Publications by authors named "Fawaz Alasmari"

35 Publications

Precursor effects on the physical, biological, and catalytic properties of Fagonia indica Burm.f. mediated zinc oxide nanoparticles.

Microsc Res Tech 2021 Jul 26. Epub 2021 Jul 26.

Department of Plant Sciences, Quaid-i-Azam University, Islamabad, Pakistan.

We report a facile, green and precursor-based comparative study on the biosynthesis of zinc oxide (ZnO) nanoparticles (NPs) using anticancerous Fagonia indica as effective chelating agent. Biosynthesis was carried out using zinc sulfate and zinc acetate as precursor salts to make ZnO and ZnO NPs under similar experimental conditions which were characterized extensively for physical and biological properties. Scherrer equation deduced a mean crystallite size of ~23.4 nm for ZnO NPs and ~41 nm for ZnO NPs. The nature of the NPs was compared using UV, diffuse reflectance spectra, Fourier transform infrared spectroscopy, thermogravimetric analysis-DTA, selected area electron diffraction, EDS, zeta potential, high resolution (HR)-SEM, and HR-TEM. Detailed in vitro pharmacognostic activities revealed a significant therapeutic potential for ZnO and ZnO . Potential antimicrobial activities for the NPs and their nanocosmeceutical formulations are reported. ZnO NPs were more cytotoxic to Leishmania tropica as compared to ZnO . Significant antioxidant and protein kinase inhibition was obtained. The hemolytic assay indicated a hemocompatible nature of both ZnO and ZnO NPs. Catalytic degradation of crystal violet dye (CVD) by NPs was examined under different parameters (light, dark, UV). Furthermore, sonophotocatalytic degradation of CVD was also studied. Our results suggested that precursor can have a significant effect on the physical, biological, and catalytic properties of the NPs. In future, we recommend different other in vitro, in vivo biological activities, and mechanistic studies of these as-synthesized NPs.
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http://dx.doi.org/10.1002/jemt.23867DOI Listing
July 2021

Development and evaluation of physiologically based pharmacokinetic drug-disease models for predicting captopril pharmacokinetics in chronic diseases.

Sci Rep 2021 Apr 21;11(1):8589. Epub 2021 Apr 21.

Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia.

The advancement in the processing speeds of computing machines has facilitated the development of complex physiologically based pharmacokinetic (PBPK) models. These PBPK models can incorporate disease-specific data and could be used to predict pharmacokinetics (PK) of administered drugs in different chronic conditions. The present study aimed to develop and evaluate PBPK drug-disease models for captopril after incorporating relevant pathophysiological changes occurring in adult chronic kidney disease (CKD) and chronic heart failure (CHF) populations. The population-based PBPK simulator Simcyp was used as a modeling and simulation platform. The visual predictive checks and mean observed/predicted ratios (ratio) of the PK parameters were used for model evaluation. The developed disease models were successful in predicting captopril PK in all three stages of CKD (mild, moderate, and severe) and CHF, as the observed and predicted PK profiles and the ratio for the PK parameters were in close agreement. The developed captopril PBPK models can assist in tailoring captopril dosages in patients with different disease severity (CKD and CHF).
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http://dx.doi.org/10.1038/s41598-021-88154-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060346PMC
April 2021

Coadministration of Ketamine and Perampanel Improves Behavioral Function and Reduces Inflammation in Acute Traumatic Brain Injury Mouse Model.

Biomed Res Int 2020 10;2020:3193725. Epub 2020 Dec 10.

College of Sciences and Health Profession, King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia.

Traumatic brain injury (TBI) is among the most debilitating neurological disorders with inadequate therapeutic options. It affects all age groups globally leading to post-TBI behavioral challenges and life-long disabilities requiring interventions for these health issues. In the current study, C57BL/6J mice were induced with TBI through the weight-drop method, and outcomes of acutely administered ketamine alone and in combination with perampanel were observed. The impact of test drugs was evaluated for post-TBI behavioral changes by employing the open field test (OFT), Y-maze test, and novel object recognition test (NOR). After that, isolated plasma and brain homogenates were analyzed for inflammatory modulators, i.e., NF-B and iNOS, through ELISA. Moreover, metabolomic studies were carried out to further authenticate the TBI rescuing potential of drugs. The animals treated with ketamine-perampanel combination demonstrated improved exploratory behavior in OFT ( < 0.05), while ketamine alone as well as in combination yielded anxiolytic effect ( < 0.05-0.001) in posttraumatic mice. Similarly, the % spontaneous alternation and % discrimination index were increased after the administration of ketamine alone ( < 0.05) and ketamine-perampanel combination ( < 0.01-0.001) in the Y-maze test and NOR test, respectively. ELISA demonstrated the reduced central and peripheral expression of NF-B ( < 0.05) and iNOS ( < 0.01-0.0001) after ketamine-perampanel polypharmacy. The TBI-imparted alteration in plasma metabolites was restored by drug combination as evidenced by metabolomic studies. The outcomes were fruitful with ketamine, but the combination therapy proved more significant in improving all studied parameters. The benefits of this new investigated polypharmacy might be due to their antiglutamatergic, antioxidant, and neuroprotective capacity.
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http://dx.doi.org/10.1155/2020/3193725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749776PMC
June 2021

Role of carnitine in regulation of blood pressure (MAP/SBP) and gene expression of cardiac hypertrophy markers (α/β-MHC) during insulin-induced hypoglycaemia: Role of oxidative stress.

Clin Exp Pharmacol Physiol 2021 04 27;48(4):478-489. Epub 2020 Dec 27.

Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Cardiovascular disease is a leading cause of death in diabetic patients. Hyperglycaemia and iatrogenic hypoglycaemia exacerbate several pathogenic mechanisms underlying hypertension and heart diseases. Carnitine is a potent endogenous antioxidant and cellular fatty acid transporter for antioxidative stress and energy production in the cardiovascular system. The current study aimed to find the role of carnitine in the regulation of hypoglycaemia-induced hypertension and cardiac hypertrophy. Male rats received insulin glargine (InG) to induce hypoglycaemia followed by D-carnitine or acetyl-L-carnitine for carnitine depletion or carnitine supplementation, respectively. The obtained results showed that carnitine deficiency provoked hypoglycaemia-induced hypertension. Mean arterial pressure was elevated from 78.16 ± 11.4 to 100 ± 5.11 mm Hg in InG treated group, and from 78.2 ± 8.5 to 123.4 ± 28.2 mm Hg in InG + D-carnitine treated group. Acetyl-L-carnitine resisted the elevation in blood pressure in all hypoglycaemic animals and kept it within the normal values (68.33 ± 6.7 mm Hg). Acetyl-L-carnitine increased myocardial carnitine content leading to the attenuation of hypoglycaemia-induced oxidative stress, which was evaluated through measurement of the oxidative stress biomarkers such as inducible nitric oxide synthase, NAD(P)H quinone dehydrogenase-1, heme oxygenase-I, and glutathione S-transferase. Moreover, acetyl-L-carnitine prevented induction of gene expression of cardiac hypertrophy markers during hypoglycaemic conditions, which was assessed via the evaluation of mRNA expression of α-myosin heavy chain and β-myosin heavy chain. These findings demonstrate that carnitine might play an essential role in prevention of hypoglycaemia-induced hypertension and cardiac hypertrophy through providing energy and antioxidants to the cardiovascular system.
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http://dx.doi.org/10.1111/1440-1681.13455DOI Listing
April 2021

E-cigarette aerosols containing nicotine modulate nicotinic acetylcholine receptors and astroglial glutamate transporters in mesocorticolimbic brain regions of chronically exposed mice.

