Dilek Taskiran

Sexually dimorphic cognitive style in rats emerges after puberty.

In a water maze (WM), rats employ different and sexually dimorphic behavioral strategies to solve a place-learning task, a test of cognitive/propositional ability. Puberty is the last step in brain development and marks an important phase with regard to sexually dimorphic cognitive performance and behavior. The present study assessed possible sex differences in cognitive style before and after puberty in a WM place-learning task. Since nitric oxide (NO) is implicated in spatial learning and hippocampal function, and since brain NO(-)(2) + NO(-)(3) levels (stable metabolites of NO) display region-specific sex differences in rat brain, NO(-)(2) + NO(-)(3) levels were determined after behavioral testing. The sex-related style difference emerged very clearly but only in the adult rats, which suggests that the female behavioral strategy in the WM place-learning task requires the presence of female sex hormones at puberty. Although NO(-)(2) + NO(-)(3) levels were higher in the adult rats and males compared to prepubertal and female rats, respectively, no significant correlations emerged between brain NO and behavior. The fact that the behavioral sexually dimorphic cognitive-style effect observed here and in previous studies appears to emerge only after puberty suggests that awareness of such postpubertal sex differences may also be important in human educational and therapeutic contexts.

Sex differences in nitrite/nitrate levels and antioxidant defense in rat brain.

THIS study assessed sex differences in stable metabolites of nitric oxide and major enzymes involved in antioxidant defense in various regions of rat brain. Nitrite/ nitrate levels and activities of superoxide dismutase and catalase were determined in cortex, hippocampus, corpus striatum, midbrain and cerebellum of adult male and female Sprague–Dawley rats. Nitrite/nitrate levels were significantly higher in the cortex and the hippocampus of male than female rats, while catalase activity was higher in the cortex of females than in males. These sex differences may have significant effects on brain function in health and disease.

Nicotine interacts with sex in affecting rat choice between “look-out” and “navigational” cognitive styles in the Morris water maze place learning task

The effect of sex and nicotine on cognitive style was examined in rats using a water maze task that allows differentiation between cognitive ability and style. During the 12-day acquisition period with the platform in the same location (either visible or hidden) there were no effects or interactions attributable to nicotine and sex, either in terms of learning rate or asymptotic latency. On the final test day the platform was visible and shifted in its location, and on the first trial the new location was proximal to the rats starting position, in contrast to the more distal location of the platform during the previous acquisition days. This platform relocation presented the rats with a choice between two competing cognitive styles: using local visual (look-out) cues vs. navigational cues. Performance on the test day yielded a nicotine x sex interaction, such that only saline-treated female rats showed a clear preference for the perceptual-proximal look-out cognitive style by swimming straight to the newly-relocated visible platform with mean escape latency that approximated the limits of swimming speed. The other three groups did not differ from each other, and preferred navigational cues. The results show that male and female rats use different strategies in problem solving, and that nicotine shifts the female pattern to that of the male.

Nicotine modulates nitric oxide in rat brain

Nicotine exerts its central actions by regulating cationic fluxes through nicotinic acetylcholine receptors (nAChRs). By this effect, the drug likely also modifies events occurring beyond the nAChR, including the regulation of nitric oxide (NO) synthesis. The present study was undertaken to assess the effects of acute and chronic nicotine administration (0.4 mg/kg, s.c.) on levels of NO(-)(2)+NO(-)(3), stable metabolites of NO, in brain regions of male and female rats. Nicotine increased levels of the metabolites, and therefore presumably of NO, with sex differences in the degree of stimulation, the brain regions affected, and the variance between the effects of acute and chronic administration. Prior inhibition of NO synthase eliminated the effect of nicotine in all regions studied. While nicotine appeared to increase NO indirectly via glutamate receptors in the cortex and hippocampus, this was not true of the corpus striatum, where blocking NMDA-type glutamate receptors with MK-801 had no effect. The findings support the view that NO is likely involved in some of the central effects of nicotine.

