Publications by authors named "Muhammad Al-Shorbagy"

24 Publications

  • Page 1 of 1

Pentoxifylline treatment alleviates kidney ischemia/reperfusion injury: Novel involvement of galectin-3 and ASK-1/JNK & ERK1/2/NF-κB/HMGB-1 trajectories.

J Pharmacol Sci 2021 Jul 9;146(3):136-148. Epub 2021 Apr 9.

Department of Pharmacology, Toxicology and Biochemistry, Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University in Egypt, Cairo, 84518, Egypt.

Despite the documented renoprotective effect of pentoxifylline (PTX), a non-selective phosphodiesterase-4 inhibitor, the studies appraised only its anti-inflammatory/-oxidant/-apoptotic capacities without assessment of the possible involved trajectories. Here, we evaluated the potential role of galectin-3 and the ASK-1/NF-κB p65 signaling pathway with its upstream/downstream signals in an attempt to unveil part of the cascades involved in the renotherapeutic effect using a renal bilateral ischemia/reperfusion (I/R) model. Rats were randomized into sham-operated, renal I/R (45 min/72 h) and I/R + PTX (100 mg/kg; p.o). Post-treatment with PTX improved renal function and abated serum levels of cystatin C, creatinine, BUN and renal KIM-1 content, effects that were reflected on an improvement of the I/R-induced renal histological changes. On the molecular level, PTX reduced renal contents of galectin-3, ASK-1 with its downstream molecule JNK and ERK1/2, as well as NF-κB p65 and HMGB1. This inhibitory effect extended also to suppress neutrophil infiltration, evidenced by diminishing ICAM-1 and MPO, as well as inflammatory cytokines (TNF-α/IL-18), oxidative stress (MDA/TAC), and caspase-3. The PTX novel renotherapeutic effect involved in part the inhibition of galectin-3 and ASK-1/JNK and ERK1/2/NF-κB/HMGB-1 trajectories to mitigate renal I/R injury and to provide basis for its anti-inflammatory, antioxidant, and anti-apoptotic impacts.
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http://dx.doi.org/10.1016/j.jphs.2021.03.011DOI Listing
July 2021

Eprosartan: A closer insight into its neuroprotective activity in rats with focal cerebral ischemia-reperfusion injury.

J Biochem Mol Toxicol 2021 May 3:e22796. Epub 2021 May 3.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Giza, Egypt.

Eprosartan (EPRO), an angiotensin receptor type-1 (AT-1) blocker, exhibited neuroprotective activities in ischemic stroke resulting from focal cerebral ischemia in rats. The current study aimed to clarify the neuroprotective role of EPRO in middle carotid artery occlusion (MCAO)-induced ischemic stroke in rats. Fifty-six male Wistar rats were divided into four groups (n = 14 per group): sham-operated group, sham receiving EPRO (60 mg/kg/day, po) group, ischemia-reperfusion (IR) group, and IR receiving EPRO (60 mg/kg/day, po) group. MCAO led to a remarkable impairment in motor function together with stimulation of inflammatory and apoptotic pathways in the hippocampus of rats. After MCAO, the AT1 receptor in the brain was stimulated, resulting in activation of Janus kinase 2/signal transducers and activators of transcription 3 signaling generating more neuroinflammatory milieu and destructive actions on the hippocampus. Augmentation of caspase-3 level by MCAO enhanced neuronal apoptosis synchronized with neurodegenerative effects of oxidative stress biomarkers. Pretreatment with EPRO opposed motor impairment and decreased oxidative and apoptotic mediators in the hippocampus of rats. The anti-inflammatory activity of EPRO was revealed by downregulation of nuclear factor-kappa B and tumor necrosis factor-β levels and (C-X-C motif) ligand 1 messenger RNA (mRNA) expression. Moreover, the study confirmed the role of EPRO against a unique pathway of hypoxia-inducible factor-1α and its subsequent inflammatory mediators. Furthermore, upregulation of caveolin-1 mRNA level was also observed along with decreased oxidative stress marker levels and brain edema. Therefore, EPRO showed neuroprotective effects in MCAO-induced cerebral ischemia in rats via attenuation of oxidative, apoptotic, and inflammatory pathways.
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http://dx.doi.org/10.1002/jbt.22796DOI Listing
May 2021

Role of pERK1/2-NFκB signaling in the neuroprotective effect of thalidomide against cerebral ischemia reperfusion injury in rats.

Eur J Pharmacol 2021 Mar 16;895:173872. Epub 2021 Jan 16.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt; Department of Pharmaceutical Sciences, College of Pharmacy, Gulf Medical University, Ajman, 4184, United Arab Emirates.

In the present investigation, we tested the hypothesis that suppression of the phospho-extracellular signal regulated kinase (pERK1/2)-nuclear factor kappa (NFκ)-B signaling, subsequent to tumor necrosis factor-α (TNF-α) inhibition, underlies thalidomide (TLM) mediated neuroprotection. Male Wistar rats (250-280 g) were divided into five groups: (1) sham; (2) negative control receiving TLM (5μg/1μl/site) and 3 groups of ischemia-reperfusion (IR) injury rats pretreated with: (3) vehicle (DMSO 100%); (4) TLM (5μg/1μl/site) or (5) PD98059 (0.16μg/1μl/site). IR rats were subjected to occlusion of both common carotid arteries for 45 min followed by reperfusion for 24 h. Drugs and/or vehicles were administered by unilateral intrahippocampal injection after removal of the carotid occlusion and at the beginning of the reperfusion period. IR rats exhibited significant infarct size, histopathological damage, memory impairment, motor incoordination and hyperactivity. Unilateral intra-hippocampal TLM ameliorated these behavioral deficits along with the following ex vivo hippocampal effects: (i) abrogation of the IR-evoked elevations in hippocampal TNF-α, pERK1/2, NFκB, BDNF, iNOS contents and (ii) partial restoration of the reduced anti-inflammatory cytokine IL-10 and p-nNOS . These neurochemical effects, which were replicated by the pERK1/2 inhibitor PD98059, likely underlie the reductions in c-Fos and caspase-3 levels as well as the anti-apoptotic effect of TLM in the IR model. These results suggest a crucial anti-inflammatory role for pERK1/2 inhibition in the salutary neuronal and behavioral effects of TLM in a model of brain IR injury.
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http://dx.doi.org/10.1016/j.ejphar.2021.173872DOI Listing
March 2021

Activation of autophagy and suppression of apoptosis by dapagliflozin attenuates experimental inflammatory bowel disease in rats: Targeting AMPK/mTOR, HMGB1/RAGE and Nrf2/HO-1 pathways.