Chem Biol Interact 2021 Jan 23;333:109308. Epub 2020 Nov 23.

Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, The University of Toledo, Toledo, OH, 43614, USA. Electronic address:

Nicotine exposure increases the release of glutamate in part through stimulatory effects on pre-synaptic nicotinic acetylcholine receptors (nAChRs). To assess the impact of chronic electronic (e)-cigarette use on these drug dependence pathways, we exposed C57BL/6 mice to three types of inhalant exposures for 3 months; 1) e-cigarette aerosol generated from liquids containing nicotine (ECN), 2) e-cigarette aerosol generated from liquids containing vehicle chemicals without nicotine (Veh), and 3) air only (AC). We investigated the effects of daily e-cigarette exposure on protein levels of α7 nAChR and α4/β2 nAChR, gene expression and protein levels of astroglial glutamate transporters, including glutamate transporter-1 (GLT-1) and cystine/glutamate antiporter (xCT), in the frontal cortex (FC), striatum (STR) and hippocampus (HIP). We found that chronic inhalation of ECN increased α4/β2 nAChR in all brain regions, and increased α7 nAChR expression in the FC and STR. The total GLT-1 relative mRNA and protein expression were decreased in the STR. Moreover, GLT-1 isoforms (GLT-1a and GLT-1b) were downregulated in the STR in ECN group. However, inhalation of e-cigarette aerosol downregulated xCT expression in STR and HIP compared to AC and Veh groups. ECN group had increased brain-derived neurotrophic factor in the STR compared to control groups. Finally, mass spectrometry detected high concentrations of the nicotine metabolite, cotinine, in the FC and STR in ECN group. This work demonstrates that chronic inhalation of nicotine within e-cigarette aerosols significantly alters the expression of nAChRs and astroglial glutamate transporters in specific mesocorticolimbic brain regions.
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http://dx.doi.org/10.1016/j.cbi.2020.109308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752837PMC
January 2021

Effects of chronic ethanol consumption on the expression of GLT-1 and neuroplasticity-related proteins in the nucleus accumbens of alcohol-preferring rats.

Brain Res Bull 2020 12 16;165:272-280. Epub 2020 Oct 16.

University of Toledo, College of Pharmacy and Pharmaceutical Sciences, Department of Pharmacology and Experimental Therapeutics, Toledo, OH 43614, USA. Electronic address:

Chronic ethanol exposure induces impairments in CNS excitatory and inhibitory activity. These impairments are associated with glutamatergic dysfunction, including altered neuroplasticity. This study examined the effects of 6-week ethanol (15% and 30% v/v) consumption, by male alcohol-preferring P rats, on protein expression associated with neuroplasticity and glutamate transporter-1 (GLT-1) function. The latter regulates intra- and extra-synaptic glutamate levels. We focused on the shell and core subregions of the nucleus accumbens (Acb); i.e., shell (AcbSh) and core (AcbCo), for these measures. Chronic ethanol exposure increased the expression of BDNF, Arc and phosphorylated (p)-post-synaptic density protein-95 (p-PSD-95) in the AcbSh of P rats. Moreover, the ratio of phospho-neuronal nitric oxide synthase (p-nNOS) to total nNOS was also increased in the AcbSh. These changes in BDNF, Arc and p-nNOS/nNOS ratio were not observed in the AcbCo. Furthermore, chronic ethanol consumption reduced GLT-1 expression in the AcbSh. Alternatively, treatment with ceftriaxone (CEF), a known GLT-1 upregulator, abolished the effect of chronic ethanol consumption on BDNF expression in the AcbSh. Overall, the present findings confirm that chronic ethanol consumption modulates activity-associated synaptic proteins, including BDNF, Arc and nNOS in a subregion-specific (i.e., in the AcbSh but not AcbCo) manner. Thus, alterations in mesocorticolimbic glutamatergic homeostasis and neuroplasticity are possible functional targets for the treatment of alcohol use disorders.
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http://dx.doi.org/10.1016/j.brainresbull.2020.10.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718081PMC
December 2020

Effect of Modulation of the Astrocytic Glutamate Transporters' Expression on Cocaine-Induced Reinstatement in Male P Rats Exposed to Ethanol.

Alcohol Alcohol 2021 Feb;56(2):210-219

Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH, USA.

Aim: Reinforcing properties of ethanol and cocaine are mediated in part through the glutamatergic system. Extracellular glutamate concentration is strictly maintained through several glutamate transporters, such as glutamate transporter 1 (GLT-1), cystine/glutamate transporter (xCT) and glutamate aspartate transporter (GLAST). Previous findings revealed that cocaine and ethanol exposure downregulated GLT-1 and xCT, and that β-lactam antibiotics restored their expression.

Methods: In this study, we investigated the effect of ampicillin/sulbactam (AMP/SUL) (200 mg/kg, i.p.), a β-lactam antibiotic, on cocaine-induced reinstatement and locomotor activity in male alcohol preferring (P) rats using free choice ethanol (15 and 30%, v/v) and water. We also investigated the effect of co-exposure to ethanol and cocaine (20 mg/kg, i.p.) on GLT-1, xCT and GLAST expression in the nucleus accumbens (NAc) core, NAc shell and dorsomedial prefrontal cortex (dmPFC).

Results: Cocaine exposure decreased ethanol intake and preference. Cocaine and ethanol co-exposure acquired place preference and increased locomotor activity compared to ethanol-exposed rats. GLT-1 and xCT expression were downregulated after cocaine and ethanol co-exposure in the NAc core and shell, but not in dmPFC. AMP/SUL attenuated reinstatement to cocaine as well attenuated the decrease in locomotor activity and ethanol intake and preference. These effects were associated with upregulation of GLT-1 and xCT expression in the NAc core/shell and dmPFC. GLAST expression was not affected after ethanol and cocaine co-exposure or AMP/SUL treatment.

