Muge Kiray

Erythropoietin improves long-term spatial memory deficits and brain injury following neonatal hypoxia-ischemia in rats

It is well known that neonatal hypoxic-ischemic brain injury leads to mental retardation and deficits in cognitive abilities such as learning and memory in human beings. The ameliorative effect of erythropoietin (Epo) on experimental hypoxic-ischemic brain injury in neonatal rats has been recently reported. However, the effect of Epo on cognitive abilities in the hypoxic-ischemic brain injury model is unknown. The aim of this study is to investigate the effects of Epo on learning-memory, behavior and neurodegeneration induced by hypoxia-ischemia. Seven days old Wistar Albino rat pups have been used in the study (n = 28). Experimental groups in the study were: (1) saline-treated hypoxia-ischemia group, (2) Epo-treated (i.p., 1000 U/kg) hypoxia-ischemia group, (3) sham-operated group, (4) control group. In hypoxia-ischemia groups, left common carotid artery was ligated permanently on the seventh postnatal day. Two hours after the procedure, hypoxia (92% nitrogen and 8% oxygen) was induced for 2.5 h. Epo was administered as a single dose immediately after the hypoxia period. When pups were 22 days old, learning experiments were performed using Morris water maze. On the 20th week, when brain development is accepted to be complete, learning experiments were repeated. Rats were then perfused and brains removed for macroscopic and microscopic evaluation. Epo treatment immediately after hypoxic-ischemic insult significantly improved long-term neurobehavioral achievements when tested during the subsequent phase of brain maturation and even into adulthood. Histopathological evaluation demonstrated that Epo also significantly diminished brain injury and spared hippocampal CA1 neurons. In conclusion, Epo administrated as a single dose immediately after neonatal hypoxic-ischemic insult provides benefit over a prolonged period in the still developing rat brain. Since the wide use of Epo in premature newborns, this agent may be potentially beneficial in treating asphyxial brain damage in the perinatal period.

Mesenchymal stem cells ameliorate the histopathological changes in a murine model of chronic asthma.

Asthma therapies are effective in reducing inflammation but airway remodeling is poorly responsive to these agents. New therapeutic options that have fewer side effects and reverse chronic changes in the lungs are essential. Mesenchymal stem cells (MSCs) are promising for the development of novel therapies in regenerative medicine. This study aimed to examine the efficacy of MSCs on lung histopathology in a murine model of chronic asthma. BALB/c mice were divided into four groups: Group 1 (control group, n=6), Group 2 (ovalbumin induced asthma only, n=10), Group 3 (ovalbumin induced asthma + MSCs, n=10), and Group 4 (MSCs only, n=10). Histological findings (basement membrane, epithelium, subepithelial smooth muscle thickness, numbers of goblet and mast cells) of the airways and MSC migration were evaluated by light, electron, and confocal microscopes. In Group 3, all early histopathological changes except epithelial thickness and all of the chronic changes were significantly ameliorated when compared with Group 2. Evaluation with confocal microscopy showed that no noteworthy amount of MSCs were present in the lung tissues of Group 4 while significant amount of MSCs was detected in Group 3. Serum NO levels in Group 3, were significantly lower than Group 2. The results of this study revealed that MSCs migrated to lung tissue and ameliorated bronchial asthma in murine model. Further studies are needed to evaluate the efficacy of MSCs for the treatment of asthma.

Effects of voluntary and involuntary exercise on cognitive functions, and VEGF and BDNF levels in adolescent rats

Abstract Regular treadmill running during adolescence improves learning and memory in rats. During adolescence, the baseline level of stress is thought to be greater than during other periods of life. We investigated the effects of voluntary and involuntary exercise on the prefrontal cortex and hippocampus, vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF) levels, and spatial learning, memory and anxiety in adolescent male and female rats. The voluntary exercise group was given free access to a running wheel for 6 weeks. The involuntary exercise group was forced to run on a treadmill for 30 min at 8 m/min 5 days/week for 6 weeks. Improved learning was demonstrated in both exercise groups compared to controls. Neuron density in the CA1 region of the hippocampus, dentate gyrus and prefrontal cortex were increased. Hippocampal VEGF and BDNF levels were increased in both exercise groups compared to controls. In females, anxiety and corticosterone levels were decreased; BDNF and VEGF levels were higher in the voluntary exercise group than in the involuntary exercise group. The adolescent hippocampus is affected favorably by regular exercise. Although no difference was found in anxiety levels as a result of involuntary exercise in males, females showed increased anxiety levels, and decreased VEGF and BDNF levels in the prefrontal cortex after involuntary exercise.