Chem Biol Interact 2021 Feb 4;335:109368. Epub 2021 Jan 4.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt; Department of Pharmacology and Toxicology, School of Pharmacy, NewGiza University, Giza, Egypt.

Dapagliflozin, a selective sodium-glucose co-transporter 2 (SGLT2) inhibitor, has featured marked anti-inflammatory effects in murine models of myocardial infarction, renal injury, and neuroinflammation. Yet, its potential impact on the pathogenesis of inflammatory bowel diseases (IBD) has not been previously investigated. The presented study aimed to explore the prospect of dapagliflozin to mitigate 2,4,6 trinitrobenzene sulfonic acid (TNBS)-induced rat colitis model which recapitulates several features of the human IBD. The molecular mechanisms pertaining to the dynamic balance between autophagy/apoptosis and colon injury were delineated, particularly, AMPK/mTOR, HMGB1/RAGE/NF-κB and Nrf2/HO-1 pathways. The colon tissues were examined using immunoblotting, ELISA, and histopathology. Dapagliflozin (0.1, 1 and 5 mg/kg; p.o.) dose-dependently mitigated colitis severity as manifested by suppression of the disease activity scores, macroscopic damage scores, colon weight/length ratio, histopathologic perturbations, and inflammatory markers. More important, dapagliflozin enhanced colonic autophagy via upregulating Beclin 1 and downregulating p62 SQSTM1 protein expression. In this context, dapagliflozin activated the AMPK/mTOR pathway by increasing the p-AMPK/AMPK and lowering the p-mTOR/mTOR ratios, thereby, favoring autophagy. Moreover, dapagliflozin dampened the colonic apoptosis via lowering the caspase-3 activity, cleaved caspase-3 expression, and Bax/Bcl-2 ratio. Furthermore, dapagliflozin attenuated the HMGB1/RAGE/NF-κB pathway via lowering HMGB1, RAGE, and p-NF-κBp65 protein expression. Regarding oxidative stress, dapagliflozin lowered the oxidative stress markers and augmented the Nrf2/HO-1 pathway. Together, the present study reveals, for the first time, the ameliorative effect of dapagliflozin against experimental colitis via augmenting colonic autophagy and curbing apoptosis through activation of AMPK/mTOR and Nrf2/HO-1 pathways and suppression of HMGB1/RAGE/NF-κB cascade.
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http://dx.doi.org/10.1016/j.cbi.2021.109368DOI Listing
February 2021

Effects of TNF-α antagonist infliximab on fructose-induced metabolic syndrome in rats.

Hum Exp Toxicol 2021 May 29;40(5):801-811. Epub 2020 Oct 29.

Clinical Pharmacy Department, Faculty of Pharmacy, British University in Egypt, Cairo, Egypt.

Public health issues have been raised regarding fructose toxicity and its serious metabolic disorders. Deleterious effects of high fructose intake on insulin sensitivity, body weight, lipid homeostasis have been identified. The new millennium has witnessed the emergence of a modern epidemic, the metabolic syndrome (MS), in approximately 25% of the world's adult population. The current study aimed to investigate the effect of the TNF-α antagonist infliximab on fructose-induced MS in rats. Rats were administered fructose (10%) in drinking water for 12 weeks to induce the experimental MS model. infliximab (5 mg/kg) was injected once weekly intraperitoneally starting on the 13th week for 4 weeks. Increase in body weight, blood glucose level, serum triglycerides (TGs), adiponectin level and blood pressure were present in MS rats. They also prompted increases in serum of leptin, TNF-α, and malondialdehyde (MDA) levels. Treatment with infliximab did not affect body weight, hyperglycemia or hypertension, but decreased serum TGs and increased serum HDL-c levels. Infliximab also decreased adiponectin levels. Surprisingly, infliximab increased MDA above its value in the MS group. These results reflect the fact that infliximab affects the manifestations of MS in rats. Though infliximab reduced TGs, increased HDL-c levels, reversed adiponectin resistance occurred by fructose, the drug failed to combat MS-mediated hyperglycemia, hypertension, and elevated MDA above the insult.
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http://dx.doi.org/10.1177/0960327120969960DOI Listing
May 2021

Mechanistic perspective of morin protection against ketoprofen-induced gastric mucosal injury: Targeting HMGB1/RAGE/NF-κB, DJ-1/Nrf2/HO-1 and PI3K/mTOR pathways.

Arch Biochem Biophys 2020 10 26;693:108552. Epub 2020 Aug 26.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt; Department of Pharmacology and Toxicology, School of Pharmacy, NewGiza University, Giza, Egypt.

