Abdulmecit Albayrak

Different Mechanisms in Formation and Prevention of Indomethacin-induced Gastric Ulcers

Indomethacin is an indol derivative, non-steroidal, anti-inflammatory drug with anti-inflammatory, analgesic, and antipyretic effects. Indomethacin became the first-choice drug to produce an experimental ulcer model as a result of having a higher ulcerogenic potential than other non-steroidal anti-inflammatory drugs (NSAIDs). There have been several conflicting reports about the ulcerogenic mechanism of indomethacin; the mechanism is still unclear. It has been suggested that indomethacin induces gastric damage via inhibiting the release of protective factors like cyclooxygenase-1 (COX-1), prostaglandin E2 (PGE2), bicarbonate, and mucus; increasing aggressive factors like acid; and increasing oxidant parameters while decreasing antioxidant parameters. Classic antiulcer drugs are known to produce antiulcer effects by activating against indomethacin (increasing PGE2, mucus, and bicarbonate production; inhibiting acid secretion; decreasing oxidant parameters; and increasing antioxidants). However, some antiulcer drugs have been shown to inhibit indomethacin-induced ulcers without affecting acid and mucus secretion or oxidant parameters, as well as to inhibit the production of protective factors like COX-1, PGE2, and bicarbonate, and to reduce antioxidant parameters. In order to resolve the contradictions in the abovementioned data, this review hypothesized a relationship between indomethacin-induced ulcers and α 2 adrenergic receptors. It is suggested that blockage of α 2 adrenergic receptors may be responsible for the increase in the aggressive factors induced by indomethacin, and stimulation of α 2 adrenergic receptors may be responsible for the increase of protective factors induced by antiulcer drugs.

Comparative study on the gastroprotective potential of some antidepressants in indomethacin-induced ulcer in rats

Clinical studies have shown that anxiolytic and antidepressant drug therapy benefits patients with ulcers. Many antidepressant drugs have been shown experimentally to produce antiulcer activity in various ulcer models. This study investigated the antiulcer activities of tianeptine, trazodone, and venlafaxine on indomethacin-induced ulcers in rats; and evaluated tianeptines effects on oxidant and antioxidant parameters in rat stomach tissue. The results show that trazodone and venlafaxine did not prevent indomethacin-induced ulcers. Tianeptine, however, decreased indomethacin-induced ulcers significantly at all doses used (6, 12, and 25 mg/kg). Famotidine, an H(2) receptor blocker, showed the highest antiulcer activity. Tianeptine significantly prevented the decrease in glutathione (GSH) content that occurred in the indomethacin-only groups damaged stomach tissues. All doses of tianeptine, but especially the 25 mg/kg dose, significantly decreased catalase (CAT) activity in stomach tissue, compared to the control. All doses of tianeptine eliminated the decrease in superoxide dismutase (SOD) activity in the stomach tissue of rats given indomethacin. Although all doses of tianeptine significantly decreased the malondialdehyde (MDA) content, all doses of tianeptine, except 6 mg/kg, decreased myeloperoxidase (MPO) activities significantly compared to the control. Our results indicate that activating enzymatic and non-enzymatic antioxidant mechanisms and inhibiting some toxic oxidant mechanisms play a role in tianeptines antiulcer effect mechanism.

