Publications by authors named "Atiah H Almalki"

16 Publications

  • Page 1 of 1

Identification of non-classical hCA XII inhibitors using combination of computational approaches for drug design and discovery.

Sci Rep 2021 Jul 30;11(1):15516. Epub 2021 Jul 30.

Pharmaceutical Chemistry Department, College of Pharmacy, Jouf University, Sakaka, 72341, Aljouf, Saudi Arabia.

Human carbonic anhydrase XII (hCA XII) isozyme is of high therapeutic value as a pharmacological target and biomarker for different types of cancer. The hCA XII is one of the crucial effectors that regulates extracellular and intracellular pH and affects cancer cell proliferation, invasion, growth and metastasis. Despite the fact that interaction features of hCAs inhibitors with the catalytic site of the enzyme are well described, lack in the selectivity of the traditional hCA inhibitors based on the sulfonamide group or related motifs is an urgent issue. Moreover, drugs containing sulfanomides can cause sulfa allergies. Thus, identification of novel non-classical inhibitors of hCA XII is of high priority and is currently the subject of a vast field of study. This study was devoted to the identification of novel potential hCA XII inhibitors using comprehensive set of computational approaches for drug design discovery: generation and validation of structure- and ligand-based pharmacophore models, molecular docking, re-scoring of virtual screening results with MMGBSA, molecular dynamics simulations, etc. As the results of the study several compounds with alternative to classical inhibitors chemical scaffolds, in particular one of coumarins derivative, have been identified and are of high interest as potential non-classical hCA XII inhibitors.
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http://dx.doi.org/10.1038/s41598-021-94809-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8324906PMC
July 2021

Development and Validation of Ecofriendly HPLC-MS Method for Quantitative Assay of Amoxicillin, Dicloxacillin, and Their Official Impurity in Pure and Dosage Forms.

J Anal Methods Chem 2021 17;2021:5570938. Epub 2021 Jun 17.

Pharmaceutical Analytical Chemistry Department, Beni-Suef University, Alshaheed Shehata Ahmad Hegazy St., Beni-Suef 62514, Egypt.

Novel, accurate, selective, and rapid high-performance liquid chromatography mass spectrometry method was developed for simultaneous analysis of amoxicillin trihydrate, dicloxacillin sodium, and their official impurity 6-aminopenicillanic acid. The chromatographic separation was carried out by applying the mixture on a C column (3.5 m ps, 100 mm × 4.6 mm id) using acetonitrile:water (65 : 35 by volume) as a mobile phase within only 4 min. The quantitative analysis was executed using single quadrupole mass spectrometer in which electrospray ionization, selected ion monitoring, and negative mode were operated. The retention times were 1.61, 2.54, and 3.50 mins for amoxicillin, 6-aminopenicillanic acid, and dicloxacillin, respectively. The method was validated in linear ranges of 2-28 g mL, 2-35 g mL, and 1-10 g mL for amoxicillin, dicloxacillin, and 6-aminopenicillanic acid, respectively. The results obtained from the suggested HPLC/MS were statistically compared with those obtained from the reported HPLC method, where no significant difference appeared respecting accuracy and precision. According to the analytical eco-scale assessment method, the proposed method was proved to be greener than the reported one, where the analysis time and the amount of the wasted effluent decreased.
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http://dx.doi.org/10.1155/2021/5570938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225453PMC
June 2021

Perception of Threat and Psychological Impact of COVID-19 among Expatriates in Makkah Region, Saudi Arabia.

Int J Environ Res Public Health 2021 06 21;18(12). Epub 2021 Jun 21.

Department of Pharmacology and Toxicology, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia.

In the first few months of the pandemic, Makkah region reported the highest number of COVID-19 cases among all regions in Saudi Arabia. More than 80% of these reported cases were non-Saudi residents. In this study, we evaluated the perceived threat from and psychological impact of COVID-19 among non-Saudi residents of Makkah region. This was a cross-sectional analysis of data collected using a standardized self-report questionnaire. A total of 292 expatriates were included in the study, the majority of whom were non-Arabic speakers. The prevalence of self-reported depression was nearly 40%, anxiety was 32%, and stress was 43%. The findings indicated variability in the prevalence of psychological symptoms among expatriates from different ethnic backgrounds. Additionally, work environment and perceived threat were strong predictors of psychological disorders. This suggested that the perceived threat from and psychological burden of COVID-19 among non-Saudis in Makkah region is substantial. Future research should investigate the reasons behind these variations in the psychological impact of the pandemic among different ethnic groups.
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http://dx.doi.org/10.3390/ijerph18126650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8296444PMC
June 2021

Novel Phenolic Compounds as Potential Dual EGFR and COX-2 Inhibitors: Design, Semisynthesis, in vitro Biological Evaluation and in silico Insights.