Ketoprofen is a widely used NSAID which incurs gastric mucosal damage. The high mobility group Box 1 (HMGB1) protein is a DNA-binding protein which exerts robust inflammatory actions, however, its role in ketoprofen-induced gastric damage has not been explored. Additionally, no previous studies have linked HMGB1/RAGE/NF-κB, DJ-1/Nrf2/HO-1 and PI3K/mTOR pathways in ketoprofen-induced gastropathy. The current work aimed to explore the potential of morin, a flavonoid with marked antioxidant/anti-inflammatory actions, to protect against ketoprofen-evoked gastric damage. Moreover, the underlying mechanisms, including the impact of morin on HMGB1/RAGE/NF-κB, DJ-1/Nrf2/HO-1 and PI3K/mTOR pathways were addressed. Immunoblotting and ELISA were used to examine the expression of target signals. Morin (50 mg/kg, p. o.) attenuated the severity of gastric injury via lowering of ulceration/hemorrhage and macroscopic damage scores. Meanwhile, it attenuated the histopathologic aberrations/damage scores. In the context of inflammation, morin suppressed TNF-α and myeloperoxidase levels and enhanced IL-10. Furthermore, it inhibited HMGB1/RAGE/NF-κB pathway through downregulating HMGB1, RAGE and phospho-NF-κBp65 protein expression. Morin successfully inhibited gastric mucosal oxidative stress through lowering of lipid peroxides and boosting of reduced glutathione, glutathione peroxidase and total antioxidant capacity. It also boosted DJ-1/Nrf2/HO-1 pathway via upregulating DJ-1, Nrf2 and HO-1 protein expression. Additionally, morin counteracted the apoptotic events by downregulating the proapoptotic Bax and Bax/Bcl-2 ratio and augmenting the PI3K/mTOR pathway through upregulating PI3Kp110α and phospho-mTOR protein expression. In conclusion, the current study demonstrates, for the first time, that morin shows a promise for the management of ketoprofen-induced mucosal insult through targeting of HMGB1/RAGE/NF-κB, DJ-1/Nrf2/HO-1 and PI3K/mTOR pathways.
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http://dx.doi.org/10.1016/j.abb.2020.108552DOI Listing
October 2020

IL-6/STAT3 and adipokine modulation using tocilizumab in rats with fructose-induced metabolic syndrome.

Naunyn Schmiedebergs Arch Pharmacol 2020 12 10;393(12):2279-2292. Epub 2020 Jul 10.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.

Metabolic syndrome (MetS) is a low-grade inflammation state that results from an interplay between genetic and environmental factors. The incidence of MetS among individuals with insulin resistance, dyslipidemia, elevated blood pressure, and obesity, which constitute the syndrome, is 40% in the Middle East. The absence of an approved therapeutic agent for MetS is one reason to investigate tocilizumab (TCZ), which might be effective in the treatment of MetS. Results have implicated interleukin 6 (IL-6) in the development of MetS, identifying inflammation as a critical factor in its etiology and offering hope for new therapeutic approaches development. Here, we evaluate whether tocilizumab can be used for metabolic syndrome treatment. We assigned rats to three groups, 8 rats each: a negative-control group, provided with standard rodent chow and water; a fructose-fed group, provided with standard rodent chow and 10% fructose in drinking water for 22 weeks; and a treatment group, fed as per the metabolic syndrome group but treated with tocilizumab (5 mg/kg/week, intraperitoneal) for the final 5 weeks. Treatment with TCZ successfully ameliorated the damaging effects of fructose by stabilizing body weight gain and through the normalization of serum biochemical parameters and histopathological examination. Significant differences in adipokine levels were perceived, resulting in a significant decline in serum leptin and interleukin 6 (IL-6) levels concurrent with adiponectin normalization. Tocilizumab might be an effective agent for the treatment of metabolic syndrome. However, further investigations on human subjects are needed before the clinical application of tocilizumab for this indication.
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http://dx.doi.org/10.1007/s00210-020-01940-zDOI Listing
December 2020

The paradox of dipeptidyl peptidase IV inhibition in enterocytic differentiation and epithelial-mesenchymal transition in rat cholestatic sepsis.

Toxicol Appl Pharmacol 2020 05 11;394:114956. Epub 2020 Mar 11.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El-Aini street, Cairo, P.O. Box 11562, Egypt; School of Pharmacy, NewGiza University, Giza, Egypt.

Proper enterocytic proliferation/differentiation, besides providing adequate adherens junctions (AJ) integrity, are responsible for strengthening of the gut barrier that acts as a first line defense against endotoxemia. However, the preferential role of the underlying PI3K/Akt (PKB) axis in triggering enterocytic proliferation/differentiation signaling and AJ assembly is still obscure in sepsis. Additionally, the potential involvement of dipeptidyl peptidase (DPP)-IV in cholestatic sepsis has not yet been reported. Common bile duct ligation (CBDL) insult was performed in adult male Sprague-Dawley rats except for sham operated animals; three doses of vildagliptin (VLD3, 10 and 30 mg/kg/d; p.o) were administered for 10 consecutive days post CBDL. VLD3/10/30 dose-dependently decreased DPP-IV and elevated GLP-1, IGF-1, PI3K, pS473-Akt (PKB), pS9-GSK-3β, pS133-CREB and cyclin-D1. VLD3/10 reduced fever, portal/aortic endotoxin and IgG, body weight loss as well as ileal NF-κB, TNF-α, MPO, TBARS, subepithelial/pericryptal and submucosal collagen deposition, vimentin immunoreactivity, N-cadherin, Zeb1 and pY654-β-catenin but increased E-cadherin, NPSH and colon/spleen indices - effects that were quite the opposite of VLD30. Accordingly, maintaining proper enterocytic proliferation/differentiation and phosphorylation inputs consequent to adequate DPP-IV inhibition is integral to AJ assembly in cholestatic sepsis; however, perturbed signals by excessive suppression of the enzyme activity induce toxic effects manifested as AJ disassembly and EMT, hence gut leakage and overt endotoxemia.
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http://dx.doi.org/10.1016/j.taap.2020.114956DOI Listing
May 2020

Nateglinide Exerts Neuroprotective Effects via Downregulation of HIF-1α/TIM-3 Inflammatory Pathway and Promotion of Caveolin-1 Expression in the Rat's Hippocampus Subjected to Focal Cerebral Ischemia/Reperfusion Injury.

Inflammation 2020 Apr;43(2):401-416

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Giza, Egypt.

