Glucocorticoid receptor activation selectively influence performance of Wistar rats in Y-maze.

Glucocorticoid receptors (GR) are ubiquitously expressed in metazoans. Different and contrasting phenotypes have been reported upon their activation. This study investigated the behavioral phenotypes characteristic of GR stimulation in male Wistar rats. Rats in each of the four groups of rats received one of the following treatments: distilled water (control) or one of three doses of dexamethasone (treatment) injected intraperitoneally for 7 days. The Rats were afterwards subjected to the Y maze, the elevated plus maze (EPM), the Morris water maze (MWM), and the novel object recognition (NOR) test. At the end of the study, the animals were anesthetized and neural activity from the prefrontal cortex recorded. Blood was collected via cardiac puncture to evaluate the levels of plasma insulin and glucose, and the prefrontal cortexes excised to determine the levels of insulin, markers of oxidative stress, and calcium in the homogenate. This study showed that treatment with dexamethasone significantly reduced the total and percentage alternation in the Y maze, but had no significant effect on object recognition in the NOR test, long-term and short-term spatial memory in the MWM, or anxiety-like behavior in the EPM. Plasma and brain insulin and calcium levels were elevated moderately following treatment with the lowest dose of dexamethasone. All doses of dexamethasone decreased brain superoxide dismutase and increased lactate dehydrogenase levels. No significant change in neural activity was observed. This study shows that activation of glucocorticoid receptors differentially affects different behavioral paradigms and provides evidence for a role for glucocorticoids in mediating insulin function in the brain.

Differential oxidative stress thresholds distinguishes cellular response to vascular occlusion and chemotoxicity in vivo.

BACKGROUND: A major effect of cyanide toxicity (CN) and vascular occlusion (VO) is the production of reactive oxygen species (ROS) linked with a defective energy coupling process in the mitochondria. In CN, oxygen is present but its conversion is blocked in the mitochondria (Complex V). By contrast, in VO, oxidative stress is induced via reduction of oxygen (blood) circulation to the occluded brain region. We hypothesize that differential oxygen concentration in both forms of ischemia affect ROS production rate in the mitochondria; thus distinguishing the cytotoxicity pattern for CN and VO. METHOD: Male, adult Wistar rats (N = 30) were separated into three groups. A set of n = 12 animals were treated with orally administered potassium ferricyanide. Global vascular occlusion (GVO) was induced in a second set of animals (n = 12) using neck cuffs to occlude the common carotid arteries and brachiocephalic vein. The control group (n = 6) received normal saline for the total duration of the treatment (10 days). Glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GPx), malondialdehyde (MDA) and acid phosphatase (ACP) levels were assayed in tissue homogenate using colorimetric assay techniques while Cathepsin D (CAD+) was demonstrated through antigen retrieval immunohistochemistry. Data were analyzed in One Way ANOVA with Tukey's post-hoc test. Significance was set p < 0.05. RESULTS/DISCUSSION: Cyanide treatment and VO caused a significant rise in SOD; attributed to ROS formation in both forms of ischemia. However, an increase in GSH levels demonstrates mitochondria-ROS production in cyanide treatment while no significant change in GSH was observed in VO versus the control (reduced mitochondria-ROS production). In addition, CN recorded a significant increase in GSH when compared with the control and VO (p < 0.001). The level of ROS was also proportional to the degree of lipid peroxidation (GPx) and autophagic cell response (ACP/CAD+). Ultimately, the lipid peroxidation/ROS effect was more significant in CN than VO. CONCLUSION: Although CN and VO induced oxidative stress through ROS production, our findings suggest a difference in the threshold of ROS production and cytotoxicity for both forms of ischemia. However, this threshold is dependent on the availability of oxygen to fuel mitochondria-ROS production in oxidative stress. Ultimately, the difference in oxygen availability in vivo determined the significance of lipid peroxidation, calcium-shift and autophagic cell response associated with the ischemia. CN treatment generated more ROS and was associated with prominent cellular changes when compared with VO.

Hepatoprotective and Pancreatoprotective Properties of the Ethanolic Extract of Nigerian Propolis.

