, the tissues were dissected out for histopathological evaluation. Significant loss in body weight, change in the level of random blood sugar ( < 0.05,  < 0.001) and significant rise in amylase and lipase levels ( < 0.05,  < 0.001) were observed. However, the same treatment has shown no significant change in the levels of alanine and aspartate transaminases ( > 0.05). The pancreas has shown derangement of beta cells and fibrotic growth. A mild to moderate focal increase in glomerular cellularity, cellular proliferation and glomerular capsules with negligible basement membranes were observed in the kidneys. No changes were observed in the architecture of the liver. The findings of this study indicated that the incidence of adverse effects associated with olanzapine could be prevented/alleviated/delayed by allowing restricted diet.
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http://dx.doi.org/10.1016/j.jsps.2015.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5094436PMC
November 2016

6-Methoxyflavanone attenuates mechanical allodynia and vulvodynia in the streptozotocin-induced diabetic neuropathic pain.

Biomed Pharmacother 2016 Dec 17;84:962-971. Epub 2016 Oct 17.

Department of Pharmacy, University of Peshawar, Peshawar, Pakistan. Electronic address:

Background: Diabetic neuropathy is the most prevalent, persistent and debilitating complication of diabetes mellitus often coupled with vulvodynia that may present as an isolated symptom or as a part of constellation of other neuropathic abnormalities.

Objective: Flavonoids have selective affinity for GABA receptors and 6-methoxyflavanone (6-MeOF) is a positive allosteric modulator of GABA responses at human recombinant GABA receptors. GABAergic and opioidergic system inhibition have been shown to facilitate neuropathic pain.

Methods: 6-MeOF was evaluated for analgesic effect in the hot plate test and streptozotocin-induced diabetic neuropathic pain in female rats using von Frey hairs. The possible involvement of opioidergic and GABAergic mechanisms was investigated using naloxone and pentylenetetrazole (PTZ) antagonists, respectively. The biodistribution of 6-MeOF in plasma and CNS was examined using a validated HPLC/UV analytical method. The binding affinity of 6-MeOF with opioid and GABA receptors was studied using molecular docking simulation approach.

Results: 6-MeOF (10 and 30mg/kg) attenuated the acute phasic thermal nociception in the hot plate test while in the case of streptozotocin-induced diabetic neuropathy model, 6-MeOF (10 and 30mg/kg) produced static/dynamic anti-allodynic (increased paw withdrawal threshold and latency) as well as static/dynamic anti-vulvodynic effects (increased flinching response threshold and latency), when compared to the vehicle and standard gabapentin (75mg/kg). In silico studies depicted the preference of 6-MeOF for the delta- and kappa-opioid and GABA receptors. Moreover, the pharmacokinetic profile revealed a quick appearance of 6-MeOF in the systemic circulation and brain areas with maximum concentration observed after 30min in the amygdala, brain stem and cerebral cortex.

Conclusion: 6-MeOF readily crosses the blood brain barrier and may be effective in attenuating the diabetes-induced allodynia as well as vulvodynia, probably through interactions with the GABAergic and opioidergic systems.
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http://dx.doi.org/10.1016/j.biopha.2016.10.017DOI Listing
December 2016

Beneficial effects of Bacopa monnieri extract on opioid induced toxicity.

Heliyon 2016 Feb 15;2(2):e00068. Epub 2016 Feb 15.

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

The present study examined the hepatotoxicity and nephrotoxicity of morphine and illicit street heroin and their amelioration by a standardized methanolic extract of Bacopa monnieri (L.) (mBME) in rats. Morphine or street heroin was administered at a dose of 20 mg/kg for 14 and 21 days. mBME (40 mg/kg) or ascorbic acid (50 mg/kg) was administered two hours before morphine or street heroin. High performance liquid chromatography (HPLC) was used for the standardization of bacoside-A major components in mBME. The antioxidant potential of mBME was evaluated by 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging assay. Administration of morphine and street heroin resulted in marked elevation of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and creatinine. Histopathological changes induced by morphine and street heroin after 14 days were of reversible nature while treatment for 21 days was associated with irreversible changes. Pretreatment with mBME or ascorbic acid restored the elevation of serum ALT, AST and creatinine and protected liver and kidneys from the toxicological influence of morphine and street heroin. HPLC analysis showed that mBME contained bacoside-A major components i.e. bacoside-A3 (37.5 μg/mg), bacopaside-II (4.62 μg/mg) and bacopasaponin-C (1.91 μg/mg). The EC50 for the DPPH free radical scavenging assay revealed that mBME possessed strong antioxidant potential. These results concluded that as compared to morphine, street heroin was associated with severe biochemical and histopathological changes in the liver and kidneys. Bacopa monnieri having strong antioxidant potential may provide a beneficial herbal remedy for the efficient management of opioid related hepatotoxicity and nephrotoxicity.
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http://dx.doi.org/10.1016/j.heliyon.2016.e00068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4945900PMC
February 2016

Molecularly Characterized Solvent Extracts and Saponins from Polygonum hydropiper L. Show High Anti-Angiogenic, Anti-Tumor, Brine Shrimp, and Fibroblast NIH/3T3 Cell Line Cytotoxicity.