Ischemic stroke is a major cause of death and motor disabilities all over the world. It is a muti-factorial disorder associated with inflammatory, apoptotic, and oxidative responses. Nateglinide (NAT), an insulinotropic agent used for the treatment of type 2 diabetes mellitus, recently showed potential anti-inflammatory and anti-apoptotic effects. The aim of our study was to elucidate the unique neuroprotective role of NAT in the middle cerebral artery occlusion (MCAO)-induced stroke in rats. Fifty-six male rats were divided to 4 groups (n = 14 in each group): the sham-operated group, sham receiving NAT (50 mg/kg/day, p.o) group, ischemia/reperfusion (IR) group, and IR receiving NAT group (50 mg/kg/day, p.o). MCAO caused potent deficits in motor and behavioral functions of the rats. Significant increase in inflammatory and apoptotic biomarkers has been observed in rats' hippocampi. Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway was significantly stimulated causing activation of series inflammatory biomarkers ending up neuro-inflammatory milieu. Pretreatment with NAT preserved rats' normal behavioral and motor functions. Moreover, NAT opposed the expression of hypoxia-inducible factor-1α (HIF-1α) resulting in downregulation of more inflammatory mediators namely, NF-κB, tumor necrosis factor-β (TNF-β), and the anti-survival gene PMAIP-1. NAT stimulated caveolin-1 (Cav-1) which prevented expression of oxidative biomarkers, nitric oxide (NO), and myeloperoxidase (MPO) and hamper the activation of apoptotic biomarker caspase-3. In conclusion, our work postulated that NAT exhibited its neuroprotective effects in rats with ischemic stroke via attenuation of different unique oxidative, apoptotic, and inflammatory pathways.
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http://dx.doi.org/10.1007/s10753-019-01154-3DOI Listing
April 2020

A novel praziquantel solid lipid nanoparticle formulation shows enhanced bioavailability and antischistosomal efficacy against murine S. mansoni infection.

Parasit Vectors 2019 Jun 17;12(1):304. Epub 2019 Jun 17.

Pharmacology Department, Theodor Bilharz Research Institute, Imbaba, Giza, Egypt.

Background: Schistosomiasis is responsible for a considerable global disease burden. This work aimed to improve the therapeutic outcome of the only available antischistosomal drug worldwide, praziquantel (PZQ), by incorporating it into a novel carrier, "solid lipid nanoparticles (SLNs)", to enhance its solubility, bioavailability and efficacy. A simple, cost-effective method was used to prepare SLN-PZQ.

Results: Compared to market PZQ (M-PZQ), SLN-PZQ was more bioavailable, as denoted by higher serum concentrations in both normal and infected mice where elevated K, AUC, C, and t with a decrease in k were demonstrated. The AUC for SLN-PZQ in normal and Schistosoma mansoni-infected groups was almost nine- and eight-fold higher, respectively, than that for M-PZQ in corresponding groups. In normal and S. mansoni-infected mice, SLN-PZQ was detectable in serum at 24 h, while M-PZQ completely vanished 8 h post-treatment. Additionally, enhanced absorption with extended residence time was recorded for SLN-PZQ. Compared to M-PZQ, SLN-PZQ revealed superior antischistosomal activity coupled with enhanced bioavailability in all treated groups where higher percentages of worm reduction were recorded with all dosages tested. This effect was especially evident at the lower dose levels. The ED of SLN-PZQ was 5.29-fold lower than that of M-PZQ, with a significantly higher reduction in both the hepatic and intestinal tissue egg loads of all treated groups and almost complete disappearance of immature deposited eggs (clearly evident at the low dose levels).

Conclusions: SLN-PZQ demonstrated enhanced PZQ bioavailability and antischistosomal efficacy with a safe profile despite the prolonged residence in the systemic circulation.
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http://dx.doi.org/10.1186/s13071-019-3563-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580642PMC
June 2019

Pharmacological Manipulation of Trk, p75NTR, and NGF Balance Restores Memory Deficit in Global Ischemia/Reperfusion Model in Rats.

J Mol Neurosci 2019 May 12;68(1):78-90. Epub 2019 Mar 12.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El Aini st., Cairo, 11562, Egypt.

Long-term memory impairment is reported in more than 50% of cardiac arrest survivors. Monosialoganglioside (GM1) provided neuroprotection in experimental models of stroke but failed to replicate its promise clinically for unknown reasons. GM1 stimulates the release of nerve growth factor (NGF), which is synthesized as a precursor protein (pro-NGF) that either mediates apoptosis through the p75 neurotrophin receptor (p75NTR) or is cleaved by the protease furin (FUR) to yield mature NGF, the latter supporting survival through tropomyosin kinase receptor (Trk). The flavanol epicatechin (EPI) inhibits p75NTR-mediated signaling and apoptosis by pro-NGF. The aim of the current work is to test whether these two drugs affect, or communicate with, each other in the setting of CNS injuries. Using the two-vessel occlusion model of global ischemia/reperfusion (I/R), we tested if pharmacological modulation of Trk, p75NTR, and NGF balance with GM1, EPI, and their combination, can correct the memory deficit that follows this insult. Finally, we tested if FUR insufficiency and/or p75NTR-mediated apoptosis negatively affect the neurotherapeutic effect of GM1. Key proteins for Trk and p75NTR, FUR, and both forms of NGF were assessed. All treatment regiments successfully improved spatial memory retention and acquisition. A week after the insult, most Trk and p75NTR proteins were normal, but pro/mature NGF ratio remained sharply elevated and was associated with the poorest memory performance. Pharmacological correction of this balance was achieved by reinforcing Trk and p75NTR signaling. GM1 increased FUR levels, while concomitant administration of EPI weakened GM1 effect on pro-survival Trk and p75NTR mediators. GM1 neuroprotection is therefore not limited by FUR but could be dependent on p75NTR. Graphical Abstract "."
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http://dx.doi.org/10.1007/s12031-019-01284-1DOI Listing
May 2019

Saroglitazar Deactivates the Hepatic LPS/TLR4 Signaling Pathway and Ameliorates Adipocyte Dysfunction in Rats with High-Fat Emulsion/LPS Model-Induced Non-alcoholic Steatohepatitis.

