Neuroprotective effects of erythropoietin on Alzheimer's dementia model in rats.

BACKGROUND: Although Alzheimer's disease (AD) is the most common age-related neurodegenerative disease and characterized by memory impairment, only symptomatic treatments are available. OBJECTIVES: Because recombinant human erythropoietin (rhEPO) has various neuroprotective effects and improves cognitive function in animal models of neurodegenerative disorders, we investigated the therapeutic effects of rhEPO in an intracerebroventricular (ICV)-streptozotocin (STZ) animal model of sporadic-AD. MATERIAL AND METHODS: A total of 24 Sprague-Dawley adult rats were divided into 4 groups of naive control (n = 6), sham-operated (n = 6), ICV-STZ + saline (n = 6) and ICV-STZ + rhEPO (n = 6). Twelve rats with Alzheimer's disease, induced by STZ injection (3 mg/kg) into both lateral ventricles using a stereotaxic frame (bilaterally ICV-STZ), were divided into 2 groups 5 days after the STZ injection: one treated with rhEPO 5000 (IU/kg/day, i.p.) and the other with 0.9% NaCl (1 mL/kg/day, i.p.) for 2 weeks. The sham-operated rats received bilaterally ICV-0.9% NaCl. No surgical operation or treatment was given to the naive-control animals. On day 20, a passive avoidance learning (PAL) test was used followed by sacrification and removal of the brain tissue in all animals. Brain TNF-α and ChAT levels were determined, and neurons in the hippocampal CA1 and CA3 regions were counted by Cresyl violet staining. RESULTS: ICV-STZ was found to significantly shorten the latency time on the PAL, increase brain TNF-α level, and decrease brain ChAT activity and the number of neurons in the hippocampal CA1 and CA3 regions. On the other hand, rhEPO significantly attenuated all these detrimental effects induced by STZ. CONCLUSIONS: RhEPO treatment significantly prevented the ICV-STZ-induced memory deficit by attenuating the hippocampal neuronal loss, neuroinflammation and cholinergic deficit in rats. This result suggests that rhEPO may be beneficial for treating AD.

Oxytocin provides protection against diabetic polyneuropathy in rats.

PURPOSE: The aim of the present study is to investigate the protective effects of oxytocin (OT) on diabetic neuropathy (DNP) in rats. MATERIALS AND METHODS: Eighteen rats were used to induce diabetes using single dose streptozotocin (STZ, 60 mg/kg). Diabetic DNP was verified by electromyography (EMG) and motor function test on 21st day following STZ injection. Six rats served as naïve control group and received no drug (n = 6). Following EMG, diabetic rats were randomly divided into three groups and administered with either 1 ml/kg saline or 80 µg/kg OT or 160 µg/kg OT intraperitoneally for four weeks. Then, EMG, motor function test, biochemical analysis (plasma lipid peroxides and glutathione), histological, and immunohistochemical analysis of sciatic nerves (bax, caspase 3, caspase 9, and NGF) were performed. RESULTS: Diabetic rats developed neuropathy, which was apparent from decreased compound muscle action potentials amplitudes and prolonged distal latency in saline-treated rats (p < 0.001) whereas 160 µg/kg OT significantly improved EMG findings. OT treatment significantly lessened the thickening of perineural fibrosis when compared with saline group (p < 0.001). Besides, OT significantly reduced plasma lipid peroxides (p < 0.05) and increased glutathione levels in diabetic rats (p < 0.001). The sciatic nerves of saline-treated rats showed considerable increase in bax, caspase 3 and caspase 8 expressions (p < 0.001) while OT treatment significantly suppressed these apoptosis markers. Also, OT improved NGF expression in diabetic rats compared to saline group. CONCLUSION: Present results demonstrate that OT appears to alleviate harmful effects of hyperglycemia on peripheral neurons by suppressing inflammation, oxidative stress and apoptotic pathways.

Detection of impaired cognitive function in rat with hepatosteatosis model and improving effect of GLP-1 analogs (exenatide) on cognitive function in hepatosteatosis.

The aims of the study were to evaluate (1) detection of cognitive function changing in rat with hepatosteatosis model and (2) evaluate the effect of GLP-1 analog (exenatide) on cognitive function in hepatosteatosis. In the study group, 30% fructose was given in nutrition water to perform hepatosteatosis for 8 weeks to 18 male rats. Six male rats were chosen as control group and had normal nutrition. Fructose nutrition group were stratified into 3 groups. In first group (n = 6), intracerebroventricular (ICV) infusion of exenatide (n = 6) was given. ICV infusion of NaCl (n = 6) was given to second group. And also, the third group had no treatment. And also, rats were evaluated for passive avoidance learning (PAL) and liver histopathology. Mean levels of latency time were statistically significantly decreased in rats with hepatosteatosis than those of normal rats (P < 0.00001). However, mean level of latency time in rats with hepatosteatosis treated with ICV exenatide was statistically significantly increased than that of rats treated with ICV NaCl (P < 0.001). Memory performance falls off in rats with hepatosteatosis feeding on fructose (decreased latency time). However, GLP-1 ameliorates cognitive functions (increased latency time) in rats with hepatosteatosis and releated metabolic syndrome.

The beneficial effects of levetiracetam on polyneuropathy in the early stage of sepsis in rats: electrophysiological and biochemical evidence.