Protective effects of erythropoietin on ischemia/reperfusion injury of rat ovary

OBJECTIVES To evaluate the effects of erythropoietin (EPO) as an antioxidant and tissue protective agent and study the biochemical and histopathological changes in experimental ischemia and ischemia/reperfusion (I/R) injury in rat ovaries. STUDY DESIGN 36 Adult female rats were used. The experimental groups were designed as Group 1: sham operation; Group 2: bilateral ovarian ischemia; and Group 3: 3 h period of ischemia followed by 3 h reperfusion. Group 4 rats were administered a 5000 IU dose of EPO, before 0.5 h of ischemia, and then bilateral ovarian ischemia was applied. After a 3 h period of ischemia, the bilateral ovaries were removed. In Group 5, a 3 h period of bilateral ovarian ischemia was applied. 2.5 h after the induction of ischemia, the rats were administered the same dose of EPO. At the end of a 3 h period of ischemia, 3h reperfusion was continued after the ovaries were removed. Group 6 underwent a sham operation after administration of 5000 IU/kg of EPO. After the experiments, superoxide dismutase (SOD), inducible nitric oxide synthase (iNOS), and myeloperoxidase (MPO) activity were determined, and histopathological changes were examined in all rat ovarian tissue. RESULTS Ischemia and ischemia/reperfusion increased the iNOS and MPO activity while decreasing the SOD activity significantly in comparison to the sham group. The 5000 IU/kg of EPO before ischemia and I/R reversed the trend in iNOS and MPO activities. The levels of SOD were decreased by the ischemia and I/R. The administration of EPO before ischemia and I/R treatments also reversed the trend in the SOD levels. In the ischemia/reperfusion plus EPO groups, though we observed minimal vascular dilation in the ovary stroma and some degenerative cell clusters, most of cellular structures did not show any pathological changes. CONCLUSIONS Administration of EPO is effective in reversing tissue damage induced by ischemia and/or ischemia/reperfusion in ovaries.

Protective effects of lithium: a new look at an old drug with potential antioxidative and anti-inflammatory effects in an animal model of sepsis.

Sepsis is the systemic response of an organism against microorganisms and toxins. Lithium is a therapeutic agent used for bipolar disorder and neurodegenerative disease, and it exerts pleiotropic effects on various cellular processes. The present study aimed to determine the effect of lithium on cecal ligation and puncture (CLP)-induced tissue injury in the lungs, by inhibiting the pro-inflammatory cytokine response, and the generation of reactive oxygen species (ROS) triggered by polymicrobial sepsis. Five groups of 20 rats each were used: 1) sham-operated control group; 2) CLP group; 3) 50mg/kg lithium-treated control healthy group; 4) 25 mg/kg lithium-treated CLP group; and 5) 50 mg/kg lithium-treated CLP group. A CLP polymicrobial sepsis model was applied to the rats. All rat groups were killed 16 h later, and lung and blood samples were analyzed histopathologically and biochemically. The 25 and 50 mg/kg of lithium decreased the level of interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and the tumor necrosis factor-α (TNF-α) in the serum, and the 8-iso-prostaglandin F2α (8-ISO) level in lung tissue. The lithium also increased the activity of superoxide dismutase (SOD) and the total levels of glutathione (GSH) in the lung tissues of rats. The histopathological scores and examinations were in accordance with the biochemical results, and revealed significant differences in the inflammation scores between the sepsis group and the other groups. The CLP+lithium 50mg/kg group had the lowest inflammation score among the CLP groups. Our results indicated that the therapeutic administration of lithium prevented oxidative stress changes and cytokine changes, and also protected vital tissues.

Boron containing poly-(lactide-co-glycolide) (PLGA) scaffolds for bone tissue engineering

Scaffold-based bone defect reconstructions still face many challenges due to their inadequate osteoinductive and osteoconductive properties. Various biocompatible and biodegradable scaffolds, combined with proper cell type and biochemical signal molecules, have attracted significant interest in hard tissue engineering approaches. In the present study, we have evaluated the effects of boron incorporation into poly-(lactide-co-glycolide-acid) (PLGA) scaffolds, with or without rat adipose-derived stem cells (rADSCs), on bone healing in vitro and in vivo. The results revealed that boron containing scaffolds increased in vitro proliferation, attachment and calcium mineralization of rADSCs. In addition, boron containing scaffold application resulted in increased bone regeneration by enhancing osteocalcin, VEGF and collagen type I protein levels in a femur defect model. Bone mineralization density (BMD) and computed tomography (CT) analysis proved that boron incorporated scaffold administration increased the healing rate of bone defects. Transplanting stem cells into boron containing scaffolds was found to further improve bone-related outcomes compared to control groups. Additional studies are highly warranted for the investigation of the mechanical properties of these scaffolds in order to address their potential use in clinics. The study proposes that boron serves as a promising innovative approach in manufacturing scaffold systems for functional bone tissue engineering.