Inflammation 2019 Jun;42(3):1056-1070

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.

The most epidemic liver disorder non-alcoholic steatohepatitis (NASH) is characterized by hepatic steatosis and inflammation with hepatocellular damage. Recently, it is predictable to be the extensive cause for liver transplantation. The absence of an approved therapeutic agent for NASH is the reason for investigating saroglitazar (SAR) which showed promising effects as a dual PPAR-α/γ agonist in recent studies on NASH. Here, we aimed to investigate the effect of SAR on NASH induced in rats by the administration of high-fat emulsion (HFE) and small doses of lipopolysaccharides (LPS) for 5 weeks. Rats were divided into three groups: negative control group (saline and standard rodent chow), model group (HFE(10 ml/kg/day, oral gavage) + LPS(0.5 mg/kg/week, i.p)), and SAR-treated group (HFE(10 ml/kg/day, oral gavage) + LPS(0.5 mg/kg/week, i.p.) + SAR(4 mg/kg/day, oral gavage) starting at week 3.Treatment with SAR successfully ameliorated the damaging effects of HFE with LPS, by counteracting body weight gain and biochemically by normalization of liver function parameters activity, glucose, insulin, homeostasis model of assessment (HOMA-IR) score, lipid profile levels, and histopathological examination. Significant changes in adipokine levels were perceived, resulting in a significant decline in serum leptin and tumor necrosis factor-α (TNF-α) level concurrent with adiponectin normalization. The positive effects observed for SAR on NASH are due to the downregulation of the LPS/TLR4 pathway, as indicated by the suppression of hepatic Toll-like receptor 4 (TLR4), NF-κB, TNF-α, and transforming growth factor-β1 (TGF-β1) expression. In conclusion, this work verified that SAR ameliorates NASH through deactivation of the hepatic LPS/TLR4 pathway and inhibition of adipocyte dysfunction.
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http://dx.doi.org/10.1007/s10753-019-00967-6DOI Listing
June 2019

Nicorandil abates arthritic perturbations induced by complete Freund's adjuvant in rats via conquering TLR4-MyD88-TRAF6 signaling pathway.

Life Sci 2019 Feb 3;218:284-291. Epub 2019 Jan 3.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El Aini st., 11562 Cairo, Egypt; School of Pharmacy, Newgiza University, Cairo, Egypt. Electronic address:

Background And Purpose: Rheumatoid arthritis (RA) is a chronic, systemic autoimmune inflammatory disease which poses a need to explore effective yet safe pharmacotherapeutic options. The current work aimed to study the therapeutic role of nicorandil in controlling RA.

Experimental Approach: Complete Freund's adjuvant (CFA)-induced arthritis model was applied by injecting 400 μL of CFA in the right hind paw at day 0 and day 7. Four groups of rats were used as follows: normal-control (CTRL), CFA-induced arthritis (ART), CFA-induced arthritis treated with diclofenac (DIC) and CFA-induced arthritis treated with nicorandil (NIC). Both NIC and DIC were administered at day 14 for two weeks. Paw volume, knee joint diameter, pain behavior assessment as well as body weight were all periodically recorded throughout the experimental period. Following the sacrifice of animals at day 28, gene expressions of TLR-4, MyD88 and TRAF6 as well as extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), nuclear factor Kappa B (NF-κB) were quantified in hind paws tissue. Finally, the serum levels of the inflammatory biomarkers (tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) together with the histopathological examination of sections in the rat hind paw were recorded.

Results: Both NIC and DIC proved promising anti-arthritic potential mediated, at least in part through switching off TLR4-MyD88-TRAF6 axis as well as downstream TRAF6 dependent activated MAP kinases and NF-κB.

Conclusion And Implications: Nicorandil, via interfering with TLR4 signaling, sheds light on a potential clinical role of the drug in pursuit for safe and effective regimens for RA.
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http://dx.doi.org/10.1016/j.lfs.2019.01.002DOI Listing
February 2019

Activation of α7 Nicotinic Acetylcholine Receptor Ameliorates Zymosan-Induced Acute Kidney Injury in BALB/c Mice.

Sci Rep 2018 11 14;8(1):16814. Epub 2018 Nov 14.

Department of Pharmacology & Toxicology, Faculty of Pharmacy, Cairo University, Giza, Egypt.

Zymosan, a natural compound, provokes acute peritonitis and multiple organ dysfunction that affects the kidney, beside other organs via exaggerated inflammatory response. The aim of the present study is to test the role of cholinergic anti-inflammatory pathway (CAP) in alleviating acute kidney injury (AKI) induced by zymosan in BALB/c mice, using galantamine, a cholinesterase inhibitor, known to act via α7 nicotinic acetylcholine receptor (α7 nAChR) to stimulate CAP. Galantamine verified its anti-inflammatory effect by elevating acetylcholine (ACh) level, while abating the interleukin-6/ janus kinase 2 (Y1007/1008)/ signal transducer and activator of transcription 3 (Y705) (IL-6/ pY(1007/1008)-JAK2/ pY705-STAT3) inflammatory axis, with a consequent inhibition in suppressor of cytokine signaling 3 (SOCS3). This effect entails also the nuclear factor-kappa B (p65)/ high mobility group box protein-1/ (NF-κB (p65)/ HMGB-1) signaling pathway. Furthermore, the reno-curattive effect of galantamine was associated by a reduction in plasma creatinine (Cr), cystatin (Cys)-C, IL-18, and renal neutrophil gelatinase-associated lipocalin (NGAL), as well as an improved histopathological structure. Blocking the α7 nAChR by methyllycaconitine abolished the beneficial effect of galantamine to document the involvement of this receptor and the CAP in the amelioration of AKI induced by zymosan.
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http://dx.doi.org/10.1038/s41598-018-35254-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235888PMC
November 2018

Design, synthesis, and screening of ortho-amino thiophene carboxamide derivatives on hepatocellular carcinomaas VEGFR-2Inhibitors.

