The effect of glycine on oxidative stress, inflammation and renin-angiotensin system in kidneys and aorta of cyclosporine-administered rats.

Cyclosporine A (CsA) is an immunosuppressive drug, used in organ transplantations. Oxidative stress, inflammation and renin-angiotensin system (RAS) activation play an important role in CsA-toxicity. Glycine (Gly) has antioxidant and anti-inflammatory effects. In this study, Gly was investigated for its protective role against CsA-induced toxicity. CsA (20 mg/kg/day; subcutaneously) was administered to rats along with Gly injection (250 or 1000 mg/kg; intraperitoneally) for 21 days. Renal function markers [serum urea and creatinine and urinary protein and kidney injury molecule levels and creatinine clearance values] together with histopathological examinations were performed. Oxidative stress (reactive oxygen species, thiobarbutiric acid reactive substances, advanced oxidation products of protein, glutathione, ferric reducing anti-oxidant power and 4-hydroxynonenal levels), and inflammation (myeloperoxidase activity) were determined in kidney tissue. The RAS system [angiotensin II (Ang II) levels, and mRNA expressions of angiotensin converting enzyme (ACE), angiotensin II type-I receptor (AT1R)] and NADPH-oxidase 4 (NOX4) were measured in kidney and aorta. CsA caused significant disturbances in renal function markers, increases in oxidative stress and inflammation parameters and renal damage. Serum angiotensin II levels and mRNA expressions of ACE, AT1R and NOX4 elevated in the aorta and kidney of CsA-rats. Gly, especially its high-dose, alleviated renal function markers, oxidative stress, inflammation and renal damage in CsA-rats. Moreover, serum Ang II levels and mRNA expressions of ACE, AT1R and NOX4 decreased significantly in aorta and kidney in CsA-rats due to Gly treatment. Our results indicate that Gly may be useful for the prevention of CsA-induced renal and vascular toxicity.

Investigation of the Protective Role of Selenium in the Changes Caused by Chlorpyrifos in Trace Elements, Biochemical and Hematological Parameters in Rats.

Organophosphate compounds are the most widely employed insecticides in countries with high agriculture activity. On average, organophosphates cause 3 million people to poison and 200 000 deaths per year due to food chain or occupational, accidental, or suicidal exposure. Our study aimed to research selenium's protective role against the toxic action of CPF, one of the most commonly used organophosphates, with an experimental model formed with rats. A total of 56 male SD rats were distributed into seven groups as follows: control (tap water), sham (corn oil), group I (5.4 mg/kg CPF), group II (13.5 mg/kg CPF), group III (3 mg/kg Se), group IV (5.4 mg/kg CPF+Se), and group V (13.5 mg/kg CPF+Se). Following 6 weeks of oral exposure, there were significant changes in AChE activity, biochemical and hematological parameters, and trace element levels in CPF-treated rats. In the high-dose CPF group, RBC values, Hb, and Hct decreased, and values of WBC, AST, ALT, ALP increased (p < 0.001) significantly compared to control, sham, and Se groups. While there was no significant change in zinc level, the copper and selenium levels were significantly higher in group IV than in control (p < 0.001) and sham (p < 0.05, p < 0.01, respectively) groups. Moreover, max. O.R.L. was found statistically more elevated in the high-dose CPF group compared to control, sham, and Se groups (p < 0.05, p < 0.05, and p < 0.01, respectively). All results indicated that Se is an antioxidant that reduces the toxic effects caused by CPF. Employing combinations of chlorpyrifos and selenium appeared greatly in restoring the harmful effects of CPF exposure.

Effects of tamoxifen and glutamate and glutamine levels in brain regions in repeated sleep deprivation-induced mania model in mice.

Protein kinase C inhibitor tamoxifen reduces symptoms of acute mania in bipolar patients and mania-like behaviors in animals. Memory impairment and altered levels of glutamate and glutamate/glutamine ratio have been reported in mania. Tamoxifen suppresses glutamate release which plays an important role in memory. The present study evaluated whether tamoxifen's activity participates in its antimanic efficacy in repeated sleep deprivation mania model. Mice were divided into control and 24-h sleep-deprived groups and were treated with vehicle or 1 mg/kg tamoxifen twice daily for 8 days. Sleep deprivation was repeated three times at intervals of 2 days. Square crossing and rearing were recorded as measures of locomotor activity. Memory and risk taking behavior were evaluated using novel object recognition and staircase tests, respectively. Glutamate and glutamine levels were measured in the frontal cortex and hippocampus. Behavioral tests were conducted 24 h after the second or immediately after the third sleep deprivations. Sleep deprivation increased locomotor activity and risk taking. Glutamate and glutamine levels and glutamate/glutamine ratio in the frontal cortex and hippocampus were unaffected. Locomotor hyperactivity was prevented by tamoxifen treatment. No change in the recognition index suggested lack of memory impairment in the model. These findings confirm the relevance of repeated sleep deprivation as a mania model and tamoxifen as an antimanic agent. However, future research is needed to further address lack of memory impairment in the model and lack of glutamatergic influence on the model and antimanic effect of tamoxifen.

Influence of hypercholesterolemia and hypertension on the integrity of the blood-brain barrier in rats.