Drug Des Devel Ther 2021 31;15:2325-2337. Epub 2021 May 31.

Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Aljouf, 72341, Saudi Arabia.

Introduction: Epidermal growth factor receptor (EGFR) inhibition is an imperative therapeutic approach targeting various types of cancer including colorectal, lung, breast, and pancreatic cancer types. Moreover, cyclooxygenase-2 (COX-2) is frequently overexpressed in different types of cancers and has a role in the promotion of malignancy, apoptosis inhibition, and metastasis of tumor cells. Combination therapy has been emerged to improve the therapeutic benefit against cancer and curb intrinsic and acquired resistance.

Methods: Three semi-synthetic series of compounds (, , and ) were prepared and evaluated biologically as potential dual epidermal growth factor receptor (EGFR) and COX-2 inhibitors. The main phenolic constituents of L. (-coumaric, caffeic and gallic) acids have been isolated and subsequently subjected to diazo coupling with various amines to get novel three chemical scaffolds with potential anticancer activities.

Results: Compounds and showed superior inhibitory activity against EGFR (IC: 0.9 and 0.5 µM, respectively) and displayed good COX-2 inhibition (IC: 4.35 and 2.47 µM, respectively). Moreover, the final compounds were further evaluated for their cytotoxic activity against human colon cancer (HT-29), pancreatic cancer (PaCa-2), human malignant melanoma (A375), lung cancer (H-460), and pancreatic ductal cancer (Panc-1) cell lines. Interestingly, compounds and exhibited the highest cytotoxic activity with average IC values of 1.5 µM and 2.8 µM against H-460 and Panc-1, respectively. The virtual docking study was conducted to gain proper understandings of the plausible-binding modes of target compounds within EGFR and COX-2 binding sites.

Discussion: The NMR of prepared compounds showed characteristic peaks that confirmed the structure of the target compounds. The synthesized benzoxazolyl scaffold containing compounds showed inhibitory activities for both COXs and EGFR which are consistent with the virtual docking study.
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http://dx.doi.org/10.2147/DDDT.S310820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178614PMC
May 2021

Involvement of the dopaminergic system in the reward-related behavior of pregabalin.

Sci Rep 2021 May 19;11(1):10577. Epub 2021 May 19.

Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH, USA.

There has been an increase in cases of drug addiction and prescription drug abuse worldwide. Recently, pregabalin abuse has been a focus for many healthcare agencies, as highlighted by epidemiological studies. We previously evaluated the possibility of pregabalin abuse using the conditioned place preference (CPP) paradigm. We observed that a 60 mg/kg dose could induce CPP in mice and that pregabalin-rewarding properties were mediated through glutamate neurotransmission. Notably, the dopaminergic reward circuitry is also known to play a crucial role in medication-seeking behavior. Therefore, this study aimed to explore the possible involvement of dopaminergic receptor-1 in pregabalin-induced CPP. Mice were randomly allocated to receive saline or the dopamine-1 receptor antagonist SKF-83566 (0.03 mg/kg, intraperitoneal). After 30 min, the mice received either saline or pregabalin (60 mg/kg) during the conditioning phase. Among the control groups that received saline or SKF-83566, the time spent in the two conditioning chambers was not significantly altered. However, among the pregabalin-treated group, there was a marked increase in the time spent in the drug-paired chamber compared to the time spent in the vehicle-paired chamber. Notably, blocking dopamine-1 receptors with SKF-83566 completely prevented pregabalin-induced place preference, thus demonstrating the engagement of the dopaminergic system in pregabalin-induced reward-related behavior.
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http://dx.doi.org/10.1038/s41598-021-88429-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134490PMC
May 2021

Potential Benefits of N-Acetylcysteine in Preventing Pregabalin-Induced Seeking-Like Behavior.

Healthcare (Basel) 2021 Mar 29;9(4). Epub 2021 Mar 29.

Addiction and Neuroscience Research Unit, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia.