Conclusion: Our findings demonstrate that astrocytic glutamate transporters within the mesocorticolimbic area are critical targets in modulating cocaine-seeking behavior while being consuming ethanol.
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http://dx.doi.org/10.1093/alcalc/agaa104DOI Listing
February 2021

Ampicillin/Sulbactam Treatment Modulates NMDA Receptor NR2B Subunit and Attenuates Neuroinflammation and Alcohol Intake in Male High Alcohol Drinking Rats.

Biomolecules 2020 07 10;10(7). Epub 2020 Jul 10.

Department of Pharmacology and Experimental Therapeutics, University of Toledo, College of Pharmacy and Pharmaceutical Sciences, Toledo, OH 43614, USA.

Exposure to ethanol commonly manifests neuroinflammation. Beta (β)-lactam antibiotics attenuate ethanol drinking through upregulation of astroglial glutamate transporters, especially glutamate transporter-1 (GLT-1), in the mesocorticolimbic brain regions, including the nucleus accumbens (Acb). However, the effect of β-lactam antibiotics on neuroinflammation in animals chronically exposed to ethanol has not been fully investigated. In this study, we evaluated the effects of ampicillin/sulbactam (AMP/SUL, 100 and 200 mg/kg, i.p.) on ethanol consumption in high alcohol drinking (HAD1) rats. Additionally, we investigated the effects of AMP/SUL on GLT-1 and -methyl-d-aspartate (NMDA) receptor subtypes (NR2A and NR2B) in the Acb core (AcbCo) and Acb shell (AcbSh). We found that AMP/SUL at both doses attenuated ethanol consumption and restored ethanol-decreased GLT-1 and NR2B expression in the AcbSh and AcbCo, respectively. Moreover, AMP/SUL (200 mg/kg, i.p.) reduced ethanol-increased high mobility group box 1 (HMGB1) and receptor for advanced glycation end-products (RAGE) expression in the AcbSh. Moreover, both doses of AMP/SUL attenuated ethanol-elevated tumor necrosis factor-alpha (TNF-α) in the AcbSh. Our results suggest that AMP/SUL attenuates ethanol drinking and modulates NMDA receptor NR2B subunits and HMGB1-associated pathways.
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http://dx.doi.org/10.3390/biom10071030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407831PMC
July 2020

Serum proteomic profiling of patients with amphetamine use disorder.

Drug Alcohol Depend 2020 09 2;214:108157. Epub 2020 Jul 2.

Proteomics Resource Unit, Obesity Research Center, College of Medicine, King Saud University, P.O. Box 2925 (98), Riyadh 11461, Saudi Arabia. Electronic address:

Background: Amphetamine use disorder has been recently classified as an epidemic condition. Amphetamine use/abuse has been associated with several neurological and inflammatory effects. However, the exact mechanism involved in these effects warrants further investigation. The aim of this study was to determine any alterations in the serum proteome of individuals classified as patients with amphetamine use disorder compared to that of control subjects.

Methods: An untargeted proteomic approach employing two-dimensional difference in gel electrophoresis coupled with mass spectrometry was used to identify the patterns of differentially expressed proteins. Serum samples were collected from 20 individuals (males) including 10 subjects with amphetamine use disorder and 10 healthy controls for the present study.

Results: The analysis revealed 78 proteins with a significant difference in protein abundance between the amphetamine-addicted subjects and controls. Among them, 71 proteins were upregulated while 7 proteins remained downregulated in the amphetamine-addicted group. These proteins were further analyzed by ingenuity pathway analysis (IPA) to investigate their correlation with other biomarkers. IPA revealed the correlation of altered proteins with mitogen-activated protein kinase (MAP2K1/K2), p38MAPK, protein kinase-B (PKB; Akt), extracellular signal-regulated kinase (ERK1/2), and nuclear factor-κB signaling pathways. Importantly, these pathways are highly involved in neurological diseases, inflammatory responses, and cellular compromise.

Conclusions: Our data suggest that the changes in the levels of serum proteins between amphetamine and control groups might affect cellular compromise, inflammatory response, and neurological diseases.
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http://dx.doi.org/10.1016/j.drugalcdep.2020.108157DOI Listing
September 2020

Elucidation of the Molecular Mechanisms Underlying Sorafenib-Induced Hepatotoxicity.

Oxid Med Cell Longev 2020 14;2020:7453406. Epub 2020 May 14.

Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.

Sorafenib is a small, orally-active multikinase inhibitor that is most frequently used for the management of renal cell carcinoma, hepatocellular carcinoma, and radioactive iodine-resistant thyroid carcinoma. However, recent reports have associated sorafenib with hepatotoxicity that can limit its clinical application, although the mechanism of hepatotoxicity is still to be elucidated. Thus, our study was designed to explore the molecular mechanisms underlying sorafenib-induced hepatotoxicity in an model. Twenty male adult Wistar rats were randomly placed into two groups; the first group received an oral dose of normal saline (vehicle), and the second received sorafenib (30 mg/kg) once daily for twenty-one consecutive days. After twenty-one days, liver tissues and blood samples were used for gene expression, protein expression, and biochemical analysis. Sorafenib treatment resulted in markedly increased levels of alanine aminotransferase and alkaline phosphatase, which indicate the presence of liver damage. Additionally, sorafenib administration induced the inflammatory and oxidative stress marker NF-B-p65, while antioxidant enzymes were attenuated. Moreover, sorafenib caused upregulation of both gene and protein for the apoptotic markers cleaved Caspase-3, Bax, and Bid, and downregulation of the antiapoptotic protein Bcl-2. In conclusion, our findings suggest that sorafenib administration is associated with hepatotoxicity, which might be due to the activation of oxidative stress and apoptotic pathways.
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http://dx.doi.org/10.1155/2020/7453406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245685PMC
December 2020

Systemic TNF-α blockade attenuates anxiety and depressive-like behaviors in mice through downregulation of inflammatory signaling in peripheral immune cells.

Saudi Pharm J 2020 May 9;28(5):621-629. Epub 2020 Apr 9.

Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Saudi Arabia.

