Uğur Aksu

The effects of atorvastatin on memory deficit and seizure susceptibility in pentylentetrazole-kindled rats

Deficits in memory function have been observed in pentylentetrazole (PTZ)-kindled rats. In the present study we examined the effects of atorvastatin ((3-hydroxy-3-methylglutaryl-coenzyme A [HMG-CoA] reductase inhibitor) on PTZ kindling and related memory deficits in rats trained with the passive avoidance test. Subconvulsive PTZ doses rendered a gradual increase in seizure activity. PTZ kindling caused long-term memory to deteriorate. Atorvastatin per se and in PTZ-kindled rats improved learning and memory functions. It also prolonged latency (time to appearance of spike potentials) and diminished the amplitude and frequency of spike potentials, which indicate epileptic discharges. These novel findings suggest that the favorable effect of the atorvastatin on memory deficits provoked by PTZ kindling might be of clinical utility.

The effect of fluoxetine on ischemia–reperfusion after aortic surgery in a rat model

BACKGROUND Aortic ischemia-reperfusion (IR) is an important factor in the development of postoperative acute lung injury after abdominal aortic surgery. The aim of the present study was to examine the effect of fluoxetine (Flx), a selective serotonin reuptake inhibitor widely used as a preoperative anxiolytic, on lung injury induced by abdominal aortic IR in rats. METHODS Wistar rats were randomized into three groups (n = 7 per group): (1) control (sham laparotomy); (2) IR without Flx (60-min ischemia and 120-min reperfusion); (3) IR with Flx (Flx + IR) (Flx 20 mg/kg/d, intraperitoneally for 3 d before surgery). Lung tissue samples and bronchoalveolar lavage (BAL) were obtained for biochemical analysis of oxidative status. Ischemia-modified albumin (IMA) level and protein concentrations in BAL and lung wet to dry weight ratios were determined. Histologic evaluation of the lung tissues was also performed. RESULTS IR without Flx led to significant increase in lipid hydroperoxide, malondialdehyde, and pro-oxidant-antioxidant balance and decrease in superoxide dismutase, glutathione, and ferric reducing antioxidant power activities (P < 0.05 versus control), whereas Flx was able to restore these parameters (P > 0.05 versus control) and decrease IMA level (P < 0.01 versus control) and protein concentration (P < 0.05 versus control) in BAL and wet to dry lung weight ratio. Histologic evaluation showed that Flx attenuated the morphologic changes associated with lung injury. CONCLUSIONS The results indicate that Flx confers protection against aortic IR-induced lung oxidative stress and cellular integrity. IMA levels in BAL may be used as a follow-up marker for the efficacy of treatment in lung injury.

Effect of tempol on redox homeostasis and stress tolerance in mimetically aged Drosophila

We aimed to test our hypothesis that scavenging reactive oxygen species (ROS) with tempol, a membrane permeable antioxidant, affects the type and magnitude of oxidative damage and stress tolerance through mimetic aging process in Drosophila. Drosophila colonies were randomly divided into three groups: (1) no D-galactose, no tempol; (2) D-galactose without tempol; (3) D-galactose, but with tempol. Mimetic aging was induced by d-galactose administration. The tempol-administered flies received tempol at the concentration of 0.2% in addition to d-galactose. Thiobarbituric acid reacting substance (TBARS) concentrations, advanced oxidation protein products (AOPPs), Cu,Zn-superoxide dismutase (Cu,Zn-SOD), sialic acid (SA) were determined. Additionally, stress tolerances were tested. Mimetically aged group without tempol led to a significant decrease in tolerance to heat, cold, and starvation (P < 0.05), but tempol was used for these parameters. The Cu,Zn-SOD activity and SA concentrations were lower in both mimetically aged and tempol-administered Drosophila groups compared to control (P < 0.05), whereas there were no significantly difference between mimetically aged and tempol-administered groups. Mimetically aged group without tempol led to a significant increase in tissue TBARS and AOPPs concentrations (P < 0.05). Coadministration of tempol could prevent these alterations. Scavenging ROS using tempol also restores redox homeostasis in mimetically aged group. Tempol partly restores age-related oxidative injury and increases stress tolerance.