Nigella Sativa Reduces Tissue Damage in Rat Ovaries Subjected to Torsion and Detorsion: Oxidative Stress, Proinflammatory Response and Histopathological Evaluation

Background: To evaluate biochemically and histopathologically the effects of Nigella sativa (NS) in experimental ischemia and ischemia/reperfusion (I/R) injury in rat ovaries. Methods: Thirty-six female rats were divided into 6 groups: group I = sham operation; group II = 500 mg/kg NS + sham operation; group III = bilateral ovarian ischemia; group IV = 500 mg/kg NS + ischemia; group V = 3-hour period of ischemia + 3-hour reperfusion, and group VI: 3-hour period of ischemia + 500 mg/kg NS 2.5 h after the induction of ischemia + 3-hour reperfusion. At the end of ischemia, the bilateral vascular clips were removed, and 3-hour reperfusion was continued. IL-1β, IL-6, and TNF-α cytokine levels in serum, and superoxide dismutase (SOD), myeloperoxidase (MPO), glutathione (GSH), and malondialdehyde (MDA) levels were determined. Results: I/R increased the MDA level and MPO activity while significantly decreasing the SOD activity and GSH level when compared to the sham. The 500-mg/kg dose of NS before I/R reversed the trend in MDA levels, MPO activity, SOD activity, and GSH levels. Ischemia and I/R increased the serum levels of IL-1β, IL-6, and TNF-α, while the administration of NS decreased the serum levels of these cytokines. Conclusions: The administration of NS is effective in reversing tissue damage induced by ischemia and/or I/R in ovaries.

Inflammation and peripheral 5-HT7 receptors: The role of 5-HT7 receptors in carrageenan induced inflammation in rats

The aim of this study was: (1) to investigate possible role for 5-HT7 receptors in carrageenan induced inflammatory paw oedema in rats; (2) to determine the presence of 5-HT7 receptors in rat paw tissue; (3) to observe the effects of 5-HT7 receptor agonist and antagonist administration on inflammation; and (4) to determine a unique mechanism for inflammatory processes via 5-HT7 receptors. Effects of 5-HT7 receptor agonist, antagonist and indomethacin were investigated in carrageenan induced paw oedema in rats. Blood and tissue samples were collected and evaluated biochemically for serum cytokine levels, tissue oxidant-antioxidant balance and histopathologically for inflammatory cell accumulation. We performed Real Time PCR analyses for tissue 5-HT7 receptor and COX mRNA expressions. The 5-HT7 receptor agonist AS-19 exerted significant anti-inflammatory effect both alone and in combination with indomethacin. Antagonist, SB269970, did not affect inflammation alone but decreased the effects of agonist when co-administered. 5-HT7 mRNA levels were higher in the carrageenan group than healthy control. Carrageenan+indometacin group decreased the mRNA expression of 5-HT7 when compared to carrageenan group. While agonist administration decreased 5-HT7 mRNA expression when compared to carrageenan group. Agonist decreased paw COX expression. Agonist also decreased serum cytokine levels and tissue oxidative stress. In conclusion, this study demonstrated for the first time that 5-HT7 receptors are expressed in rat paw tissue and that this expression responds to inflammatory stimuli. The 5-HT7 receptor may be a promising new therapeutic target for prevention of inflammation and inflammatory disorders and may also provide a new glimpse into inflammation pathophysiology.

Effect of Mirtazapine on Oxidative Stress Created in Rat Kidneys by Ischemia-Reperfusion

Abstract In this study, the effect of mirtazapine on rat kidneys versus ischemia-reperfusion (IR) damage was biochemically and histopathologically investigated. The results have shown that malondialdehyde (MDA) level of healthy rat group is 15.2 mol/g protein. The level of this substance was measured as 26.7 mol/g in only ischemia group. The MDA levels of IR and mirtazapine + renal ischemia-reperfusion (MRIR) groups were 39 ± 17.6 mol/g protein. While myeloperoxidase activity of healthy rat group was 20.2 u/g, the activities of only ischemia, IR, and MRIR groups were 28, 36.3, and 21 u/g, respectively. The glutathione levels were measured as 17.7, 12.8, 7.5, and 16.2 nmol/g in healthy, only ischemia, IR, and MRIR groups, respectively. Finally, glutathione S-transferase activities of healthy, only ischemia, IR, and MRIR groups were determined as 20, 13.8, 7.1, and 18.3 u/g, respectively. Histopathologically, while hemorrhage in interstitial area was observed in only ischemia group, significant tubular epithelial swelling, necrosis, and cast accumulation were seen in IR group. In MRIR group, only mild tubular epithelial swelling and mild hyaline cast accumulation were observed in kidney tissue. Consequently, it can be said that mirtazapine has a protective effect on IR-induced kidney damage.