Substance-use disorder is globally prevalent and responsible for numerous social and medical problems. Pregabalin (Lyrica), typically used to treat diabetic neuropathy, has recently emerged as a drug of abuse. Drug abuse is associated with several neuronal changes, including the downregulation of glutamate transporters such as glutamate transporter 1 and cystine/glutamate antiporter. We investigated the effects of N-acetylcysteine, a glutamate transporter 1 and xCT upregulator, on pregabalin addiction using a conditioned place preference paradigm. Pregabalin (60 mg/kg) was found to induce conditioned place preference when compared to a vehicle. A 100 mg/kg dose of N-acetylcysteine was found to block pregabalin-seeking behaviors. These results support previous findings showing that glutamate transporters play an important role in pregabalin-induced seeking behaviors. N-acetylcysteine may represent a beneficial agent in preventing the abuse potential of pregabalin.
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http://dx.doi.org/10.3390/healthcare9040376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066267PMC
March 2021

Nanomaterials for Antiangiogenic Therapies for Cancer: A Promising Tool for Personalized Medicine.

Int J Mol Sci 2021 Feb 5;22(4). Epub 2021 Feb 5.

Addiction and Neuroscience Research Unit, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia.

Angiogenesis is one of the hallmarks of cancer. Several studies have shown that vascular endothelium growth factor (VEGF) plays a leading role in angiogenesis progression. Antiangiogenic medication has gained substantial recognition and is commonly administered in many forms of human cancer, leading to a rising interest in cancer therapy. However, this treatment method can lead to a deteriorating outcome of resistance, invasion, distant metastasis, and overall survival relative to its cytotoxicity. Furthermore, there are significant obstacles in tracking the efficacy of antiangiogenic treatments by incorporating positive biomarkers into clinical settings. These shortcomings underline the essential need to identify additional angiogenic inhibitors that target numerous angiogenic factors or to develop a new method for drug delivery of current inhibitors. The great benefits of nanoparticles are their potential, based on their specific properties, to be effective mechanisms that concentrate on the biological system and control various important functions. Among various therapeutic approaches, nanotechnology has emerged as a new strategy for treating different cancer types. This article attempts to demonstrate the huge potential for targeted nanoparticles and their molecular imaging applications. Notably, several nanoparticles have been developed and engineered to demonstrate antiangiogenic features. This nanomedicine could effectively treat a number of cancers using antiangiogenic therapies as an alternative approach. We also discuss the latest antiangiogenic and nanotherapeutic strategies and highlight tumor vessels and their microenvironments.
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http://dx.doi.org/10.3390/ijms22041631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915670PMC
February 2021

Sex differences in pregabalin-seeking like behavior in a conditioned place preference paradigm.

Saudi Pharm J 2020 Dec 9;28(12):1749-1755. Epub 2020 Nov 9.

Addiction and Neuroscience Research Unit, Taif University, Health Science Campus, Al Haweiah, Taif 21974, Saudi Arabia.

Substance abuse is a chronic, relapsing disorder characterized by compulsive drug use regardless of negative consequences. Incremental increases in pregabalin abuse have been observed in Saudi Arabia and throughout the world. In previous studies, the potential for pregabalin abuse with escalating doses of the drug (30, 60, 90, and 120 mg/kg) were investigated in male mice. Notably, researchers have argued that women may exhibit a greater tendency to consume drugs without a prescription to alleviate stress and depression. Moreover, female subjects are more prone to impulsivity in drug intake or abuse than their male counterparts. Therefore, in the present study, we compared the potential for pregabalin abuse between male and female mice using a conditioned place preference paradigm. Male and female BALB/c mice were divided into four groups based on the pregabalin dose administered (30, 60, 90, or 120 mg/kg, intraperitoneal). Preference scores were then calculated and compared between male and female mice in each dosage group. Interestingly, preference scores were significantly higher in female mice than in male mice at dosages of 30 and 120 mg/kg. These findings indicate that female mice may be more prone to pregabalin abuse and tolerance than male mice. These results might be helpful to the healthcare providers and policymakers to consider these sex differences in choosing therapeutic plans and consider alternatives to the misused prescription medications.
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http://dx.doi.org/10.1016/j.jsps.2020.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783229PMC
December 2020

Progress in Clinical Trials of Photodynamic Therapy for Solid Tumors and the Role of Nanomedicine.

Cancers (Basel) 2020 Sep 29;12(10). Epub 2020 Sep 29.

Use-Inspired Biomaterials and Integrated Nano Delivery Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48021, USA.