Unilateral Antegrade Cerebral Perfusion and Moderate Hypothermia: Assessing Safety With Novel Biomarkers

BACKGROUND Antegrade cerebral perfusion in aortic surgery is a well-established brain protection method. Open distal anastomosis during aortic surgery has some well-known advantages. Antegrade cerebral perfusion allows repair to some extent of the aortic arch, even in isolated ascending aortic aneurysm. The present study aims to investigate the adequacy of contralateral perfusion with novel oxidative stress parameters during unilateral antegrade cerebral perfusion. METHOD The study included 30 consecutive patients undergoing thoracic aortic surgery with unilateral antegrade cerebral perfusion (uACP) under moderate hypothermia (28° C). Blood samples from right and left jugular vein were obtained at four time intervals during surgery (after the anaesthetic induction - Phase 1, at the beginning of cardiopulmonary bypass - Phase 2, 15th minute of uACP - Phase 3 and after weaning from cardiopulmonary bypass - Phase 4). Novel oxidative stress parameters (advanced oxidation protein products, sialic acid, thiol reagents and ischaemia-modified serum albumin), blood gas analysis, and serum glucose and lactate levels were measured. In addition, intraoperative and early postoperative follow-up parameters were recorded. RESULTS Mean unilateral antegrade cerebral perfusion time was observed to be 16.4±5.9min (9 - 46min). No significant differences between right and left hemispheres were observed in novel oxidative parameters or biochemical values. There was only one temporary neurological deficit (3.3%) in the patient group. CONCLUSIONS The present study demonstrated that open distal anastomosis for hemiarch repair can be performed safely with unilateral antegrade cerebral perfusion under moderate hypothermia with both clinical outcome and novel biomarkers.

The effects of fluoxetine on circulating oxidative damage parameters in rats exposed to aortic ischemia–reperfusion

Oxidative stress and reperfusion injury may develop in different ischemia-reperfusion (IR) models. Growing evidence links altered lipid protein redox-homeostasis with IR. The effect of fluoxetine (FLX; N-methyl-3-[4-(trifluoromethyl) phenoxy] benzenepropanamine), on the lipid protein redox-homeostasis mechanisms in the rats exposed to aortic IR is unclear. We aimed to investigate the effects of FLX on circulating protein oxidation and lipid peroxidation parameters, such as ischemia modified albumin (IMA), lipid hydroperoxide (LOOH), prooxidant antioxidant balance (PAB), erythrocyte glutathione (GSH), CuZn-superoxide dismutase (CuZn-SOD), ferric reducing antioxidant power (FRAP), as potential IR biomarkers. Wistar rats were randomized into three groups (n=7/group): 1) Control (sham laparotomy); 2) IR without FLX, (60min ischemia and 120min reperfusion); 3) IR with FLX (FLX+IR) (FLX 20mg/kg/day, i.p. for three days before surgery). All of the aforementioned parameters (IMA, LOOH, PAB, GSH, CuZn-SOD, and FRAP) were measured spectrophotometrically. IMA, LOOH, and PAB levels in IR group were significantly higher than the control (P<0.01 respectively) and fluoxetine groups (P<0.01, P<0.01, and P<0.05 respectively), whereas CuZn-SOD activities, GSH and FRAP were significantly lower in IR groups. Fluoxetine group significantly reduced IMA when compared to IR group (P<0.001) and control group (P<0.01). With respect to IMA, LOOH and PAB, impaired redox homeostasis is substantially more prominent in aortic IR. The antidepressant FLX has profitable effects on circulating redox status in rats exposed to aortic IR. FLX administration before IR might decrease the surgery-enhanced free radical production; taken together, the antioxidant effects of FLX supplementation should be considered in future studies.