Research studies have indicated that the comorbidity burden of mood disorders and obesity is reasonably high. Insulin signaling has been shown to modulate multiple physiological functions in the brain, indicating its association with neuropsychiatric diseases, including mood disorders. Leptin is a hormone responsible for regulating body weight and insulin homeostasis. Previous studies on mice (a mouse model that carries a spontaneous genetic mutation in leptin receptor ) have shown that they exhibit inflammation as well as neurobehavioral traits associated with mood. Therefore, targeting inflammatory pathways such as TNF-α may be an effective strategy in the treatment of obesity-linked mood disorders. The objective of this study was to investigate the effect of long-term administration of etanercept (a TNF-α blocker) on anxiety and depressive-like behaviors in mice. This was performed using light/dark box, forced swim, and open field tests with lean littermate wild type (WT) mice serving as a control group. Using flow cytometry in peripheral blood, we further examined the molecular effects of etanercept on NF-κB p65, TNF-α, IL-17A, and TLR-4 expressing CD4+, CD8+, and CD14+ cells in the peripheral blood. Our data show that peripheral administration of etanercept decreased these cells in mice. Furthermore, our results indicated that peripheral administration of etanercept reduced anxiety and depressive-like behaviors. Therefore, targeting TNF-α signaling might be an effective strategy for modulating obesity-associated depression and anxiety.
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http://dx.doi.org/10.1016/j.jsps.2020.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229333PMC
May 2020

Renin angiotensin system blockage by losartan neutralize hypercholesterolemia-induced inflammatory and oxidative injuries.

Redox Rep 2020 Dec;25(1):51-58

Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

This study explores the protective role of losartan (LT) against oxidative and inflammatory damages in different physiological systems including heart, liver, and kidney tissue in hypercholesterolemic rats. After induction of hypercholesterolemia by high cholesterol diet for 6 weeks, LT was administered for 4 weeks. In serum, the levels of lipoproteins, aminotransferases, creatine kinases, urea, apoptosis, and inflammatory markers were measured. In cardiac, hepatic, and renal tissues, lipid peroxidation product and GSH as well as antioxidant enzymatic activities were assayed. Finally, histopathological assessment evaluated the structural damage in cardiac, hepatic, and renal tissues. Serum markers of cardiac, hepatic, and renal toxicities including creatine kinases, aminotransferases, and urea were attenuated by LT in hypercholesterolemic animals. Moreover, LT markedly corrected the elevated levels of lipoproteins, apoptosis, and inflammatory biomarkers. Hypercholesterolemia-induced lipid peroxidation, low GSH levels, and diminished activities of antioxidant enzymes were prominently improved in LT treated animals. Histopathological alterations by hypercholesterolemia in heart, liver, and kidney tissues were ameliorated by LT. This study confirmed the pathological enrollment of renin-angiotensin system in hypercholesterolemia-associated metabolic alterations. LT had a significant cardiac, hepatic, and renal protective role against these impairments through down-regulation of oxidative damage, inflammation and necrosis.
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http://dx.doi.org/10.1080/13510002.2020.1763714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269056PMC
December 2020

Investigating the Role of Altered Systemic Albumin Concentration on the Disposition of Theophylline in Adult and Pediatric Patients with Asthma by Using the Physiologically Based Pharmacokinetic Approach.

Drug Metab Dispos 2020 07 11;48(7):570-579. Epub 2020 May 11.

Departments of Pharmacy Practice (M.F.R., R.K., A.M.) and Pharmacology (I.I.), Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan; Section of Pharmaceutics, University College of Pharmacy, Allama Iqbal Campus, University of the Punjab, Lahore, Pakistan (H.S.); and Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia (F.F.A., M.M.A., F.A.).

Theophylline is commonly used for the treatment of asthma and has a low hepatic clearance. The changes in plasma albumin concentration occurring in asthma may affect the exposure of theophylline. The aim of the presented work was to predict theophylline pharmacokinetics (PK) after incorporating the changes in plasma albumin concentration occurring in patients with asthma into a physiologically based pharmacokinetic (PBPK) model to see whether these changes can affect the systemic theophylline concentrations in asthma. The PBPK model was developed following a systematic model building approach using Simcyp. The predictions were performed initially in healthy adults after intravenous and oral drug administration. Only when the developed adult PBPK model had adequately predicted theophylline PK in healthy adults, the changes in plasma albumin concentrations were incorporated into the model for predicting drug exposure in patients with asthma. After evaluation of the developed model in the adult population, it was scaled to children on physiologic basis. The model evaluation was performed by using visual predictive checks and comparison of ratio of observed and predicted (R) PK parameters along with their 2-fold error range. The developed PBPK model has effectively described theophylline PK in both healthy and diseased populations, as R for all the PK parameters were within the 2-fold error limit. The predictions in patients with asthma showed that there were no significant changes in PK parameters after incorporating the changes in serum albumin concentration. The mechanistic nature of the developed asthma-PBPK model can facilitate its extension to other drugs. SIGNIFICANCE STATEMENT: Exposure of a low hepatic clearance drug like theophylline may be susceptible to plasma albumin concentration changes that occur in asthma. These changes in systemic albumin concentrations can be incorporated into a physiologically based pharmacokinetic model to predict theophylline pharmacokinetics in adult and pediatric asthma populations. The presented work is focused on predicting theophylline absorption, distribution, metabolism, and elimination in adult and pediatric asthma populations after incorporating reported changes in serum albumin concentrations to see their impact on the systemic theophylline concentrations.
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http://dx.doi.org/10.1124/dmd.120.090969DOI Listing
July 2020

Liraglutide attenuates gefitinib-induced cardiotoxicity and promotes cardioprotection through the regulation of MAPK/NF-κB signaling pathways.

Saudi Pharm J 2020 Apr 19;28(4):509-518. Epub 2020 Mar 19.

Department of Pharmacy Services, Prince Mohammed Bin Abdulaziz Hospital, Riyadh 14214, Saudi Arabia.

Gefitinib is an effective treatment for patients with locally advanced non-small cell lung cancer. However, it is associated with cardiotoxicity that can limit its clinical use. Liraglutide, a glucagon-like peptide 1 receptor agonist, showed potent cardioprotective effects with the mechanism is yet to be elucidated. Therefore, this study aimed to determine the efficiency of liraglutide in protecting the heart from damage induced by gefitinib. Adult male Wistar rats were randomly divided into control group, liraglutide group (200 µg/kg by i.p. injection), gefitinib group (30 mg/kg orally) and liraglutide plus gefitinib group. After 28 days, blood and tissue samples were collected for histopathological, biochemical, gene and protein analysis. We demonstrated that gefitinib treatment (30 mg/kg) resulted in cardiac damage as evidenced by histopathological studies. Furthermore, serum Creatine kinase-MB (CK-MB), N-terminal pro B-type natriuretic peptide (NT-proBNP) and cardiac Troponin-I (cTnI) were markedly elevated in gefitinib group. Pretreatment with liraglutide (200 µg/kg), however, restored the elevation in serum markers and diminished gefitinib-induced cardiac damage. Moreover, liraglutide improved the gene and protein levels of anti-oxidant (superoxide dismutase) and decreased the oxidative stress marker (NF-κB). Mechanistically, liraglutide offered protection through upregulation of the survival kinases (ERK1/2 and Akt) and downregulation of stress-activated kinases (JNK and P38). In this study, we provide evidence that liraglutide protects the heart from gefitinib-induced cardiac damage through its anti-oxidant property and through the activation of survival kinases.
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http://dx.doi.org/10.1016/j.jsps.2020.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7132601PMC
April 2020

Caffeine induces neurobehavioral effects through modulating neurotransmitters.