Relationship between circulating IGF-1 levels and traumatic brain injury-induced hippocampal damage and cognitive dysfunction in immature rats.

It is well known that traumatic brain injury (TBI) induces the cognitive dysfunction resulting from hippocampal damage. In the present study, we aimed to assess whether the circulating IGF-I levels are associated with cognition and hippocampal damage in 7-day-old rat pups subjected to contusion injury. Hippocampal damage was examined by cresyl violet staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. Spatial memory performance was assessed in the Morris water maze. Serum IGF-1 levels decreased in both early and late period of TBI. Decreased levels of serum IGF-1 were correlated with hippocampal neuron loss and spatial memory deficits. Circulating IGF-1 levels may be predictive of cognitive dysfunction resulted from hippocampal damage following traumatic injury in developing brain. Therapy strategies that increase circulating IGF-1 may be highly promising for preventing the unfavorable outcomes of traumatic damage in young children.

Protective effect of erythropoietin pretreatment in testicular ischemia-reperfusion injury in rats

BACKGROUND/PURPOSE This study was designed to investigate the effects of recombinant erythropoietin (EPO), a hormone widely used for treatment of uremic anemia, in rats subjected to testicular ischemia and reperfusion (I/R). METHODS Thirty-five male rats were divided into the following: control, sham operated, ischemia (I), I/R, and I/R + EPO groups. In the I group, 2 hours of left unilateral testicular torsion were performed, and in the I/R and I/R + EPO groups, an additional 2 hours of testicular detorsions were performed. The I/R + EPO group was pretreated intraperitoneally with EPO (500 IU/kg) before reperfusion. Testicular tissue samples were examined for biochemical and histopathologic parameters. Apoptotic cells in all testes were detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling technique and caspase 3 immunohistochemistry. RESULTS At histopathologic examination, ischemic changes in primary spermatocytes were noted in all torted testes. Cellular damage and apoptosis were more severe in ischemic groups than the EPO-pretreated group. There were statistically significant differences in tissue biochemical parameters in the I and I/R groups compared with the I/R + EPO group. CONCLUSIONS The results of the present study suggest that EPO exerts protective effects against I/R injury via the modulation of free radical scavengers activities, which decreases lipid peroxidation levels and attenuation of apoptosis.

Anxiety correlates to decreased blood and prefrontal cortex IGF-1 levels in streptozotocin induced diabetes

It is well known that diabetes mellitus may cause neuropsychiatric disorders such as anxiety disorders. Diabetes may also cause reduced IGF-1 (insulin like growth factor-1) levels in brain and blood. The purpose of the present study was to investigate the relationship between diabetes induced anxiety and IGF-1 levels in diabetic rats. The anxiety levels of rats were assessed 2 weeks after intraperitoneal injection of streptozotocin. Diabetic rats had higher levels of anxiety, as they spent more time in closed branches in elevated-plus-maze-test and less time in the center cells of open-field-arena. Prefrontal cortex (PFC) IGF-1 levels and neuron numbers were decreased and apoptosis was increased in diabetic rats. Blood IGF-1 levels decreased in a time dependent fashion following streptozotocin injection while blood corticosterone levels increased. They had higher malondialdehyde levels and lower superoxide dismutase enzyme activity. Oxidative stress may negatively affect blood and PFC tissue IGF-1 levels. Reduction in IGF-1 may cause PFC damage, which may eventually trigger anxiety in diabetic rats. Therapeutic strategies that increase blood and brain tissue IGF-1 levels may be promising to prevent psychiatric sequelae of diabetes mellitus.

Positive effects of deprenyl and estradiol on spatial memory and oxidant stress in aged female rat brains

Increasing age decreases spatial learning and memory. Spatial learning is coordinated with different brain regions. Since the oxidative damage may play a role in the aging process, including the associated cognitive decline, age-related impairment in spatial learning and memory may be alleviated by antioxidant treatment. The present study examined the effects of the monoamine oxidase B inhibitor L-deprenyl, alone and in combination with estradiol, on spatial memory using the Morris water maze and oxidant stress in aged female rat brains. We demonstrated that co-administration of deprenyl and estradiol caused a synergistic effect on spatial memory. However, use of either deprenyl or estradiol alone increased antioxidant enzyme activities in brain and reduced lipid peroxidation. Therefore, positive effects of deprenyl and estradiol on spatial memory may occur due not only to their antioxidant activities but also to the different actions.