ABSTRACT Critical illness polyneuropathy (CIP) is a common complication in long (≥1 week) critical/intensive care hospitalizations. Rapidly progressing atrophy and weakness of the limb, trunk and, particularly, respiratory muscles may lead to severe morbidity or mortality. The aim of the present study was to investigate the protective effects of levetiracetam (LEV) on CIP in the early stage of sepsis in rats. We simulated CIP by a surgically induced sepsis model and verified it by lower-limb electromyography (EMG) (amplitude and duration of CMAP, and distal latency). We evaluated the effects of various doses of LEV treatment (300, 600, and 1200 mg/kg i.p.) on CIP by performing electrophysiology, and determining plasma tumor necrosis factor (TNF)-α, lipid peroxides (malondialdehyde, MDA) levels, and total antioxidant capacity (TAC). Our data showed: (1) significant suppression of CMAP amplitude and prolongation of distal latency in the saline-treated sepsis group, and distal latency as well as CMAP amplitudes benefiting best from the 600 mg/kg LEV treatment; (2) significant rise in plasma TNF-α and MDA levels in the saline-treated sepsis group, but significant ameliorations by the 600 and 1200 mg/kg LEV treatment; (3) highly significant suppression of TAC in the saline-treated group, but profound reversals in all LEV-treated groups. We conclude that 300, 600, and 1200 mg/kg i.p. doses of post-septic treatment by LEV has possibly acted in a dose-dependent manner to both protect and restore the affected peripheral nerves' axon and myelin following surgical disturbance of the cecum to induce sepsis and consequent polyneuropathy.

Manganese-enhanced MRI to evaluate neurodegenerative changes in a rat model of kainic acid-induced excitotoxicity.

PURPOSE: Manganese-enhanced magnetic resonance imaging (MEMRI) has been used to detect brain activity based on the ability of active neurons to take up manganese ions through calcium channels. Kainic acid (KA), an analog of excitotoxic glutamate, can elicit selective neuronal death in the brains of rodents, of which the pathological changes partially mimic neurodegeneration in the central nervous system. We used in vivo MEMRI to evaluate neurodegenerative changes in an excitotoxicity model induced by KA in rats. MATERIALS AND METHODS: Adult Sprague-Dawley rats (220-250 g) were injected with either KA or saline into the right lateral ventricle. Precontrast and postcontrast MEMRI sessions were obtained. Region of interest (ROI) analyses were performed on both injected (saline and KA) and contralateral (normal) sites in the hippocampal area. All brains were evaluated histologically following MEMRI. RESULTS: Analysis of percentage change in ROI intensities of T1-weighted fluid-attenuated inversion-recovery MR images in the hippocampal area revealed a significant difference between the KA-injected (ipsilateral) and contralateral sites (P = 0.008), whereas no significant difference was observed between the saline-injected and contralateral sites. Furthermore, there was a significant difference between ipsilateral sites of the saline-treated and KA-treated groups (P = 0.026). The histological results supported these findings. CONCLUSION: MEMRI is a simple and useful in vivo method for detecting neurodegenerative changes due to excitotoxicity in the rat brain. The development of a manganese-based contrast agent that can be safely used in humans is warranted to investigate neurological disorders.

Oxytocin inhibits pentylentetrazol-induced seizures in the rat.

We aimed to reveal the anti-convulsant effects of oxytocin (OT) in pentylenetetrazol (PTZ)-induced seizures in rats. Thirty rats were randomly divided into 5 equal groups. Using stereotaxy, we implanted electroencephologram (EEG) electrodes in the left nucleus of the posterior thalamus. After 2 days, the first and second groups were used as the control and PTZ (35 mg/kg) groups, respectively. We administered 40, 80 and 160 nmol/kg OT+35 mg/kg PTZ to the rats, constituting the third, fourth, and fifth groups, respectively, for 5 days. At the end of 5 days, we recorded EEGs via bipolar EEG electrodes. After 12h, all groups except the first received 70 mg/kg PTZ and we determined the dose-response ratio. Racine's Convulsion Scale was used to evaluate seizures. The spike-wave complex percentage in the EEG was determined as 0% for the first group, 38.6%±7.2 for the second group, 36.4%±5.6 for the third group, 4.3%±1.8 for the fifth group and 4.1%±1.1 for the fifth group. The fourth and fifth groups had significantly decreased spike-wave complex percentages compared to the second group (p<0.0001). OT may prevent PTZ-induced epilepsy on an EEG. OT may also be considered for use in the treatment of epilepsy in the future.

Neuroprotective agents: is effective on toxicity in glial cells?

1. Glial cells are the most abundant cell population in the central nervous system. The aim of this study was to examine the effects of melatonin, 7-nitroindazole, and riluzole on glutamate toxicity in primary glial cell culture. 2. Glutamate toxicity was induced by addition of 100 microM glutamate to the cultures, and then 100 microM melatonin, 500 microM 7-nitroindazole, and 10 (M riluzole were administered in different groups. Lactate Dehydrogenase activity and nitrite levels were determined at the 1st, 6th, and 24th h. 3. Melatonin, 7-nitroindazole, and riluzole decrease Lactate Dehydrogenase activity at the 1st, 6th, and 24th h (at all hours, p<0.05). Nitrite levels were decreased by melatonin and riluzole at the 1st, 6th, and 24th h. 4. In this study, we observed that melatonin, 7-nitroindazole, and riluzole are effective as protective agents on glutamate toxicity in mixed glial cells.