Authors:
Fawaz Alasmari

Saudi Pharm J 2020 Apr 17;28(4):445-451. Epub 2020 Feb 17.

Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.

Evidence demonstrates that chronic caffeine exposure, primarily through consumption of coffee or tea, leads to increased alertness and anxiety. Preclinical and clinical studies showed that caffeine induced beneficial effects on mood and cognition. Other studies using molecular techniques have reported that caffeine exhibited neuroprotective effects in animal models by protecting dopaminergic neurons. Moreover, caffeine interacts with dopaminergic system, which leads to improvements in neurobehavioral measures in animal models of depression or attention deficit hyperactivity disorder (ADHD). Glutamatergic receptors have been found to be involved on the neurobiological effects of caffeine. Additionally, caffeine has been found to suppress the inhibitory (GABAergic) activity and modulate GABA receptors. Studies have also found that modulating these neurotransmitters leads to neurobehavioral effects. The linkage between the modulatory role of caffeine on neurotransmitters and neurobehavioral effects has not been fully discussed. The purpose of this review is to discuss in detail the role of neurotransmitters in the effects of caffeine on neurobehavioral disorders.
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http://dx.doi.org/10.1016/j.jsps.2020.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7132598PMC
April 2020

Upregulation of enzymatic antioxidants in CD4 T cells of autistic children.

Biochimie 2020 Apr - May;171-172:205-212. Epub 2020 Mar 12.

Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder which begins in early childhood and presents itself with characteristic symptoms such as repetitive behavioral patterns and problems in speech/social interactions. Adaptive immune system is thought to be involved in the etiology of ASD. T cells orchestrate amplification of inflammation through release of inflammatory mediators; however, antioxidant defenses have not been evaluated in CD4 T cells of ASD subjects. In this study we evaluated intracellular enzymatic antioxidant potential through measurement of major antioxidant enzymes (SOD, GPx, and GR) in ASD subjects and typically developing control (TDC) children and further assessed its role in modulation of inflammation. Our data reveal that there is an increase in antioxidant potential (SOD, GPx, GR) in CD4 T cells of ASD subjects as compared to TDC children at both protein and activity level. Further, this antioxidant increase was associated with upregulated IL-17A levels in CD4 T cells. This was corroborated by oxidant treatment in vitro. Pretreatment with oxidant, HO led to attenuation of IL-17A levels along with increased oxidative stress in stimulated CD4 T cells from ASD subjects. These data reveal that antioxidant play an essential role in modulation of inflammatory potential in CD4 T cells of ASD subjects.
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http://dx.doi.org/10.1016/j.biochi.2020.03.009DOI Listing
December 2020

Bruton's tyrosine kinase inhibitor suppresses imiquimod-induced psoriasis-like inflammation in mice through regulation of IL-23/IL-17A in innate immune cells.

Int Immunopharmacol 2020 Mar 24;80:106215. Epub 2020 Jan 24.

Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Psoriasis is an unchecked chronic inflammation characterized by thick, erythematous, and scaly plaques on the skin. The role of innate immune cells in the pathogenesis of psoriasis is well documented. Bruton's tyrosine kinase (BTK) has been reported to execute important signaling functions in innate immune cells such as dendritic cells (DCs) and gamma delta T cells. However, whether inhibition of BTK would lead to modulation of innate immune function in the context of psoriatic inflammation remains largely unexplored. In the present study, we investigated the effect of selective BTK inhibitor, PCI-32765 on inflammatory signaling in CD11c + DCs and gamma delta T cells in imiquimod (IMQ)-induced mouse model of psoriasis-like inflammation. Our results show that IMQ treatment led to induction of p-BTK expression along with concomitant increase in inflammatory cytokines (IL-23, TNF-α) in CD11c + DCs in the skin. Preventive treatment with BTK inhibitor led to significant reversal in IMQ-induced inflammatory changes in CD11c + DCs of skin. Further, there was a significant decrease in dermal IL-17A levels and IL-17A + γδ + T cells after treatment with BTK inhibitor. Furthermore, short treatment of back skin with IMQ led to upregulated expression of p-BTK along with inflammatory cytokines in CD11c + DCs (IL-23, TNF-α) and IL-17A in γδ + T cells which were reversed by BTK inhibitor. Overall, our study proposes that BTK signaling serves a crucial signaling function in innate immune cells in the context of psoriatic inflammation in mice. Therefore, BTK might be a promising therapeutic target to treat psoriatic inflammation.
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http://dx.doi.org/10.1016/j.intimp.2020.106215DOI Listing
March 2020

5-aminoisoquinolinone attenuates social behavior deficits and immune abnormalities in the BTBR T Itpr3/J mouse model for autism.

Pharmacol Biochem Behav 2020 02 23;189:172859. Epub 2020 Jan 23.

Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia; Department of Pharmacology and Toxicology, College of Pharmacy, Al-Azhar University, Cairo, Egypt.

Autism spectrum disorder (ASD) is diagnosed by core symptoms including impaired social communication and the presence of repetitive and stereotypical behaviors. There is also evidence for immune dysfunction in individuals with ASD, but it is a disease that is still insufficiently controlled by current treatment strategies. The use of 5-aminoisoquinolinone (5-AIQ) ameliorates several immune-mediated symptoms including rheumatoid arthritis and colitis, and has neuroprotective properties; however, its role in ASD is not yet characterized. In this study, we investigated the effect of 5-AIQ on sociability tests, self-grooming, marble burying, and locomotor activities in BTBR T Itpr3tf/J (BTBR) mice, which serve as an ASD animal model. We further investigated the possible molecular mechanism of 5-AIQ administration on CXCR4-, CXCR6-, IFN-γ-, IL-22-, NOS2-, STAT1-, T-bet-, and RORγT-producing CD3 T cells isolated from the spleens of treated mice. We also explored its effects on mRNA expression in brain tissue. Our results showed that in BTBR mice, 5-AIQ treatment significantly prevented self-grooming and marble burying behaviors and enhanced social interactions without any adverse effects on locomotor activity/anxiety level. Additionally, 5-AIQ treatment substantially decreased CXCR4-, CXCR6-, IFN-γ-, IL-22-, NOS2-, STAT1-, T-bet-, and RORγT-producing CD3 T cells in the spleen. Furthermore, 5-AIQ treatment decreased CXCR4, IFN-γ, IL-22, STAT1, and RORγT mRNA expression levels in brain tissue. Our findings demonstrated that 5-AIQ improved behavioral and immune abnormalities associated with ASD, which supports the hypothesis that 5-AIQ has important therapeutic potential for the treatment of behavioral and neuroimmune dysfunctions in ASD.
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http://dx.doi.org/10.1016/j.pbb.2020.172859DOI Listing
February 2020

Changes in the Fluorescence Tracking of NaV1.6 Protein Expression in a BTBR T+Itpr3tf/J Autistic Mouse Model.