J Enzyme Inhib Med Chem 2018 Dec;33(1):1472-1493

f Department of Radiation Biology , National Center for Radiation Research and Technology , Cairo , Egypt.

In this work, design, synthesis, and screening of thiophene carboxamides 4-13 and 16-23 as dual vascular endothelial growth factor receptors (VEGFRs) and mitotic inhibitors was reported. All compounds were screened against two gastrointestinal solid cancer cells, HepG-2 and HCT-116 cell lines. The most active cytotoxic derivatives 5 and 21 displayed 2.3- and 1.7-fold higher cytotoxicity than Sorafenib against HepG-2 cells. Cell cycle and apoptosis analyses for compounds 5 and 21 showed cells accumulation in the sub-G1 phase, and cell cycle arrest at G2/M phase. The apoptotic inducing activities of compounds 5 and 21were correlated to the elevation of p53, increase in Bax/Bcl-2 ratio, and increase in caspase-3/7.Compounds 5 and 21 showed potent inhibition againstVEGFR-2 (IC = 0.59 and 1.29 μM) and β-tubulin polymerization (73% and 86% inhibition at their IC values).Molecular docking was performed with VEGFR-2 and tubulin binding sites to explain the displayed inhibitory activities.
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http://dx.doi.org/10.1080/14756366.2018.1503654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6136361PMC
December 2018

Role of Wnt4/β-catenin, Ang II/TGFβ, ACE2, NF-κB, and IL-18 in attenuating renal ischemia/reperfusion-induced injury in rats treated with Vit D and pioglitazone.

Eur J Pharmacol 2018 Jul 30;831:68-76. Epub 2018 Apr 30.

Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Egypt.

Renal ischemia-reperfusion injury (I/RI) remains a critical clinical situation. Several evidence revealed the potential reno-protective effects of Vitamin D and/or pioglitazone, on renal I/RI. This study addresses the possible involvement of the Wnt4/β-catenin signaling, p-S536NF-κBp65, PPARγ, Ang II/TGF-β, and ACE2 as potential effectors to vitamin D and pioglitazone-mediated renoprotective effects. Two sets of Sprague-Dawley rats (n = 30 rat each), were randomized into sham, I/R, Vit D "alfacalcidol" (5 ng/kg/day), pioglitazone (5 mg/kg/day), and Vit D + pioglitazone groups. In all groups renal biochemical parameters, as well as inflammatory and structural profiles were assessed, besides the expression/contents of Wnt4/β-catenin and pS536-NF-κBp65. All treatments started 7 days before I/RI and animals were killed 24 h after I/RI in the first set, while those in the 2nd set continued their treatments for 14 days. After 24 h, all pre-treatments impeded theI/R effect on neutrophils recruitment, p-S536NF-κBp65, IL-18, NGAL, caspase-3, AngII, ACE-2, PPARγ and TGF-β, besides the expression of Wnt4 and ACE-2 with notable reflection on histological changes. Two weeks after I/RI, except a marked up regulation in Wnt4 expression and a striking elevation in the β-catenin content, the magnitude of the injurious events was relatively less pronounced, an effect that was mostly augmented by the different treatments. The current study pledges a promising and novel reno-protective role of the administration of Vit D and pioglitazone entailing a potential involvement of ICAM-1, MPO, NF-κB, Ang II, ACE2, TGFβ, and a modulation of Wnt4/β-catenin pathway.
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http://dx.doi.org/10.1016/j.ejphar.2018.04.032DOI Listing
July 2018

Development and Pre-Clinical Evaluation of Recombinant Human Myelin Basic Protein Nano Therapeutic Vaccine in Experimental Autoimmune Encephalomyelitis Mice Animal Model.

Sci Rep 2017 04 20;7:46468. Epub 2017 Apr 20.

AgRresearch, Ruakura Research Centre, Hamilton, New Zealand.

Recombinant human myelin basic protein (rhMBP) was previously produced in the milk of transgenic cows. Differences in molecular recognition of either hMBP or rhMBP by surface-immobilized anti-hMBP antibodies were demonstrated. This indicated differences in immunological response between rhMBP and hMBP. Here, the activity of free and controlled release rhMBP poly(ε-caprolactone) nanoparticles (NPs), as a therapeutic vaccine against multiple sclerosis (MS) was demonstrated in experimental autoimmune encephalomyelitis (EAE) animal model. Following optimization of nanoformulation, discrete spherical, rough-surfaced rhMBP NPs with high entrapment efficiency and controlled release pattern were obtained. Results indicated that rhMBP was loaded into and electrostatically adsorbed onto the surface of NPs. Subcutaneous administration of free or rhMBP NPs before EAE-induction reduced the average behavioral score in EAE mice and showed only mild histological alterations and preservation of myelin sheath, with rhMBP NPs showing increased protection. Moreover, analysis of inflammatory cytokines (IFN-γ and IL-10) in mice brains revealed that pretreatment with free or rhMBP NPs significantly protected against induced inflammation.

In Conclusion: i) rhMBP ameliorated EAE symptoms in EAE animal model, ii) nanoformulation significantly enhanced efficacy of rhMBP as a therapeutic vaccine and iii) clinical investigations are required to demonstrate the activity of rhMBP NPs as a therapeutic vaccine for MS.
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http://dx.doi.org/10.1038/srep46468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5397842PMC
April 2017

Trigonelline and vildagliptin antidiabetic effect: improvement of insulin signalling pathway.

J Pharm Pharmacol 2017 Jul 8;69(7):856-864. Epub 2017 Mar 8.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.

Objectives: Trigonelline (TRG) is known to have an antidiabetic efficacy; however, its mechanism is not entirely elucidated.

Methods: Hence, its effect on insulin signaling, besides its effectiveness in combination with vildagliptin (VLD) in a Type 2 diabetes model has been tested.