OBJECTIVE: Increased oxidative stress is associated with the progression of diabetic mellitus. In the present study, we investigated the effects of the ethanolic extract of Nigerian propolis (N. propolis) on markers of oxidative stress, histology of the liver and pancreas and glycaemia in alloxan-induced diabetic rats. MATERIALS AND METHODS: Alloxan-induced hyperglycemic Wistar rats were treated with either metformin (150 mg/kg/d) or N. propolis (200 mg/kg/d and 300 mg/kg/d) for 28 days. At the end of the treatment period, the rats were sacrificed; blood was collected for biochemical analysis while their pancreases and liver were excised and processed for histological studies. RESULTS: Serum oxidative stress markers and blood glucose concentration were compared between the treated and control rats. In contrast to the non-treated diabetic rats, blood glucose concentration were not significantly different between treated rats and control (P < 0.05) at 28 days of treatment with N. propolis and metformin. Serum malondialdehyde levels was reduced while superoxide dismutase levels were elevated in the N. propolis group; these levels were converse in the diabetic group, these differences are statistically significant (P<0.05) when compared with the control. Histologically, there was improvement in the treated group compared to the untreated group. CONCLUSION: These findings suggest that the N. propolis confers protection against hyperglycemia-induced oxidative stress in both liver and pancreas of adult Wistar rats.

-NMDA R/+VDR pharmacological phenotype as a novel therapeutic target in relieving motor-cognitive impairments in Parkinsonism.

BACKGROUND: Parkinsonism describes Parkinson's disease and other associated degenerative changes in the brain resulting in movement disorders. The motor cortex, extrapyramidal tracts and nigrostriatal tract are brain regions forming part of the motor neural system and are primary targets for drug or chemotoxins induced Parkinsonism. The cause of Parkinsonism has been described as wide and elusive, however, environmental toxins and drugs accounts for large percentage of spontaneous cases in humans. A common mechanism in the cause and progression of drug/chemotoxin induced Parkinsonism involves calcium signalling in; oxidative stress, autophagy, cytoskeletal instability and excitotoxicity . AIM: This study sets to investigate the effect of targeting calcium controlling receptors, specifically activation of Vitamin D3 receptor (VDR) and inhibition of N-Methyl-D-Aspartate Receptor (NMDAR) in the motor cortex of mice model of drug induced Parkinsonism. Also we demonstrated how these interventions improved neural activity, cytoskeleton, glia/neuron count and motor-cognitive functions in vivo. METHODS: Adult mice were separated into six groups of n = 5 animals each. Body weight (5 mg/kg) of haloperidol was administered intraperitoneally for 7 days to block dopaminergic D2 receptors and induce degeneration in the motor cortex following which an intervention of VDR agonist (VDRA), and (or) NMDAR inhibitor was administered for 7 days. A set of control animals received normal saline while a separate group of control animals received the combined intervention of VDRA and NMDAR inhibitor without prior treatment with haloperidol. Behavioral tests for motor and cognitive functions were carried out at the end of the treatment and intervention periods. Subsequently, neural activity in the motor cortex was recorded in vivo using unilateral wire electrodes. We also employed immunohistochemistry to demonstrate neuron, glia, neurofilament and proliferation in the motor cortex after haloperidol treatment and the intervention. RESULT/DISCUSSION: We observed a decline in motor function and memory index in the haloperidol treatment group when compared with the control. Similarly, there was a decline in neural activity in the motor cortex (a reduced depolarization peak frequency). General cell loss (neuron and glia) and depletion of neurofilament were characteristic anatomical changes seen in the motor cortex of this group. However, Vitamin D3 intervention facilitated an improvement in motor-cognitive function, neural activity, glia/neuron survival and neurofilament expression. NMDAR inhibition and the combined intervention improved motor-cognitive functions but not as significant as values observed in VDRA intervention. Interestingly, animals treated with the combined intervention without prior haloperidol treatment showed a decline in motor function and neural activity. CONCLUSION: Our findings suggest that calcium mediated toxicity is primary to the cause and progression of Parkinsonism and targeting receptors that primarily modulates calcium reduces the morphological and behavioral deficits in drug induced Parkinsonism. VDR activation was more effective than NMDAR inhibition and a combined intervention. We conclude that targeting VDR is key for controlling calcium toxicity in drug/chemotoxin induced Parkinsonism.

