Nazan Uysal

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.

The effects of regular aerobic exercise in adolescent period on hippocampal neuron density, apoptosis and spatial memory

It is known that positive effects of regular aerobic exercise on cognitive functions in humans and also animals; but how to the effects of aerobic exercise in adolescent period is unknown. The present study examined the effects of regular aerobic exercise on spatial memory using the Morris water maze, cell density and apoptosis of hippocampus in adolescent rats. Twenty-two days of age male rats were run on a treadmill for 30 min/session at a speed of 8m/min and 0 degrees slope, five times a week for 8 weeks. The present study showed that exercise induced significant cognitive improvement throughout brain maturation in rats. The number of hippocampal CA1 and CA3 neurons, and gyrus dentatus neurons were significantly increased in the exercised rats. There was no significant difference of CA2 neuron density between exercise and control groups. There was no significantly differences in any groups according to the results of apoptosis that account of TUNEL positive cells. The present results suggest that regular moderate aerobic treadmill exercise benefit in cognitive functions. This result may derive from treadmill exercise-induced increase cell density without altering of apoptosis in the hippocampus and dentate gyrus of adolescent rats.

Effect of Melatonin on Testicular Damage in Streptozotocin-Induced Diabetes Rats

Background: It is well known that diabetes mellitus is associated with impairment of testicular function. In the present study, we aimed to demonstrate the effect of melatonin on testicular damage in male rats with streptozotocin (STZ)-induced diabetes. Methods: Male Wistar rats were divided into 4 groups: (1) control group, (2) melatonin-treated nondiabetic group, (3) diabetic group and (4) melatonin-treated diabetic group. Diabetes was induced by STZ injection. Melatonin was administered intraperitoneally at the dose of 10 mg/kg for 5 days. Testicular damage was examined by using hematoxylin and eosin staining and periodic acid-Schiff staining, and apoptosis was determined by terminal-deoxynucleotidyl-transferase-mediated dUTP nick end labeling (TUNEL). Potential disorders associated with seminiferous tubular sperm formation were evaluated using the Johnsen score. Results: Diabetic rats showed a reduction in seminiferous tubule diameter, increased thickening of the basement membrane in seminiferous tubules and degenerated germ cells. TUNEL-positive cells were significantly more numerous in diabetic rats than in control rats. Melatonin significantly attenuated the diabetes-induced morphological changes and germ cell apoptosis in the diabetic rat testis. The number of polymorphonuclear leukocytes was significantly decreased in group 4 when compared to group 3. Conclusions: These results suggest that intraperitoneal administration of melatonin for 5 days is a potentially beneficial agent to reduce testicular damage in adult diabetic rats, probably by decreasing oxidative stress.

Methamphetamine causes lipid peroxidation and an increase in superoxide dismutase activity in the rat striatum.

The administration of methamphetamine to experimental animals results in damage to nigrostriatal dopaminergic neurons. In the present study, we demonstrated that both the acute repeated and the chronic administration of methamphetamine causes an increase in thiobarbituric acid reactive substances, which are indicators of lipid peroxidation, and superoxide dismutase activity in the rat striatum. The results of present study strengthen the notion that reactive oxygen species may play an important role in the methamphetamine-induced neurotoxicity.

Protective effect of melatonin against head trauma-induced hippocampal damage and spatial memory deficits in immature rats

It is well known that head trauma induces the cognitive dysfunction resulted from hippocampal damage. In the present study, we aimed to demonstrate the effect of melatonin on hippocampal damage and spatial memory deficits in 7-day-old rat pups subjected to contusion injury. Melatonin was injected intraperitoneally at the doses of 5 or 20 mg/kg of body weight immediately after induction of traumatic 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. Melatonin significantly attenuated trauma-induced neuronal death in hippocampal CA1, CA3 regions and dentate gyrus, and improved spatial memory deficits, which was equally effective at doses of 5-20 mg/kg. The present results suggest that melatonin is a highly promising agent for preventing the unfavorable outcomes of traumatic brain injury in young children.

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.

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.

Maternal treadmill exercise during pregnancy decreases anxiety and increases prefrontal cortex VEGF and BDNF levels of rat pups in early and late periods of life

In a previous study we demonstrated that, regular aerobic exercise during pregnancy decreased maternal deprivation induced anxiety. The purpose of this study is to investigate whether the positive effects of maternal exercise on the male and female offsprings early and late period of life. Half of the test subjects in each group were evaluated when they were 26 days old, and the other half were evaluated when they were 4 months old. The anxiety levels of maternally exercised groups were less than the control groups in both sexes and in both prepubertal and adult periods. The locomotor activity more increased in females. The prefrontal VEGF and BDNF levels were greater for both age groups and sexes in the maternally exercised group compared to control group. Moreover, there was a strong positive correlations between prefrontal cortex BDNF levels and results of open field tests; and VEGF levels and results of elevated plus maze tests. There was no difference in serum corticosterone levels between groups. These results indicate that maternal exercise during pregnancy may protect the pups from anxiety in early and late periods of life, and affects the prefrontal cortex positively.