Neural Plast 2019 17;2019:4893103. Epub 2019 Dec 17.

Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Saudi Arabia.

The axon initial segment (AIS), the site of action potential initiation in neurons, is a critical determinant of neuronal excitability. Growing evidence indicates that appropriate recruitment of the AIS macrocomplex is essential for synchronized firing. However, disruption of the AIS structure is linked to the etiology of multiple disorders, including autism spectrum disorder (ASD), a condition characterized by deficits in social communication, stereotyped behaviors, and very limited interests. To date, a complete understanding of the molecular components that underlie the AIS in ASD has remained elusive. In this research, we examined the AIS structure in a BTBR T+Itpr3tf/J mouse model (BTBR), a valid model that exhibits behavioral, electrical, and molecular features of autism, and compared this to the C57BL/6J wild-type control mouse. Using Western blot studies and high-resolution confocal microscopy in the prefrontal frontal cortex (PFC), our data indicate disrupted expression of different isoforms of the voltage-gated sodium channels (NaV) at the AIS, whereas other components of AIS such as ankyrin-G and fibroblast growth factor 14 (FGF14) and contactin-associated protein 1 (Caspr) in BTBR were comparable to those in wild-type control mice. A Western blot assay showed that BTBR mice exhibited a marked increase in different sodium channel isoforms in the PFC compared to wild-type mice. Our results provide potential evidence for previously undescribed mechanisms that may play a role in the pathogenesis of autistic-like phenotypes in BTBR mice.
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http://dx.doi.org/10.1155/2019/4893103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942885PMC
September 2020

The potent immunomodulatory compound VGX-1027 regulates inflammatory mediators in CD4 T cells, which are concomitant with the prevention of neuroimmune dysregulation in BTBR T Itpr3/J mice.

Life Sci 2019 Nov 11;237:116930. Epub 2019 Oct 11.

Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia; Department of Pharmacology and Toxicology, College of Pharmacy, Al-Azhar University, Cairo, Egypt.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by symptoms that include social communication impairments, interaction deficits, and repetitive and stereotyped behaviors. Recent studies have suggested that imbalanced cytokine levels are associated with impaired behavioral outcomes in individuals with ASD. VGX-1027 is a potent immunomodulatory compound that has shown promise for the treatment of several neuroinflammatory disorders. Here, we studied the effects of VGX-1027 on BTBR T Itpr3/J (BTBR) mice, an animal model of autism. BTBR mice exhibit most of the core behavioral features of ASD, such as reduced sociability and increased repetitive behaviors. In this study, we investigated the effects of VGX-1027 on self-grooming, marble burying and sociability tests using BTBR mice. We further examined its effect on IL-1β, IL-6, IL-10, TNF-α, IFN-γ, and NF-κB p65 production in splenic CD4 cells and on IL-1β, IL-6, IL-10, TNF-α, IFN-γ, COX-2, and iNOS (NOS2) protein and mRNA expression in brain tissues. The administration of VGX-1027 was found to attenuate self-grooming and marble burying behaviors, and enhance social interactions in BTBR mice. Additionally, VGX-1027 treatment resulted in a substantial decrease in IL-1β, IL-6, TNF-α, IFN-γ, and NF-κB p65 production, but increased IL-10 production in CD4 T cells. Moreover, this agent was also found to significantly decrease IL-1β, IL-6, TNF-α, IFN-γ, COX-2, and NOS2 levels and increase IL-10 expression at the protein and mRNA level in brain tissues. Based on results using BTBR mice, our data provide the first evidence that VGX-1027 could potentially be used for the amelioration of autism-like symptoms.
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http://dx.doi.org/10.1016/j.lfs.2019.116930DOI Listing
November 2019

Effects of Chronic Inhalation of Electronic Cigarette Vapor Containing Nicotine on Neurotransmitters in the Frontal Cortex and Striatum of C57BL/6 Mice.

Front Pharmacol 2019 12;10:885. Epub 2019 Aug 12.

Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH, United States.

Electronic (E)-cigarettes are the latest form of nicotine delivery device and are highly popular in the general population. It is currently unknown whether vaping E-cigarettes (E-CIGs) leads to nicotine addiction. Alterations in the levels of the neurotransmitters in the mesocorticolimbic areas have been reported to mediate the initiation and development of nicotine addiction. Therefore, to determine whether E-CIGs activate the same addiction pathways as conventional cigarettes, we investigated for the effects of daily inhalation of nicotine (24 mg/ml)-containing E-CIG vapor for 6 months on the concentrations of these neurotransmitters in the frontal cortex (FC) and striatum (STR) of male C57BL/6 mice as compared to control group that was exposed to air only. We reported here that 6-month E-CIG vapor containing nicotine inhalation decreased dopamine concentration only in the STR. There were no changes in serotonin concentrations in the FC or STR. Chronic E-CIG exposure also increased glutamate concentration in the STR alone, while glutamine concentrations were increased in both the FC and STR. We found that E-CIG exposure also decreased GABA concentration only in the FC. These data suggest that chronic E-CIG use alters homeostasis of several neurotransmitters in the mesocorticolimbic areas, which may result in the development of nicotine dependence in E-CIG users.
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http://dx.doi.org/10.3389/fphar.2019.00885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6699083PMC
August 2019

SAR and molecular mechanism studies of monoamine oxidase inhibition by selected chalcone analogs.

J Enzyme Inhib Med Chem 2019 Dec;34(1):863-876

a Department of Pharmaceutical Sciences, College of Pharmacy , Qatar University , Doha , Qatar.

The present study describes the synthesis of a series of 22 chalcone analogs. These compounds were evaluated as potential human MAO-A and MAO-B inhibitors. The compounds showed varied selectivity against the two isoforms. The IC values were found to be in the micromolar to submicromolar range. The K values of compound 16 were determined to be 0.047 and 0.020 μM for the inhibition of MAO-A and MAO-B, respectively. Dialysis of enzyme-inhibitor mixtures indicated a reversible competitive mode of inhibition. Most of the synthesized chalcone analogs showed a better selectivity toward MAO-B. However, introducing of 2,4,6-trimethoxy substituents on ring B shifted the selectivity toward MAO-A. In addition, we investigated the molecular mechanism of MAO-B inhibition by selected chalcone analogs. Our results revealed that these selected chalcone analogs increased dopamine levels in the rat hepatoma (H4IIE) cells and decreased the relative mRNA expression of the MAO-B enzyme.
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http://dx.doi.org/10.1080/14756366.2019.1593158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442233PMC
December 2019

Amelioration of sepsis-induced acute kidney injury through inhibition of inflammatory cytokines and oxidative stress in dendritic cells and neutrophils respectively in mice: Role of spleen tyrosine kinase signaling.