Serum and cerebrospinal fluid nitrite and nitrate levels in relapsing-remitting and secondary progressive multiple sclerosis patients

Nitric oxide (NO) has been implicated in immune mediated cellular cytotoxicity and inflammatory processes including multiple sclerosis (MS). We aimed to assess NO production in MS patients and to delineate its involvement in different stages. The stable end-products of NO; nitrite(NO2-) and nitrate(NO3-) were analysed both in serum and CSF (cerebrospinal fluid) of patients with MS and non-inflammatory neurological diseases. Nitrite levels were quantified by calorimetric assay based on the Griess reaction. Nitrate levels were examined spectrophotometrically. MS patients exhibited significantly increased serum and CSF levels of NO2-+NO3- compared with the control subjects. CSF NO2-+NO3- levels were raised significantly in MS patients with both relapsing remitting (RR) and secondary progressive (SP) course. There was no significant difference between RR and SP MS patients with regard to NO metabolites. No significant correlation was found between NO metabolites and disability score, disease progression index, MRI (magnetic resonance imaging) activity and development of cortical atrophy on MRI. This study provides further evidence for excessive NO production both in CSF and peripheral blood of MS patients. Excessive CSF NO2-+NO3- levels being more increased than the levels in sera supports pathological inflammatory process within CNS (central nervous system) in both stages of MS. Another implication for the role of NO and INOS inhibitors in the treatment of MS patients with both RR and SP courses was also suggested.

Effects of nitric oxide synthase inhibition on spatial discrimination learning and central DA2 and mACh receptors.

Cholinergic and dopaminergic systems are involved in spatial memory and are modulated by nitric oxide (NO); NO has well documented effects on place learning in rodents. The aim of the present study was to investigate the effect of NOS inhibition on place learning in the water maze and to evaluate the relationships between NOS inhibition, learning performance, dopamine (DA) D2 and muscarinic acetylcholine (mACh) receptors. Male Sprague-Dawley rats received the NOS inhibitor Nomega-Nitro-l-Arginine (l-NA), or saline and were trained in the water maze. Rats that were not trained, but received the same treatments were also included. Following treatments with or without water maze training, [3H]-QNB and [3H]-spiperone binding in cortex, striatum and hippocampus were determined to assess the effects of NOS inhibition and/or learning on DA D2 and mACh receptor regulation. The overall results of the present study showed that: (1) NOS inhibition impairs performance in the MWM; (2) NOS inhibition does not affect specific binding to DA D2 (striatum and hippocampus) and mACh (cortex and hippocampus) receptors; (3) MWM training lowers D2 and mACh receptor binding in cortical regions.

The Effects of Melatonin on the Antioxidant Systems in Experimental Spinal Injury

Melatonin has been recently shown by various in-vivo and in-vitro studies to exert potent neutralising effects on hydroxyl radicals, stimulate glutathione peroxidase (GSH-Px) activity, and protect catalase (CAT) from the destructive activity of hydroxyl radicals in neural tissue. We aimed to investigate the possible effects of pharmacological dose of melatonin on some of the antioxidant defence systems in an in-vivo study of experimental spinal injury. Seven groups of adult male Sprague Dawley rats were used in the following scheme: Group I: Naïve (n = 6), Group II: Lesion (n = 8), Group III: Melatonin (n = 5), Group IV: Melatonin + Lesion (n = 8), Group V: Placebo + Lesion (n = 5), Group VI: Sham operation (n = 5), and Group VII: Placebo (n = 5). Experimental spinal injury was induced at level T7-T8 by 5 sec compression of the total cord with an aneurism clip on anaesthetised and laminectomized animals. The total 10mg/kg dose of melatonin (Sigma) dissolved in alcohol-water was administered i.p. four times in 2.5 mg/kg doses, at 20min pre-, at the time of and at 1h and 2h post-compression. At 24±2h post-injury, the rats were euthanized and the lesioned segments of cord were dissected and homogenised with special care taken to distribute equal amount of injured tissue in each sample for analysis of reduced glutathione (GSH), oxidised glutathione (GSSG), superoxide dismutase (SOD), and CAT activity. Compression injury decreased GSH/GSSG ratio significantly (p <. 0001). Melatonin, by itself, significantly decreased GSSG content (p <. 05) and increased CAT activity (p <. 05) in the naive rats. Melatonin treatment decreased GSSG activity, thus elevating GSH/GSSG ratio, and also increased SOD and CAT activity without reaching statistical significance in the lesioned animals. In conclusion, pharmacological dose of systemically applied melatonin seemed to support some features of the antioxidant defence systems in our hands.