Front Pharmacol 2016 31;7:74. Epub 2016 Mar 31.

Department of Pharmacy, University of Malakand Khyber Pakhtoonkhwa, Pakistan.

Polygonum hydropiper is used as anti-cancer and anti-rheumatic agent in folk medicine. This study was designed to investigate the anti-angiogenic, anti-tumor, and cytotoxic potentials of different solvent extracts and isolated saponins. Samples were analyzed using GC, Gas Chromatography-Mass Spectrometry (GC-MS) to identify major and bioactive compounds. Quantitation of antiangiogenesis for the plant's samples including methanolic extract (Ph.Cr), its subsequent fractions; n-hexane (Ph.Hex), chloroform (Ph.Chf), ethyl acetate (Ph.EtAc), n-Butanol (Ph.Bt), aqueous (Ph.Aq), saponins (Ph.Sp) were performed using the chick embryo chorioallantoic membrane (CAM) assay. Potato disc anti-tumor assay was performed on Agrobacterium tumefaciens containing tumor inducing plasmid. Cytotoxicity was performed against Artemia salina and mouse embryonic fibroblast NIH/3T3 cell line following contact toxicity and MTT cells viability assays, respectively. The GC-MS analysis of Ph.Cr, Ph.Hex, Ph.Chf, Ph.Bt, and Ph.EtAc identified 126, 124, 153, 131, and 164 compounds, respectively. In anti-angiogenic assay, Ph.Chf, Ph.Sp, Ph.EtAc, and Ph.Cr exhibited highest activity with IC50 of 28.65, 19.21, 88.75, and 461.53 μg/ml, respectively. In anti-tumor assay, Ph.Sp, Ph.Chf, Ph.EtAc, and Ph.Cr were most potent with IC50 of 18.39, 73.81, 217.19, and 342.53 μg/ml, respectively. In MTT cells viability assay, Ph.Chf, Ph.EtAc, Ph.Sp were most active causing 79.00, 72.50, and 71.50% cytotoxicity, respectively, at 1000 μg/ml with the LD50 of 140, 160, and 175 μg/ml, respectively. In overall study, Ph.Chf and Ph.Sp have shown overwhelming results which signifies their potentials as sources of therapeutic agents against cancer.
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http://dx.doi.org/10.3389/fphar.2016.00074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4814464PMC
April 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

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

Sertraline enhances the activity of antimicrobial agents against pathogens of clinical relevance.

J Biol Res (Thessalon) 2015 Dec 16;22(1). Epub 2015 Apr 16.

Department of Pharmacy, Kohat University of Science and Technology, Kohat, Pakistan.

Background: Serotonin reuptake inhibitors were recently reported to possess antimicrobial potentials, potentiate activity of several antibiotics, reverse multidrug resistant phenotypes of bacteria and make them susceptible to previously resistant drugs. We investigated antimicrobial potentials of sertraline (SR) against ATCC strains, clinical isolates of Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa alone and in-combination with seven antibiotics. Antifungal activity was investigated against four fungal strains including Aspergillus niger, Aspergillus fumigatus, Aspergillus flavus, and Fusarium solani. Intrinsic antibacterial action and Minimum Inhibitory Concentrations (MICs) were determined using well assay, nutrient broth and agar dilution techniques. Disk diffusion and nutrient broth methods were used to study bacterial susceptibility to SR. Minimum Fungicidal Concentrations (MFCs) of SR were determined using Sabouraud dextrose Agar (SDA).

Results: Sertraline possesses strong intrinsic antibacterial, antifungal activities and has augmented the antibacterial activities of antibiotics. For S. aureus ATCC 6538, E. coli ATCC 8739 and P. aeruginosa ATCC 9027, the MICs of SR were 20, 40 and 60 μg ml(-1), respectively, whereas 55.5% clinical isolates of S. aureus and 50% of E. coli strains were inhibited at 20 and 60 μg ml(-1) of SR, respectively. Among the tested fungi, 60% of A. niger and A. fumigatus were inhibited at 40 and 80 μg ml(-1), respectively. MFCs were 60 and 80 μg ml(-1) for A. flavus and F. solani, respectively. Antibacterial activities of all antibiotics were significantly increased (p < 0.001) with the addition of SR 100 μg ml(-1) against all tested bacteria.