Biochimie 2019 Mar 29;158:102-110. Epub 2018 Dec 29.

Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Sepsis often leads to complications such as acute kidney injury (AKI) which is reported to range from 30 to 50% in critically ill patients. Dendritic (DCs) and neutrophils play a decisive role in the advancement of AKI through release of inflammatory cytokines and reactive oxygen species (ROS) respectively. Both of these processes are assumed to be controlled by spleen tyrosine kinase (Syk) signaling in DCs and neutrophils. However, the role of Syk signaling in these immune cells in sepsis-induced AKI has not been investigated. Therefore, the purpose of this study was to evaluate the effect of a Syk inhibitor, R406 on sepsis-induced AKI in a mouse model. Renal function (creatinine/blood urea nitrogen), inflammatory cytokines (IL-6/MCP-1) in CD11c + DCs and oxidant parameters in neutrophils [inducible nitric oxide synthase (iNOS), NADPH oxidase (NOX2), nitrotyrosine] were assessed. Our results showed elevated expression of Syk in neutrophils and CD11c + DC which was linked with increased IL-6/MCP-1 in CD11c + DCs, and iNOS, NOX2 and nitrotyrosine in neutrophils during sepsis-induced AKI. Inhibitor of Syk signaling, R406 led to improvement of sepsis-induced AKI as depicted by an attenuation of creatinine/blood urea nitrogen in serum, renal myeloperoxidase activity, and repair of tubular structures in kidney. Further, R406 led to a decrease in IL-6/MCP-1 in CD11c + DCs, and iNOS, NOX2 and nitrotyrosine in neutrophils during sepsis-induced AKI. In conclusion, our study proposes that Syk signaling in DCs and neutrophils plays a critical role during sepsis-induced AKI. Therefore, Syk inhibition in innate immune cells might serve as an effective strategy to limit inflammatory cascade during AKI.
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http://dx.doi.org/10.1016/j.biochi.2018.12.014DOI Listing
March 2019

Neuroinflammatory Cytokines Induce Amyloid Beta Neurotoxicity through Modulating Amyloid Precursor Protein Levels/Metabolism.

Biomed Res Int 2018 25;2018:3087475. Epub 2018 Oct 25.

Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Neuroinflammation has been observed in association with neurodegenerative diseases including Alzheimer's disease (AD). In particular, a positive correlation has been documented between neuroinflammatory cytokine release and the progression of the AD, which suggests these cytokines are involved in AD pathophysiology. A histological hallmark of the AD is the presence of beta-amyloid (A) plaques and tau neurofibrillary tangles. Beta-amyloid is generated by the sequential cleavage of beta () and gamma () sites in the amyloid precursor protein (APP) by - and -secretase enzymes and its accumulation can result from either a decreased A clearance or increased metabolism of APP. Previous studies reported that neuroinflammatory cytokines reduce the efflux transport of A, leading to elevated A concentrations in the brain. However, less is known about the effects of neuroinflammatory mediators on APP expression and metabolism. In this article, we review the modulatory role of neuroinflammatory cytokines on APP expression and metabolism, including their effects on - and -secretase enzymes.
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http://dx.doi.org/10.1155/2018/3087475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222241PMC
March 2019

Role of glutamatergic system and mesocorticolimbic circuits in alcohol dependence.

Prog Neurobiol 2018 12 11;171:32-49. Epub 2018 Oct 11.

Department of Pharmacology and Experimental Therapeutics, University of Toledo, College of Pharmacy and Pharmaceutical Sciences, Toledo, OH, USA. Electronic address:

Emerging evidence demonstrates that alcohol dependence is associated with dysregulation of several neurotransmitters. Alterations in dopamine, glutamate and gamma-aminobutyric acid release are linked to chronic alcohol exposure. The effects of alcohol on the glutamatergic system in the mesocorticolimbic areas have been investigated extensively. Several studies have demonstrated dysregulation in the glutamatergic systems in animal models exposed to alcohol. Alcohol exposure can lead to an increase in extracellular glutamate concentrations in mesocorticolimbic brain regions. In addition, alcohol exposure affects the expression and functions of several glutamate receptors and glutamate transporters in these brain regions. In this review, we discussed the effects of alcohol exposure on glutamate receptors, glutamate transporters and glutamate homeostasis in each area of the mesocorticolimbic system. In addition, we discussed the genetic aspect of alcohol associated with glutamate and reward circuitry. We also discussed the potential therapeutic role of glutamate receptors and glutamate transporters in each brain region for the treatment of alcohol dependence. Finally, we provided some limitations on targeting the glutamatergic system for potential therapeutic options for the treatment alcohol use disorders.
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http://dx.doi.org/10.1016/j.pneurobio.2018.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6261463PMC
December 2018

A computerized exposure system for animal models to optimize nicotine delivery into the brain through inhalation of electronic cigarette vapors or cigarette smoke.

Saudi Pharm J 2018 Jul 27;26(5):622-628. Epub 2018 Feb 27.

Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH, USA.

Pre-clinical studies investigated the effects of chronic exposure to nicotine on lungs, kidneys and brains using animal models. Most of these studies delivered nicotine into the circulatory and central nervous systems (CNS) through intraperitoneal injection or oral consumption methods. Few studies used inhalation machine system for nicotine delivery into brains in rodents to mimic human exposure to cigarettes. However, finding a more accurate and clinically relevant method of nicotine delivery is critical. A computerized inhalation machine has been designed (SciReq) and is currently employed in several institutions. The computerized machine delivers electronic (e)-cigarette vapor as well as tobacco smoke to rodents using marketed e-cigarette devices or tobacco cigarettes. This provides evidence about clinical effects of nicotine delivery by traditional methods (combustible cigarettes) and new methodologies (e-cigarettes) in physiological systems. Potential neurobiological mechanisms for the development of nicotine dependence have been determined recently in mice exposed to e-cigarette vapors in our laboratory using SciReq system. In this review article, the discussion focuses on the efficiency and practical applicability of using this computerized inhalation exposure system in inducing significant changes in brain protein expression and function as compared to other nicotine delivery methods. The SciReq inhalation system utilized in our laboratory and others is a method of nicotine delivery to the CNS, which has physiological relevance and mimics human inhalant exposures. Translation of the effects of inhaled nicotine on the CNS into clinical settings could provide important health considerations.
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http://dx.doi.org/10.1016/j.jsps.2018.02.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035328PMC
July 2018

Alcohol and Cocaine Exposure Modulates ABCB1 and ABCG2 Transporters in Male Alcohol-Preferring Rats.