Current research to find effective anticancer treatments is being performed on photodynamic therapy (PDT) with increasing attention. PDT is a very promising therapeutic way to combine a photosensitive drug with visible light to manage different intense malignancies. PDT has several benefits, including better safety and lower toxicity in the treatment of malignant tumors over traditional cancer therapy. This reasonably simple approach utilizes three integral elements: a photosensitizer (PS), a source of light, and oxygen. Upon light irradiation of a particular wavelength, the PS generates reactive oxygen species (ROS), beginning a cascade of cellular death transformations. The positive therapeutic impact of PDT may be limited because several factors of this therapy include low solubilities of PSs, restricting their effective administration, blood circulation, and poor tumor specificity. Therefore, utilizing nanocarrier systems that modulate PS pharmacokinetics (PK) and pharmacodynamics (PD) is a promising approach to bypassing these challenges. In the present paper, we review the latest clinical studies and preclinical in vivo studies on the use of PDT and progress made in the use of nanotherapeutics as delivery tools for PSs to improve their cancer cellular uptake and their toxic properties and, therefore, the therapeutic impact of PDT. We also discuss the effects that photoimmunotherapy (PIT) might have on solid tumor therapeutic strategies.
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http://dx.doi.org/10.3390/cancers12102793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601252PMC
September 2020

Gabapentin-induced drug-seeking-like behavior: a potential role for the dopaminergic system.

Sci Rep 2020 06 26;10(1):10445. Epub 2020 Jun 26.

Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, OH, USA.

Drugs of abuse represent a growing public health crisis. Accumulating evidence indicates that gabapentin (GBP), a prescription drug, is prone to misuse, abuse, withdrawal, and dependence. Commonly, drugs of abuse modulate the dopaminergic system to induce addiction. In this study, we used the conditioned place preference (CPP) model to investigate the involvement of the dopamine 1 (D1) receptor on the reward and reinforcement behavior of GBP. Under a CPP paradigm, male BALB/c mice were intraperitoneally injected either saline or 100, 200, or 300 mg/kg of GBP and confined to the injection-paired chamber for 30 min. In the pre-conditioning phase, mice were conditioned for 3 days, and baseline data were collected. In the conditioning phase, mice were given once-daily alternating injections of either GBP or saline for 8 days and subsequently assessed in a post-conditioning test. Injections of 300 mg/kg of GBP significantly increased the time spent in the drug-paired chamber compared to the saline-paired chamber. However, lower doses of GBP (100 and 200 mg/kg) showed no effect. Pre-treatment with SKF-83566, a D1 receptor antagonist, attenuated GBP-induced CPP. Thus, for the first time, we show that GBP can induce CPP through a dopaminergic-dependent mechanism.
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http://dx.doi.org/10.1038/s41598-020-67318-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7320158PMC
June 2020

Generating homogenous cortical preplate and deep-layer neurons using a combination of 2D and 3D differentiation cultures.

Sci Rep 2020 04 14;10(1):6272. Epub 2020 Apr 14.

Department of Anesthesiology, Perioperative and Pain Medicine, Stanford Medical School, Stanford University, California, CA, USA.

Embryonic stem cells (ESCs) can be used to derive different neural subtypes. Current differentiation protocols generate heterogeneous neural subtypes rather than a specific neuronal population. Here, we present a protocol to derive separate two-deep layer cortical neurons from mouse ESCs (mESCs). mESCs were differentiated into mature Tbr1 or Ctip2-positive neurons using a monolayer-based culture for neural induction and neurosphere-based culture for neural proliferation and expansion. The differentiation protocol relies on SMAD inhibition for neural induction and the use of FGF2 and EGF for proliferation and it is relatively short as mature neurons are generated between differentiation days 12-16. Compared with the monolayer-based differentiation method, mESCs can be directed to generate specific deep-layer cortical neurons rather than heterogeneous cortical neurons that are generated using the monolayer differentiation culture. The early analysis of progenitors using flow cytometry, immunocytochemistry, and qRT-PCR showed high neuralization efficiency. The immunocytochemistry and flow cytometry analyses on differentiation days 12 and 16 showed cultures enriched in Tbr1- and Ctip2-positive neurons, respectively. Conversely, the monolayer differentiation culture derived a mixture of Tbr1 and Ctip2 mature neurons. Our findings suggested that implementing a neurosphere-based culture enabled directing neural progenitors to adopt a specific cortical identity. The generated progenitors and neurons can be used for neural-development investigation, drug testing, disease modelling, and examining novel cellular replacement therapy strategies.
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http://dx.doi.org/10.1038/s41598-020-62925-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156727PMC
April 2020

Effects of environmental enrichment on reinstatement of methamphetamine-induced conditioned place preference.