Conclusion: Combination study revealed that SR had significantly increased the activity of antibiotics, and some previously resistant strains were made susceptible. Thus antidepressants are potential sources of resistance modifying agents when used in combination.
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http://dx.doi.org/10.1186/s40709-015-0028-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4449573PMC
December 2015

Anti-emetic mechanisms of Zingiber officinale against cisplatin induced emesis in the pigeon; behavioral and neurochemical correlates.

BMC Complement Altern Med 2015 Feb 26;15:34. Epub 2015 Feb 26.

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

Background: Zingiber officinale (ZO, family Zingiberaceae) has been reported for its antiemetic activity against cancer chemotherapy induced emesis in animal models and in clinics. Current study was designed to investigate ZO for potential usefulness against cisplatin induced vomiting in pigeon and its effects on central and peripheral neurotransmitters involved in the act of vomiting.

Methods: Zingiber officinale acetone fraction (ZO-ActFr) was investigated for attenuation of emesis induced by cisplatin in healthy pigeons. Neurotransmitters DA, 5HT and their metabolites DOPAC, HVA and 5HIAA were analyzed using High Performance Liquid Chromatography system coupled with electrochemical detector in area postrema, brain stem and intestine. Antiemetic effect of ZO-ActFr was correlated with central and intestinal neurotransmitters levels in pigeon.

Results: Cisplatin (7 mg/kg i.v.) induced emesis without lethality upto the observation period. ZO-ActFr (25, 50 & 100 mg/kg) attenuated cisplatin induced emesis ~ 44.18%, 58.13% (P < 0.05) and 27.9%, respectively; the reference drug, metoclopramide (MCP; 30 mg/kg), produced ~ 48.83% reduction (P < 0.05). ZO-ActFr reduced (P < 0.05 - 0.001) 5-hydroxytryptamine (5HT) concentration in the area postrema, brain stem and intestine at 3(rd) hour of cisplatin administration, while at the 18(th) hour ZO treatments attenuated the dopamine upsurge (P < 0.001) caused by cisplatin in the area postrema and 5HT concentration (P < 0.01 - 0.001) in the brain stem and intestine. ZO treatments alone did not altered the basal neurotransmitters and their metabolites in the brain areas and intestine.

Conclusion: The behavioral study verify the antiemetic profile of ZO against cisplatin induced emesis in the pigeon, where central and peripheral neural evidences advocate the involvement of serotonergic mechanism at initial time point (3(rd) hr), while the later time point (18(th) hr) is associated with serotonergic and dopaminergic component in the mediation of its antiemetic effect.
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http://dx.doi.org/10.1186/s12906-015-0556-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4355376PMC
February 2015

Synthetically modified bioisosteres of salicyl alcohol and their gastroulcerogenic assessment versus aspirin: biochemical and histological correlates.

Naunyn Schmiedebergs Arch Pharmacol 2014 Mar 29;387(3):281-90. Epub 2013 Nov 29.

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

The present study was conducted to synthesize nitrogen containing derivatives of salicyl alcohol and to investigate in vivo their ulcerogenic potential in comparison with aspirin in rats. The compounds [4-(2-hydroxybenzyl) morpholin-4-iumchloride (I)] and [1,4-bis(2-hydroxybenzyl) piperazine-1,4-diium chloride (II)] were synthesized and their chemical structures were characterized using spectral data. In our previous study (Ali et al., Afr J Pharm Pharmacol 7:585-596, 2013), both compounds showed anti-inflammatory, antinociceptive, and antipyretic properties in standard animal models and a greater binding affinity for cyclooxygenase-2 versus cyclooxygenase-1 in molecular docking and dynamics analysis. For in vivo studies, animals were randomly divided into four groups. The synthetic compounds (both at 100 or 150 mg/kg), aspirin (150 mg/kg), or saline vehicle was administered orally, once daily for 6 days and then tested for ulcerogenic activity. At the end of the procedure, gastric juice and tissues were collected and subjected to biochemical and histological analyses. The results of the study revealed that in the case of the aspirin-treated group, there was a significant increase in gastric juice volume, free acidity, total acidity, and ulcer score and a decrease in gastric pH. Moreover, histological examination of the gastric mucosa of the aspirin-treated group indicated morphological changes while neither of the synthetic compounds showed any significant ulcerogenic or cytotoxic properties. The results of the present study suggest that both compounds are free from ulcerogenic side effects and may represent a better alternative to aspirin.
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http://dx.doi.org/10.1007/s00210-013-0941-5DOI Listing
March 2014

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
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