Key Findings: TRG (50 mg/kg; p.o) lowered serum glucose, fructosamine, insulin, and HOMA-IR index and increased insulin sensitivity in soleus muscle via augmenting insulin receptor autophosphorylation (IR-PH), pT308-Akt, and glucose transporter 4 (GLUT4). Additionally, it reduced muscle advanced glycation end products and lipid peroxides with increased glutathione. TRG showed an anti-lipidemic effect lowering serum and/or muscle total cholesterol, triglycerides, and FFAs to decrease body weight, and visceral/epididymal indices. Furthermore, VLD (3 and 10 mg/kg, p.o) increased IR-PH, pT308-Akt, and GLUT4 to improve insulin signaling. The combined effect of TRG with the low dose of VLD was mostly confined to the reduction of the aberrant lipid profile.

Conclusions: The beneficial effect of TRG on insulin sensitivity and glucose/ lipid homeostasis is mediated by the enhancement of the insulin signaling and antioxidant property. Moreover, the positive impact of VLD on pT308-Akt is an integral part in insulin signaling, and hence its antidiabetic effect.
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http://dx.doi.org/10.1111/jphp.12713DOI Listing
July 2017

Evaluation of the relaxant effect of levetiracetam on isolated rat duodenum.

Fundam Clin Pharmacol 2017 Feb 5;31(1):75-82. Epub 2016 Oct 5.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt.

Levetiracetam (LEV) is an approved drug for the treatment of some epileptic disorders. With few and controversial reports addressing its possible pharmacodynamic interactions, the current study aimed at studying the effect of LEV on isolated rat duodenal strips to enlighten its possible intestinal adverse effects using the isolated smooth muscle strips of rat duodenum. LEV showed a dose-dependent inhibition in KCl (80 mm)-induced contractions in normal Tyrode's solution. Moreover, preincubation with LEV (3 mm) in K -rich/Ca -free medium led to a significant decrease in the maximum contractions (E ) coupled to a right shift of the cumulative CaCl concentration curves implying a possible Ca channel blocking potential. In addition, LEV exhibited a typical noncompetitive inhibition in the cumulative carbachol concentration curves evidenced as a decrease in E without the alteration of EC , thus eliminating any possible role of the muscarinic receptors in the relaxant effect. To rule out other possible relaxant mechanisms, tests were conveyed in Tyrode's solution containing either 100 μm l-NAME or 10 μm glimepiride to test the possible relaxant roles exhibited by nitric oxide (NO) and K channel opening, respectively. None of the tested pathways was involved in LEV-mediated relaxation. Taken altogether, the results of the current study entail that LEV might exert a relaxant effect on intestinal smooth muscles through blocking L-type voltage-operated calcium channels, but not involving either NO release or K channel opening.
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http://dx.doi.org/10.1111/fcp.12240DOI Listing
February 2017

Correlation of In Vivo and In Vitro Assay Results for Assessment of Free Radical Scavenging Activity of Green Tea Nutraceuticals.

J Food Sci 2016 Jul 8;81(7):C1707-15. Epub 2016 Jun 8.

Analytical Chemistry Dept., Faculty of Pharmacy, Cairo Univ, Egypt.

Green tea (GT)-derived catechins; epigallocatechin gallate (EGCG) in particular are commonly used nutraceuticals for their free-radical scavenging activity (FRSA). The influence of photodegradation on the protective power of GT nutracenticals against oxidative stress was thoroughly explored. Photodegradation of GT extracts was carried out and monitored using orthogonal stability-indicating testing protocol; in vitro and in vivo assays. Total polyphenol content (TPC) and FRSA were determined spectrophotometrically while EGCG was selectively monitored using SPE-HPLC. In vivo assessment of photodegraded samples was investigated via measuring a number of biomarkers for hepatic oxidative stress and apoptosis (caspase-3, inducible nitric oxide synthase, nitric oxide, mitogen-activated protein kinase, glutathione, thiobarbituric acid reactive substances, nuclear factor kappa beta, and nuclear factor erythroid 2-related factor) as well as liver damage (alanine transaminase and aspartate transaminase) in serum of rats previously subjected to oxidative stress. Results showed complete degradation of EGCG in photodegraded green tea samples with no correlation with either TPC or FRSA. On the other hand, in vivo assay results revealed not only loss of activity but formation of harmful pro-oxidants. Photostability was found crucial for the protective effect of GT extract against lead acetate insult. Results confirmed that careful design of quality control protocols requires correlation of chemical assays to bioassays to verify efficacy, stability, and most importantly safety of nutraceuticals.
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http://dx.doi.org/10.1111/1750-3841.13362DOI Listing
July 2016

Saxagliptin: a novel antiparkinsonian approach.

Neuropharmacology 2015 Feb;89:308-17

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.

The emergence of glucagon-like peptide-1 as a crucial contender in modifying neurodegenerative diseases in the preclinical studies has instigated interest in investigating the antiparkinsonian effect of dipeptidyl peptidase (DPP)-4 inhibition. Notably, saxagliptin (SAX), the DPP-4 inhibitor, recently showed efficacy in ameliorating streptozotocin-induced Alzheimer's disease; however, its effect on Parkinson's disease (PD) has not yet been elucidated. In a rat rotenone (ROT) model, SAX prominently improved motor performance as well as muscle coordination and corrected akinesia. Moreover, SAX preserved substantia nigra pars compacta tyrosine hydroxylase (TH) immunoreactivity while halting the reduction in the striatal TH, dopamine (DA) and complex I. Meanwhile, SAX prevented the ROT-induced increment of striatal DPP-4 and the decline in cAMP, ATP/ADP and brain-derived neurotropic factor levels. Improvement in striatal energy level was associated with partial hindrance of ROT-induced body weight reduction. In addition, through its anti-inflammatory potential, SAX decreased the ROT-induced nuclear factor-κΒ, inducible nitric oxide synthase, tumor necrosis factor-α, intracellular adhesion molecule-1 and myeloperoxidase. The antiapoptotic marker B-cell lymphoma-2 was enhanced by SAX, versus reduction in caspase-3 and its intrinsic apoptotic activator cytochrome C. Furthermore, SAX amended alterations induced by ROT in the thiobarbituric acid reactive substances and the transcriptional factor Nrf-2 level. In conclusion, SAX can be introduced as a novel approach for the management of PD based on the remarkable improvement in motor functions denoting antiparkinsonian efficacy via antioxidant, anti-inflammatory, antiapoptotic, neuroprotective and neurorestorative mechanisms. These effects were linked to DPP-4 inhibition, reduced neurodegeneration and enhanced DA synthesis.
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http://dx.doi.org/10.1016/j.neuropharm.2014.10.007DOI Listing
February 2015

Telmisartan attenuates colon inflammation, oxidative perturbations and apoptosis in a rat model of experimental inflammatory bowel disease.