Mol Neurobiol 2019 Mar 6;56(3):1921-1932. Epub 2018 Jul 6.

Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Health Science Campus, 3000 Arlington Avenue, Toledo, OH, 43614, USA.

Two efflux transporters, ATP-binding cassettes B1 (ABCB1) and G2 (ABCG2), are highly expressed in the endothelial cells of the brain, where they regulate the bioavailability and distribution of several endogenous and xenobiotic compounds. However, whether ABCB1 or ABCG2 has any link with drug dependence, drug withdrawal effects, or the incidence of adverse effects in drug abuser is not known. In this study, we determined the effects of voluntary ethanol consumption following repeated exposure to cocaine or vehicle on the relative mRNA and protein expression of Abcg2/ABCG2 and Abcb1/ABCB1 in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) of male alcohol-preferring (P) rats. Male P rats were allowed free choice access to ethanol (15 and 30% v/v) and water for 5 weeks to establish baseline drinking behavior. The following week, rats were either injected with 20 mg/kg i.p. of cocaine or saline, once a day, for 7 days. The relative mRNA and protein expression of Abcb1/ABCB1 and Abcg2/ABCG2 in the NAc and mPFC were significantly decreased in ethanol-saline- and ethanol-cocaine-exposed rats compared to control rats that received neither ethanol nor cocaine. Thus, prolonged exposure to commonly abused drugs, ethanol and cocaine, alters the expression of Abcb1/ABCB1 and Abcg2/ABCG2 mRNA and protein levels in brain areas that play a role in drug dependence.
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http://dx.doi.org/10.1007/s12035-018-1153-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780301PMC
March 2019

Modulation of the ATP-Binding Cassette B1 Transporter by Neuro-Inflammatory Cytokines: Role in the Pathogenesis of Alzheimer's Disease.

Front Pharmacol 2018 20;9:658. Epub 2018 Jun 20.

Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

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http://dx.doi.org/10.3389/fphar.2018.00658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6020013PMC
June 2018

Peri-adolescent drinking of ethanol and/or nicotine modulates astroglial glutamate transporters and metabotropic glutamate receptor-1 in female alcohol-preferring rats.

Pharmacol Biochem Behav 2018 07 10;170:44-55. Epub 2018 May 10.

University of Toledo, College of Pharmacy and Pharmaceutical Sciences, Department of Pharmacology and Experimental Therapeutics, Toledo, OH 43614, USA. Electronic address:

Impairment in glutamate neurotransmission mediates the development of dependence upon nicotine (NIC) and ethanol (EtOH). Previous work indicates that continuous access to EtOH or phasic exposure to NIC reduces expression of the glutamate transporter-1 (GLT-1) and cystine/glutamate antiporter (xCT) but not the glutamate/aspartate transporter (GLAST). Additionally, metabotropic glutamate receptors (mGluRs) expression was affected following exposure to EtOH or NIC. However, little is known about the effects of EtOH and NIC co-consumption on GLT-1, xCT, GLAST, and mGluR1 expression. In this study, peri-adolescent female alcohol preferring (P) rats were given binge-like access to water, sucrose (SUC), SUC-NIC, EtOH, or EtOH-NIC for four weeks. The present study determined the effects of these reinforcers on GLT-1, xCT, GLAST, and mGluR1 expression in the nucleus accumbens (NAc), hippocampus (HIP) and prefrontal cortex (PFC). GLT-1 and xCT expression were decreased in the NAc following both SUC-NIC and EtOH-NIC. In addition, only xCT expression was downregulated in the HIP in both of these latter groups. Also, glutathione peroxidase (GPx) activity in the HIP was reduced following SUC, SUC-NIC, EtOH, and EtOH-NIC consumption. Similar to previous work, GLAST expression was not altered in any brain region by any of the reinforcers. However, mGluR1 expression was increased in the NAc in the SUC-NIC, EtOH, and EtOH-NIC groups. These results indicate that peri-adolescent binge-like drinking of EtOH or SUC with or without NIC may exert differential effects on astroglial glutamate transporters and receptors. Our data further parallel some of the previous findings observed in adult rats.
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http://dx.doi.org/10.1016/j.pbb.2018.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714273PMC
July 2018

Modulatory effects of Ampicillin/Sulbactam on glial glutamate transporters and metabotropic glutamate receptor 1 as well as reinstatement to cocaine-seeking behavior.

Behav Brain Res 2017 08 15;332:288-298. Epub 2017 Jun 15.

Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH, USA. Electronic address:

Glutamatergic system has an important role in cocaine-seeking behavior. Studies have reported that chronic exposure to cocaine induces downregulation of glutamate transporter-1 (GLT-1) and cystine/glutamate exchanger (xCT) in the central reward brain regions. Ceftriaxone, a β-lactam antibiotic, restored GLT-1 expression and consequently reduced cue-induced reinstatement of cocaine-seeking behavior. In this study, we investigated the reinstatement to cocaine (20mg/kg, i.p.) seeking behavior using a conditioned place preference (CPP) paradigm in male alcohol-preferring (P) rats. In addition, we investigated the effects of Ampicillin/Sulbactam (AMP/SUL) (200mg/kg, i.p.), a β-lactam antibiotic, on cocaine-induced reinstatement. We also investigated the effects of AMP/SUL on the expression of glial glutamate transporters and metabotropic glutamate receptor 1 (mGluR1) in the nucleus accumbens (NAc) core and shell and the dorsomedial prefrontal cortex (dmPFC). We found that AMP/SUL treatment reduced cocaine-triggered reinstatement. This effect was associated with a decrease in locomotor activity. Moreover, GLT-1 and xCT were downregulated in the NAc core and shell, but not in the dmPFC, following cocaine-primed reinstatement. However, cocaine exposure increased the expression of mGluR1 in the NAc core, but not in the NAc shell or dmPFC. Importantly, AMP/SUL treatment normalized GLT-1 and xCT expression in the NAc core and shell; however, the drug normalized mGluR1 expression in the NAc core only. Additionally, AMP/SUL increased the expression of GLT-1 and xCT in the dmPFC as compared to the water naïve group. These findings demonstrated that glial glutamate transporters and mGluR1 in the mesocorticolimbic area could be potential therapeutic targets for the attenuation of reinstatement to cocaine-seeking behavior.
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http://dx.doi.org/10.1016/j.bbr.2017.06.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5551456PMC
August 2017
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