Behav Brain Res 2020 02 20;379:112372. Epub 2019 Nov 20.

Taif University, College of Pharmacy, Addiction and Neuroscience Research Unit, Taif, Saudi Arabia; Taif University, College of Pharmacy, Department of Pharmaceutical chemistry, Taif, Saudi Arabia.

Objective: The influence of environmental enrichment (EE) on reinstatement to methamphetamine (METH) seeking in rat model was investigated.

Methods: Wistar rats were divided to receive saline (1 ml/kg) or METH (1 mg/kg, i.p.) for 8 days during the conditioning training in the conditioned place preference (CPP) paradigm, which is one of the most popular models to study the motivational effects of drugs and non-drug treatments in experimental animals. Rats were then kept in either isolated (IE) or enriched environment (EE) for 30 days during the extinction training. Animals were finally examined for reinstatement provoked by i.p. injections of METH.

Results: Saline injections during the conditioning phase did not change CPP during reinstatement in animals of IE or EE control groups. METH injections reinstated place preference in the IE animal group. Interestingly, EE significantly blocked this reinstatement effects of METH.

Conclusion: These results show the important role of social interactions and positive environment conditions in preventing reinstatement to drug use.
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http://dx.doi.org/10.1016/j.bbr.2019.112372DOI Listing
February 2020

Effects of sequential ethanol exposure and repeated high-dose methamphetamine on striatal and hippocampal dopamine, serotonin and glutamate tissue content in Wistar rats.

Neurosci Lett 2018 02 22;665:61-66. Epub 2017 Nov 22.

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

Alcohol (ethanol) and methamphetamine (METH) co-abuse is a major public health issue. Ethanol or METH exposure has been associated with changes in neurotransmitter levels in several central brain regions. However, little is known about the effect of sequential exposure to ethanol and METH on glutamate, dopamine and serotonin tissue content in striatum and hippocampus. In this study, we investigated the effects of sequential exposure to ethanol and METH on tissue content of these neurotransmitters. Male Wistar rats were orally gavaged with either ethanol (6g/kg) or water for seven days. Rats were administered with high dose of METH (10mg/kg, i.p. every 2h×4) or saline on Day 8 and euthanized 48h of last METH or saline i.p. injection. In the striatum, sequential exposure to ethanol and METH increased glutamate tissue content while reducing dopamine and serotonin tissue content as compared to the group exposed to ethanol alone. In the hippocampus, sequential exposure to ethanol and METH decreased serotonin tissue content as compared to the group that was exposed to ethanol alone. However, this study showed that ethanol has no additive effect to METH on tissue content of dopamine and serotonin as compared to METH in the striatum and hippocampus. This study demonstrated that sequential exposure of ethanol and METH has an additive effect on tissue content of certain neurotransmitters in the brain.
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http://dx.doi.org/10.1016/j.neulet.2017.11.043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5801213PMC
February 2018

Effects of repeated high-dose methamphetamine and ceftriaxone post-treatments on tissue content of dopamine and serotonin as well as glutamate and glutamine.

Neurosci Lett 2016 Nov 1;634:25-31. Epub 2016 Oct 1.

University of Toledo, College of Pharmacy and Pharmaceutical Sciences, Department of Pharmacology and Experimental Therapeutics, Toledo, OH, United States; University of Toledo, College of Pharmacy and Pharmaceutical Sciences, Department of Medicinal and Biological Chemistry, Toledo, OH, United States. Electronic address:

Repeated exposure to high doses of methamphetamine (METH) is known to alter several neurotransmitters in certain brain regions. Little is known about the effects of ceftriaxone (CEF), a β-lactam antibiotic, known to upregulate glutamate transporter subtype 1, post-treatment on METH-induced depletion of dopamine and serotonin (5-HT) tissue content in brain reward regions. Moreover, the effects of METH and CEF post-treatment on glutamate and glutamine tissue content are not well understood. In this study, Wistar rats were used to investigate the effects of METH and CEF post-treatment on tissue content of dopamine/5-HT and glutamate/glutamine in the nucleus accumbens (NAc) and prefrontal cortex (PFC). Rats received either saline or METH (10mg/kg, i.p. every 2h×4) followed by either saline or CEF (200mg/kg, i.p, every day×3) post-treatment. METH induced a significant depletion of dopamine and 5-HT in the NAc and PFC. Importantly, dopamine tissue content was completely restored in the NAc following CEF post-treatment. Additionally, METH caused a significant decrease in glutamate and glutamine tissue content in PFC, and this effect was attenuated by CEF post-treatment. These findings demonstrate for the first time the attenuating effects of CEF post-treatment on METH induced alterations in the tissue contents of dopamine, glutamate, and glutamine.
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http://dx.doi.org/10.1016/j.neulet.2016.09.058DOI Listing
November 2016

Effects of Ceftriaxone on Glial Glutamate Transporters in Wistar Rats Administered Sequential Ethanol and Methamphetamine.