Gender and chronological age affect erythrocyte membrane oxidative indices in citrate phosphate dextrose adenine-formula 1 (CPDA-1) blood bank storage condition.

It is well known that in vitro storage lesions lead to membrane dysfunction and decreased number of functional erythrocytes. As erythrocytes get older, in storage media as well as in peripheral circulation, they undergo a variety of biochemical changes. In our study, the erythrocytes with different age groups in citrate phosphate dextrose adenine-formula 1 (CPDA-1) storage solution were used in order to investigate the possible effect of gender factor on oxidative damage. Oxidative damage biomarkers in erythrocyte membranes such as ferric reducing antioxidant power, pro-oxidant-antioxidant balance, protein-bound advance glycation end products, and sialic acid were analyzed. Current study reveals that change in membrane redox status during blood-bank storage condition also depends on both gender depended homeostatic factors and the presence of CPDA-1. During the storage period in CPDA-1, erythrocytes from the male donors are mostly affected by free radical-mediated oxidative stress but erythrocytes obtained from females are severely affected by glyoxidative stress.

Comparative Effects of Hemodilutional Anemia and Transfusion during Cardiopulmonary Bypass on Acute Kidney Injury: A Prospective Randomized Study

AIM Acute kidney injury after cardiopulmonary bypass has been associated with dilutional anemia during surgery. We aimed both to explore if this relation is modulated by blood transfusion and to understand the postoperative contribution of protein oxidation. METHODS In this randomized prospective study, after ethics committee approval and informed consent, 30 patients undergoing first-time elective coronary artery bypass grafting (CABG) with hematocrit between 21% and 25% at any time during extracorporeal circulation (ECC) were randomly and equally allocated into two groups. Group I consisted of patients who received red blood cells (RBC) during ECC, while in Group II, patients did not receive any RBCs. Besides routine hemodynamic and biochemical parameters, markers of renal injury such as neutrophil gelatinase-associated lipocalin (NGAL), creatinine clearance, and protein oxidation parameters (advanced oxidative protein products [AOPP], total thiol [T-SH]) were determined in both groups. RESULTS (1) Both cardiovascular parameters (MAP, HR) and the hospitalization period of the transfused group were not significantly different compared to the non-transfused group (P > .05); (2) While urine NGAL level (P < .05) increased and GFR (P < .01) decreased in the transfused group compared to the preoperative period, there were no significant changes in respective parameters of the non-transfused group compared to preoperative period; (3) AOPP concentrations did not change compared to postoperative periods in both groups (P > .05). However, T-SH concentration showed a transient increased at postoperative hour 6 (P < .001 vs preoperative period) but normalized at postoperative hour 24 (P > .05 versus preoperative period). CONCLUSION These findings suggest that a hematocrit value over 21% during ECC is safe for renal functions. RBC transfusion just to increase hematocrit may be deleterious.

Correction of dilutional anemia induces renal dysfunction in diabetic patients undergoing coronary artery bypass grafting: a consequence of microcirculatory alterations?

BackgroundIn this study we aimed to evaluate the effects of dilutional anemia resulting from cardiopulmonary bypass (CPB) and its correction with red blood cell (RBC) transfusion on tissue oxygenation and renal function in diabetic patients undergoing coronary artery bypass grafting (CABG).Method70 diabetic patients who underwent elective CABG and whose hematocrit values had been between 24–28% at any time during CBP were prospectively randomized and equally allocated to two groups: patients who received RBC during CPB (group I, n = 35) vs. did not receive RBC during CPB (group II, n = 35). Besides routine hemodynamic and biochemical parameters, biomarkers of ischemia and renal injury such as ischemia modified albumin (IMA), protein oxidation parameters [advanced oxidative protein products (AOPP), total thiol (T-SH)], neutrophil gelatinase-associated lipocalin (NGAL) and estimated glomerular filtration rate (eGFR) were measured in both groups.ResultsIn group I, T-SH, NGAL and urea levels were found to be significantly increased postoperatively compared to preoperative measurements (p < 0.05). Also, postoperatively, NGAL, creatinine, aspartate aminotransferase and AOPP levels were higher in group I than group II (p < 0.05).ConclusionThe correction of anemia with RBC transfusion in diabetic patients undergoing CABG could increase the risk of renal injury. Further studies verifying the effects of blood transfusions at the microcirculatory level are needed to optimize the efficacy of transfusions.