The effect of alpha-lipoic acid in ovariectomy and inflammation-mediated osteoporosis on the skeletal status of rat bone

Osteoporosis is a high mortality and morbidity ranged skeletal disease and results in high costs of medical care in the European Union. We evaluated the possible protective effect of alpha-lipoic acid (ALA) on rat bone metabolism in ovariectomy and inflammation-mediated osteoporosis models. Groups were designed as: (1) sham; (2) sham+inflammation; (3) ovariectomy (OVX); (4) ovariectomy+ALA-25mg/kg; (5) ovariectomy+ALA-50mg/kg; (6) ovariectomy+inflammation; (7) ovariectomy+inflammation+ALA-25mg/kg; and (8) ovariectomy+inflammation+ALA-50mg/kg groups. OVX groups were allowed to recover for two months. Then, inflammation was induced in inflammation groups by subcutaneous talc injection. ALA-25mg/kg and 50mg/kg were administered to drug groups chronically. The skeletal response was assessed by bone mineral density (BMD), osteopontin and osteocalcin measurements. Pro-inflammatory cytokine measurements (interleukin (IL)-1 beta, interleukin-6, and tumor necrosis factor-alpha) were performed to observe inflammatory process. In OVX, INF and OVX+INF groups, BMD levels were lowest and osteocalcin, osteopontin, IL-1 beta, IL-6, and TNF-alpha levels were highest when compared to sham group. ALA administration increased BMD levels and decreased osteocalcin, osteopontin, IL-1 beta, IL-6, and TNF-alpha levels versus OVX and OVX+INF control groups. Both in senile and postmenopausal osteoporosis, the balance in coupling were destroyed on behalf of bone resorption. ALA had a protective effect on both senile and postmenopausal osteoporosis. The positive effect of this drug in these osteoporosis models might originate from its positive effects on bone turnover markers and cytokine levels. From this perspective, ALA may be a candidate for radical osteoporosis treatment both in senile and postmenopausal types clinically at the end of advanced studies.

Beneficial pharmacological effects of levosimendan on antioxidant status of acute inflammation induced in paw of rat: involvement in inflammatory mediators.

Levosimendan (LEVO) is a new calcium sensitizer with positive inotropic and vasodilating properties that represents a new pharmacological class of inotropic drugs that stimulate elevated cardiac output. The purpose of this study was to examine anti‐inflammatory effect and antioxidant activity of LEVO in a carrageenan (CAR)‐induced inflammatory paw oedema rat model. The CAR‐induced rat groups received LEVO 1, 2 and 3 mg/kg by intraperitonally and indomethacin (IND) 25 mg/kg by oral gavage. LEVO inhibited CAR‐induced paw oedema and suppressed the production of TNF‐α, IL‐1 and IL‐6 at doses of 2 and 3 mg/kg. In contrast to CAR‐injected paws, 2 and 3 mg/kg doses of LEVO and IND increased superoxide dismutase (SOD) activity and also both doses of LEVO, and IND decreased the 8‐isoprostaglandin F2α (8‐ISO) level. A 2 mg/kg dose of LEVO produced 39%, 46%, 61% and 64.7% anti‐inflammatory effects (p < 0.0001) for the 1st, 2nd, 3rd and 4th hours, respectively. Other results of our current study have shown that SOD and glutathione for CAR‐injected groups were lower, and 8‐ISO level was higher than those for the healthy rat group. LEVO may be provided as a pharmacological agent in the prevention or treatment of diseases in which acute or chronic inflammation occurs based on a pathogenic factor.