Front Neurosci 2016 22;10:427. Epub 2016 Sep 22.

Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of ToledoToledo, OH, USA; Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of ToledoToledo, OH, USA.

Methamphetamine (METH) is one of the psychostimulants that is co-abused with ethanol. Repeated exposure to high dose of METH has been shown to cause increases in extracellular glutamate concentration. We have recently reported that ethanol exposure can also increase the extracellular glutamate concentration and downregulate the expression of glutamate transporter subtype 1 (GLT-1). GLT-1 is a glial transporter that regulates the majority of extracellular glutamate. A Wistar rat model of METH and ethanol co-abuse was used to examine the expression of GLT-1 as well as other glutamate transporters such as cystine/glutamate exchanger (xCT) and glutamate aspartate transporter (GLAST). We also examined the body temperature in rats administered METH, ethanol or both drugs. We further investigated the effects of ceftriaxone (CEF), a β-lactam antibiotic known to upregulate GLT-1, in this METH/ethanol co-abuse rat model. After 7 days of either ethanol (6 g/kg) or water oral gavage, Wistar rats received either saline or METH (10 mg/kg i.p. every 2 h × 4), followed by either saline or CEF (200 mg/kg) posttreatment. METH administered alone decreased GLT-1 expression in the nucleus accumbens (NAc) and prefrontal cortex (PFC) and increased body temperature, but did not reduce either xCT or GLAST expression in ethanol and water-pretreated rats. Interestingly, ethanol and METH were found to have an additive effect on the downregulation of GLT-1 expression in the NAc but not in the PFC. Moreover, ethanol alone caused GLT-1 downregulation in the NAc and elevated body temperature compared to control. Finally, CEF posttreatment significantly reversed METH-induced hyperthermia, restored GLT-1 expression, and increased xCT expression. These findings suggest the potential therapeutic role of CEF against METH- or ethanol/METH-induced hyperglutamatergic state and hyperthermia.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5031687PMC
http://dx.doi.org/10.3389/fnins.2016.00427DOI Listing
September 2016

Effects of Benzodiazepines on Acinar and Myoepithelial Cells.

Front Pharmacol 2016 24;7:173. Epub 2016 Jun 24.

Department of Pharmacology, College of Pharmacy and Pharmaceutical, The University of ToledoToledo, OH, US; Program of Post-Graduation, Department of Pharmacology, School of Dentistry, Health and Bioscience School, Pontifical Catholic University of ParanáCuritiba, Brazil.

Background: Benzodiazepines (BZDs), the most commonly prescribed psychotropic drugs with anxiolytic action, may cause hyposalivation. It has been previously shown that BZDs can cause hypertrophy and decrease the acini cell number. In this study, we investigated the effects of BZDs and pilocarpine on rat parotid glands, specifically on acinar, ductal, and myoepithelial cells.

Methods: Ninety male Wistar rats were divided into nine groups. Control groups received a saline solution for 30 days (C30) and 60 days (C60), and pilocarpine (PILO) for 60 days. Experimental groups received lorazepam (L30) and midazolam (M30) for 30 days. Another group (LS60 or MS60) received lorazepam or midazolam for 30 days, respectively, and saline for additional 30 days. Finally, other groups (LP60 or MP60) received either lorazepam or midazolam for 30 days, respectively, and pilocarpine for additional 30 days. The expression of calponin in myoepithelial cells and the proliferating cell nuclear antigen (PCNA) in acinar and ductal cells were evaluated.

Results: Animals treated with lorazepam showed an increase in the number of positive staining cells for calponin as compared to control animals (p < 0.05). Midazolam administered with pilocarpine (MP60) induced an increase in the proliferation of acinar and ductal cells and a decrease in the positive staining cells for calponin as compared to midazolam administered with saline (MS60).

Conclusion: We found that myoepithelial cells might be more sensitive to the effects of BZD than acinar and ductal cells in rat parotid glands.
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http://dx.doi.org/10.3389/fphar.2016.00173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4919344PMC
July 2016
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