Increased Cerebrospinal Fluid and Serum Nitrite and Nitrate Levels in Amyotrophic Lateral Sclerosis

Abnormal glutamate metabolism is implied in the pathogenesis of Amyotrophic Lateral Sclerosis (ALS) and cerebrospinal fluid (CSF) glutamate levels appear to be elevated. Since nitric oxide (NO) inhibits glutamate transport, excessive amounts of nitrie oxide could underlie the glutamate induced neurotoxicity in ALS. Stable metabolites of NO (NO−2 + NO−3) levels were determined in serum and CSF of sporadic ALS patients and control subjects. NO−2 + NO−3 levels were higher in ALS, in males and in serum samples compared to controls, females and CSF, respectively. Furthermore, while the difference between serum and CSF NO−2 + NO−3 levels was significant in males (higher in serum) no such difference was observed in females. Our results suggest that nitrie oxide may be involved in the pathogenesis of ALS directly or indirectly and in a sexually dimorphic manner.

Comparison of melatonin and oxytocin in the prevention of critical illness polyneuropathy in rats with experimentally induced sepsis

BACKGROUND Critical illness polyneuropathy is an acute neuromuscular disorder of critically ill patients and is characterized by limb and respiratory muscle weakness. The purpose of the study was to evaluate the neuroprotective effects of melatonin (MEL) and oxytocin (OT) on the early stage of sepsis by recording compound muscle action potentials and measuring plasma tumor necrosis factor (TNF)-α levels, lipid peroxidation (malondialdehyde; MDA), and total antioxidant capacity. MATERIALS AND METHODS One hundred adult male Sprague-Dawley rats were included in the study. The cecal ligation and puncture (CLP) procedure was performed to induce the sepsis model. MEL (10, 20, and 40 mg/kg), OT (0.4, 0.8, and 1.6 mg/kg), and a combination of MEL (20 mg/kg) and OT (0.8 mg/kg) were administered intraperitoneally in the first hour of surgery. Electromyography (EMG) studies were achieved 24 h after CLP surgery and then blood samples were collected for biochemical measurements. RESULTS EMG findings revealed that compound muscle action potential amplitude was significantly decreased and distal latency was prolonged in the CLP group compared with the sham group (P < 0.05 and P < 0.0005). Moreover, the animals that received CLP surgery showed significantly higher TNF-α and MDA levels and lower total antioxidant capacity values than the sham group. The administration of MEL and OT to rats significantly abolished the EMG alterations and suppressed oxidative stress and TNF-α release in CLP-induced rats. CONCLUSIONS The inflammatory processes and imbalance in oxidative/antioxidative status play important roles in the pathogenesis of critical illness polyneuropathy. We suggest that both oxytocin and melatonin may have beneficial effects against sepsis-induced polyneuropathy in critical illness.

Exenatide reduces TNF-α expression and improves hippocampal neuron numbers and memory in streptozotocin treated rats.

Recent studies suggest a possible link between type 2 diabetes and Alzheimers disease (AD). Glucogan-like peptide 1 (GLP-1) facilitates insulin release from pancreas under hyperglycemic conditions. In addition to its metabolic effects, GLP-1 and its long-lasting analogs, including exenatide can stimulate neurogenesis and improve cognition in rodent AD model. The aim of the present study was to investigate the effects of exenatide on hippocampal cellularity, cognitive performance and inflammation response in a rat model of AD. Fourteen rats were used to create AD model using intracerebroventricular (ICV) streptozotocin (STZ) infusion while 7 rats were administered 0.9% NaCl only (sham-operated group). Following stereotaxic surgery, STZ received rats were randomly distributed into two groups, and treated with either saline or exenatide 20 µgr/kg/day through intraperitoneally for two weeks. Then, cognitive performance (passive avoidance learning), brain tumor necrosis factor alpha (TNF-α) levels, choline acetyltransferase (ChAT) activity and hippocampal neuronal count were determined. While the brain TNF-α levels were significantly high in the saline-treated STZ group, exenatide treatment suppressed the increase in TNF-α levels. Saline-treated STZ group showed reduced ChAT activity compared to sham group. However, exenatide significantly preserved brain ChAT activity. The cognitive performance was also impaired in saline group while exenatide improved memory in rats. Moreover, exenatide treatment significantly prevented the decrease in hippocampal neurons. Overall, the results of the present study clearly indicated exenatide might have beneficial effects on impaired cognitive performance and hippocampal neuronal viability in AD by suppressing the inflammation response and increasing cholinergic activity.