Evaluation of serum ischemia-modified albumin levels in anemia of prematurity

Abstract Purpose: Ischemia-modified albumin (IMA) is used to determine tissue hypoxia. We aimed to evaluate the serum IMA levels in preterm infants requiring transfusion due to anemia of prematurity, a clinical condition to cause tissue hypoxia. Materials and methods: This prospective study was performed in Etlik Zubeyde Hanim Hospital, Turkey. Preterm infants with birth weight less than 1500 g and born between 25 and 32 weeks were included during assessment for anemia of prematurity. The transfused infants with anemia of prematurity formed the “transfusion group”, the control group consisted of gender, gestational and postnatal age-matched infants without transfusion requirement. Serum samples of control group and pre-transfusion and post-transfusion samples of transfusion group were analyzed for IMA (ABS unit). Serum IMA levels were compared between control group and pre-transfusion samples of transfusion group and were also evaluated for the significance of change after transfusion. Results: Sixty-two infants were included (transfusion group: 31, control group: 31). The pretransfusion serum IMA levels were higher than that of infants in the control group [ABS unit; transfusion group; pre-transfusion: 1.00 (0.76–1.09) and control group: 0.81 (0.52?1.04); p = .03]. Serum IMA levels decreased significantly to 0.79 (0.59–0.95) after transfusion; p = .007. Infants with hematocrit higher than 30% had lower IMA levels [0.69 (0.54−0.96)] than infants with lower hematocrit [0.96 (0.75−1.05)]; p = .002. Conclusions: Clinicians may bear in mind that serum IMA levels could be utilized as a marker in deciding on erythrocyte transfusion in premature anemia.

Remote Myocardial Injury: The Protective Role of Fluoxetine

Aortic cross-clamping-induced ischemia-reperfusion (IR) is an important factor in the development of postoperative acute cardiac injury following abdominal aortic surgery. We investigated the possible anti-oxidant/anti-inflammatory effects of fluoxetine (FLX), which is used widely as a preoperative anxiolytic on cardiac injury induced by IR of the infrarenal abdominal aorta. FLX was administered to IR-performed (60 min of ischemia and 120 min of reperfusion) rats for 3 days, once daily at 20 mg/kg i.p. dosage. Results were compared to control and non-FLX-treated IR-performed rats. Serum creatine kinase (CK) and CK-MB levels, lipid hydroperoxide, thiobarbituric acid reactive substances, and pro-oxidant/anti-oxidant balance levels in the IR group were significantly higher whereas superoxide dismutase activity, glutathione, and ferric reducing/anti-oxidant power levels were lower than for the control. IR also increased myeloperoxidase activity, tumor necrosis factor-α, interleukin-1β, and interleukin-6 and decreased interleukin-10 levels. FLX decreased CK, CK-MB, lipid hydroperoxide, thiobarbituric acid reactive substances, and pro-oxidant/anti-oxidant balance levels while increasing superoxide dismutase activity, glutathione, and ferric reducing/anti-oxidant power levels. FLX also decreased myeloperoxidase activity, tumor necrosis factor-α, interleukin-1β, and interleukin-6 levels and increased interleukin-10 levels compared to IR. FLX attenuated the morphological changes associated with cardiac injury. Our study clearly demonstrates that FLX confers protection against aortic IR-induced cardiac injury, tissue leucocyte infiltration, and cellular integrity via its anti-oxidant/anti-inflammatory effects.