CARNOSINE ATTENUATES OXIDATIVE STRESS AND APOPTOSIS IN TRANSIENT CEREBRAL ISCHEMIA IN RATS

Cerebral ischemia leads to cognitive decline and neuronal damage in the hippocampus. Reactive oxygen species (ROS) play an important role in the neuronal loss after cerebral ischemia and reperfusion injury. Carnosine has both antioxidant and neuroprotective effects against ROS. In the present study, the effects of carnosine on oxidative stress, apoptotic neuronal cell death and spatial memory following transient cerebral ischemia in rats were investigated. Transient ischemia was induced by occlusion of right common carotid artery of rats for 30 min and reperfusion for 24 h or 1 week. Rats received intraperitoneal injection of 250 mg/kg carnosine or saline 30 min prior to experiment. Determination of antioxidant enzyme activities was performed spectrophotometrically. To detect apoptotic cells, TUNEL staining was performed using an In Situ Cell Death Detection Kit. Carnosine treatment elicited a significant decrease in lipid peroxidation and increase in antioxidant enzyme activities in ischemic rat brains. The number of TUNEL-positive cells was decreased significantly in carnosine-treated group when compared with the ischemia-induction group. Carnosine treatment did not provide significant protection from ischemia induced deficits in spatial learning. The results show that carnosine is effective as a prophylactic treatment for brain tissue when it is administered before ischemia without affecting spatial memory.

Effects of Curcumin on Lung Histopathology and Fungal Burden in a Mouse Model of Chronic Asthma and Oropharyngeal Candidiasis

BACKGROUND AND AIMS Oropharyngeal candidiasis (OPC) is one of the most common local side effects of current therapy in chronic asthma. New therapeutic options with fewer side effects and reverse chronic changes are needed. Curcumin, as a promising antiinflammatory and antifungal agent, could be a candidate of alternative therapy in asthma. This study aimed to determine the efficacy of orally administrated curcumin on lung histopathology, serum nitric oxide levels and fungal burden in a murine model of asthma and OPC. METHODS Thirty five BALB/c mice were divided into five groups: I, II, III, IV (placebo) and V (control). All groups except the control were sensitized and challenged with ovalbumin. OPC model was established after the model of chronic asthma. Lung histology, serum nitric oxide levels and fungal burden were evaluated after 5 days of treatment with curcumin, dexamethasone, curcumin-dexamethasone combination and placebo. Evaluation of lung histology included subepithelial smooth muscle and epithelial thickness and number of goblet and mast cells by using light microscopy. RESULTS All histological parameters improved in curcumin group similar to dexamethasone group. Curcumin and dexamethasone-curcumin combination were also as effective as dexamethasone on decreasing nitric oxide levels. Oral fungal burden was significantly lower in curcumin-treated group than dexamethasone. CONCLUSIONS In our study we demonstrated that curcumin administration alleviates the pathological changes in asthma and decreases the fungal burden. Curcumin may have a potential effect on treating chronic asthma and decreasing the frequency of the OPC.

The effects of exposure to electromagnetic field on rat myocardium

Exposure to electromagnetic fields (EMFs) causes increased adverse effects on biological systems. The aim of this study was to investigate the effects of EMF on heart tissue by biochemical and histomorphological evaluations in EMF-exposed adult rats. In this study, 28 male Wistar rats weighing 200–250 g were used. The rats were divided into two groups: sham group (n = 14) and EMF group (n = 14). Rats in sham group were exposed to same conditions as the EMF group except the exposure to EMF. Rats in EMF group were exposed to a 50-Hz EMF of 3 mT for 4 h/day and 7 days/week for 2 months. After 2 months of exposure, rats were killed; the hearts were excised and evaluated. Determination of oxidative stress parameters was performed spectrophotometrically. To detect apoptotic cells, terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling (TUNEL) staining and caspase-3 immunohistochemistry were performed. In EMF-exposed group, levels of lipid peroxidation significantly increased and activities of superoxide dismutase and glutathione peroxidase decreased compared with sham group. The number of TUNEL-positive cells and caspase-3 immunoreactivity increased in EMF-exposed rats compared with sham. Under electron microscopy, there were mitochondrial degeneration, reduction in myofibrils, dilated sarcoplasmic reticulum and perinuclear vacuolization in EMF-exposed rats. In conclusion, the results show that the exposure to EMF causes oxidative stress, apoptosis and morphologic damage in myocardium of adult rats. The results of our study indicate that EMF-related changes in rat myocardium could be the result of increased oxidative stress. Further studies are needed to demonstrate whether the exposure to EMF can induce adverse effects on myocardium.