Cerebrovascular changes in the rat brain in two models of ischemia.

BACKGROUND: Vascular occlusion and cyanide neurotoxicity induces oxidative stress and degeneration in the brain. This oxidant induced stress changes the vascular dynamics of cerebral blood vessels, and participates in homeostatic response mechanisms which balance oxygen supply to hypoxic stress-sensitive neurons. The associated changes in vascular morphology include remodeling of the microvasculature and endothelial changes, alterations in regional circulation and variations in the blood brain barrier (BBB). This study compares alterations in physiology of the cerebral artery after a short-term oxidative stress induced by cyanide toxicity and vascular occlusion. METHOD: Adult Wistar rats (N=30) were divided into three groups; vascular occlusion (VO) (n=12), potassium cyanide administration (CN) (n=12) and Control-CO (n=6). The CN rates were treated with 30mg/kg of orally administered KCN while the VO was subjected to global vascular occlusion, both for a duration of 10 days, described as the treatment phase. Control animals were fed on normal rat chow and water for 10 days. At the end of the treatment phase, n=6 animals in each of the VO, CN and VO groups were anesthetized with sodium pentobarbital (50IP) and the CCA exposed, after which pin electrodes were implanted to record the spikes form the tunica media of the CCA. After day 10, treatment was discontinued for these animals, each remaining in the VO and CN groups (VO-I and CN-I) until day 20 (withdrawal phase) following which the spikes were recorded using the procedure described above. RESULTS/DISCUSSION: Vascular occlusion and cyanide toxicity increased vascular resistance in the MCA (reduced lumen thickness ratio) and increased the diameter of the CCA after the treatment phase of 10 days. After 10 days of withdrawal, the VO group showed a reduction in resistance and an increase in the lumen width/wall thickness ratio (LWR) while the CN group showed increased resistance and a reduction in LWR. CONCLUSION: Cyanide toxicity increased vascular resistance by inducing degenerative changes in the wall of the artery while vascular occlusion increased resistance through mechanical stress and increased thickness of arterial wall. After the withdrawal phase, vascular resistance diminished in the VO to a significantly greater extent than the CN.

Motor and memory function in rat models of cyanide toxicity and vascular occlusion induced ischemic injury.

Although oxidative stress is characteristic of global vascular occlusion and cyanide toxicity, the pattern of cerebral metabolism reconditioning and rate of progression or reversal of neural tissue damage differ for both forms of ischemia. Thus, it is important to compare cognitive and motor functions in both models of ischemia involving cyanide treatment (CN) and vascular occlusion (VO). Adult Wistar rats (N=30) were divided into three groups; VO (n=12), CN (n=12) and Control-CO (n=6). The CN was treated with 30mg/Kg of potassium cyanide (KCN); VO was subjected to global vascular occlusion-both for duration of 10 days. The control (CO) was fed on normal rat chow and water for the same duration. At day 10, the test and control groups (CN, VO and CO) were subjected to motor function tests (Table edge tests and Open Field Test) and memory function tests (Y-Maze and Novel object recognition) while the withdrawal groups CN-I and VO-I were subjected to the same set of tests at day 20 (the withdrawal phase). The results show that both cyanide toxicity and vascular occlusion caused a decline in motor and memory function when compared with the control. Also, the cyanide treatment produced a more rapid decline in these behavioral parameters when compared with the vascular occlusion during the treatment phase. After the withdrawal phase, cyanide treatment (CN-I) showed either an improvement or restoration of motor and memory function when compared to the CN and control. Withdrawal of vascular occlusion caused no improvement, and in some cases a decline in motor and memory function. In conclusion, cyanide toxicity caused a decline in motor and memory function after the treatment while vascular occlusion caused no significant decline in cognition and motor function at this time. After the withdrawal phase, the effect of cyanide toxicity was reduced and significant improvements were observed in the behavioral tests (motor and cognitive), while a decline in these functions were seen in the vascular occlusion group after this phase.