PLoS One 2014 15;9(5):e97193. Epub 2014 May 15.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.

Accumulating evidence has indicated the implication of angiotensin II in the pathogenesis of inflammatory bowel diseases (IBD) via its proinflammatory features. Telmisartan (TLM) is an angiotensin II receptor antagonist with marked anti-inflammatory and antioxidant actions that mediated its cardio-, reno- and hepatoprotective actions. However, its impact on IBD has not been previously explored. Thus, we aimed to investigate the potential alleviating effects of TLM in tri-nitrobenezene sulphonic acid (TNBS)-induced colitis in rats. Pretreatment with TLM (10 mg/kg p.o.) attenuated the severity of colitis as evidenced by decrease of disease activity index (DAI), colon weight/length ratio, macroscopic damage, histopathological findings and leukocyte migration. TLM suppressed the inflammatory response via attenuation of tumor necrosis factor-α (TNF-α), prostaglandin E2 (PGE2) and myeloperoxidase (MPO) activity as a marker of neutrophil infiltration besides restoration of interleukin-10 (IL-10). TLM also suppressed mRNA and protein expression of nuclear factor kappa B (NF-κB) p65 and mRNA of cyclo-oxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) proinflammatory genes with concomitant upregulation of PPAR-γ. The alleviation of TLM to colon injury was also associated with inhibition of oxidative stress as evidenced by suppression of lipid peroxides and nitric oxide (NO) besides boosting glutathione (GSH), total anti-oxidant capacity (TAC) and the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx). With respect to apoptosis, TLM downregulated the increased mRNA, protein expression and activity of caspase-3. It also suppressed the elevation of cytochrome c and Bax mRNA besides the upregulation of Bcl-2. Together, these findings highlight evidences for the beneficial effects of TLM in IBD which are mediated through modulation of colonic inflammation, oxidative stress and apoptosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0097193PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4022743PMC
January 2015

Additional antiepileptic mechanisms of levetiracetam in lithium-pilocarpine treated rats.

PLoS One 2013 3;8(10):e76735. Epub 2013 Oct 3.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.

Several studies have addressed the antiepileptic mechanisms of levetiracetam (LEV); however, its effect on catecholamines and the inflammatory mediators that play a role in epilepsy remain elusive. In the current work, lithium (Li) pretreated animals were administered LEV (500 mg/kg i.p) 30 min before the induction of convulsions by pilocarpine (PIL). Li-PIL-induced seizures were accompanied by increased levels of hippocampal prostaglandin (PG) E2, myeloperoxidase (MPO), tumor necrosis factor-α, and interleukin-10. Moreover, it markedly elevated hippocampal lipid peroxides and nitric oxide levels, while it inhibited the glutathione content. Li-PIL also reduced hippocampal noradrenaline, as well as dopamine contents. Pretreatment with LEV protected against Li-PIL-induced seizures, where it suppressed the severity and delayed the onset of seizures in Li-PIL treated rats. Moreover, LEV reduced PGE2 and MPO, yet it did not affect the level of both cytokines in the hippocampus. LEV also normalized hippocampal noradrenaline, dopamine, glutathione, lipid peroxides, and nitric oxide contents. In conclusion, alongside its antioxidant property, LEV anticonvulsive effect involves catecholamines restoration, as well as inhibition of PGE2, MPO, and nitric oxide.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0076735PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3789684PMC
April 2014

Diverse effects of variant doses of dexamethasone in lithium-pilocarpine induced seizures in rats.

Can J Physiol Pharmacol 2012 Jan 15;90(1):13-21. Epub 2011 Dec 15.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El-Aini Str, 11562 Cairo, Egypt.

Corticosteroids are used in the management of several epileptic aliments; however, their effectiveness in combating seizures remains controversial, with pro- and anti-convulsive effects ascribed. The current study aimed to address the modulatory effect of dexamethasone (DEX) utilizing 3 dose levels (5, 10, and 20 mg/kg body mass of male Wistar rat) in the rat lithium-pilocarpine (Li-PIL) epilepsy model. Li-PIL induced seizures that were associated with neuronal cell loss in the CA3 region, and increased prostaglandin (PG)E(2), tumor necrosis factor (TNF)-α, interleukin (IL)-10, nitric oxide, and neutrophil infiltration in the hippocampus. However, Li-PIL compromised the oxidant-antioxidant balance of the hippocampus. Effective anticonvulsant activity was only observed with 10 mg DEX/kg body mass, which reduced seizure production and incidence, as well as neuronal cell loss in the CA3 region. At this anticonvulsant dose, enhancements in the antioxidant system and IL-10, as well as suppression of altered inflammatory markers were observed. Conversely, doubling the dose showed a tendency to shorten seizure latency, and neither affected seizure incidence nor CA3 neuronal cell loss. These effects were associated with an increase in levels of PGE(2) and TNF-α. The present study found a lack of protection at 5 mg DEX/kg body mass, an anticonvulsant effect at 10 mg/kg, and a loss of protection at 20 mg/kg in the Li-PIL epilepsy model, which indicates that there is an optimal dose of DEX for preventing the induction of seizures.
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http://dx.doi.org/10.1139/y11-096DOI Listing
January 2012