Hypercholesterolemia and/or hypertension impair endothelial function in peripheral vasculature; however, their impact on endothelial cells of brain microvessels is unclear. We investigated the effects of hypercholesterolemia on the integrity of the blood-brain barrier (BBB) and the activity of astrocytes during N(omega)-nitro-L-arginine methyl ester (L-NAME) hypertension followed by angiotensin (ANG) II. We found significant decreases in superoxide dismutase levels with all treatments except ANG II and L-NAME plus ANG II, and in catalase concentrations except ANG II and cholesterol plus L-NAME. Nitric oxide (NO) concentrations were significantly decreased by L-NAME but significantly increased by cholesterol. L-NAME-stimulated plasma malondialdehyde (MDA), Ox-LDL, and cholesterol levels were significantly augmented by cholesterol. Glutathione (GSH) levels significantly decreased, while MDA, TNF-alpha, and Ox-LDL levels significantly increased in cholesterol and/or L-NAME. The increase in BBB permeability by acute hypertension in hypercholesterolemic hypertensive animals was less than that observed in chronically hypertensive animals. Brain vessels of L-NAME-treated animals showed a considerable loss of immunoreactivity for tight junction proteins, occludin, and ZO-1. Immunoreactivity for occludin and ZO-1 increased in cholesterol plus L-NAME and decreased in cholesterol. Glial fibrillary acidic protein (GFAP) immunoreactivity was seen in few astrocytes in the brain sections of L-NAME-treated animals, but increased in cholesterol plus L-NAME. Positive immunoreactivity for vascular endothelial growth factor (VEGF) was observed in cholesterol and cholesterol plus L-NAME plus ANG II. We suggest that hypercholesterolemia may affect BBB integrity through increasing the expression of tight junction proteins and GFAP and leading to the production of VEGF, at least partly, via increased NO, TNF-alpha, and catalase in hypertensive conditions.

Morphological and functional changes of blood-brain barrier in kindled rats with cortical dysplasia.

Cortical dysplasia (CD) is one of the major causes contributing to epileptogenesis associated with blood-brain-barrier (BBB) disturbances. The current study investigated the functional and ultrastructural changes of BBB in pentylenetetrazole (PTZ)-kindled rats with CD. Pregnant rats on E17 were exposed to 145 cGy of gamma-irradiation and offspring were used for experiments. The rats were given PTZ three times per week to induce kindling. The permeability of BBB was determined by using sodium fluorescein (NaFlu). Immunohistochemistry for occludin, GFAP and c-fos, western-blot analysis for occludin and electron microscopy for the ultrastructural alterations in BBB were performed. The brain level of NaFlu did not increase in rats with CD and/or kindling. Following administration of a convulsive dose of PTZ, a significant increase in BBB permeability was observed in kindled rats with CD. Occludin immunoreactivity and expression remained essentially unchanged in all groups. Slightly enhanced immunoreactivity for GFAP was observed in all groups except control. c-fos immunoreactivity in brain sections of kindled rats with CD displayed a striking increase by convulsive PTZ challenge. Tight junctions were ultrastructurally intact, whereas markedly increased number of pinocytotic vesicles was noted in brain endothelium of kindled rats with CD by convulsive dose of PTZ. The present study showed that epileptic seizures induced by convulsive PTZ challenge during kindling-mediated epileptogenesis in the presence of CD changed both functional and ultrastructural properties of the BBB and considerably enhanced transendothelial vesicular transport, while paracellular pathway was apparently not involved in this setting.

Long-term L-NAME treatment potentiates the blood-brain barrier disruption during pentylenetetrazole-induced seizures in rats.

We investigated whether the severity of blood-brain barrier disruption caused by pentylenetetrazole-induced seizures is modified by long-term nitric oxide synthase inhibition in rats. Rats were given N-omega-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, in drinking water for 4 weeks, and then treated with pentylenetetrazole to induce seizures. Damage to the blood-brain barrier was investigated using Evans blue dye extravasation. Serum nitric oxide concentration was decreased in L-NAME-treated rats (P<0.01). L-NAME and/or pentylenetetrazole treatments elevated systolic blood pressure of animals (P<0.01). L-NAME caused an increase in the mortality rate after pentylenetetrazole injection leading to the death of animals at about 15 min after the onset of the seizure. Pentylenetetrazole-induced seizures in rats treated with L-NAME caused a significant increase in Evans blue dye extravasation into cerebral cortex, diencephalon and cerebellum, as compared with seizures evoked by pentylenetetrazole injection to L-NAME-untreated rats (P<0.01). Data presented here suggest that the degree of blood-brain barrier disruption induced by seizures is more pronounced in long-term nitric oxide deficiency.

Effects of lipopolysaccharide on blood-brain barrier permeability during pentylenetetrazole-induced epileptic seizures in rats.

We investigated the effects of lipopolysachharide (LPS) on functional and structural properties of the blood-brain barrier (BBB) during pentylenetetrazole (PTZ)-induced epileptic seizures in rats. Arterial blood pressure was significantly elevated during epileptic seizures irrespective of LPS pretreatment. Plasma levels of interleukin (IL)-1, interleukin (IL)-6, nitric oxide (NO) and malondialdehyde (MDA) increased while catalase concentrations decreased in animals treated with LPS, PTZ and LPS plus PTZ. The significantly increased BBB permeability to Evans blue (EB) dye in the cerebral cortex, diencephalon and cerebellum regions of rats by PTZ-induced seizures was markedly reduced upon LPS pretreatment. Immunoreactivity for tight junction proteins, zonula occludens-1 and occludin, did not change in brain vessels of animals treated with PTZ and LPS plus PTZ. Glial fibrillary acidic protein immunoreactivity was increased in LPS, but not in PTZ and LPS plus PTZ. These results indicate that LPS pretreatment reduces the passage of EB dye bound to albumin into the brain, at least partly, by increasing plasma NO and IL-6 levels during PTZ-induced epileptic seizures. We suggest that LPS may provide protective effects on the BBB integrity during epileptic seizures through transcellular pathway, since the paracellular route remained unaffected by LPS and LPS plus PTZ.

Effects of atorvastatin on blood-brain barrier permeability during L-NAME hypertension followed by angiotensin-II in rats.

Recent studies suggest that 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, statins, can have direct effects on blood vessels beyond their cholesterol-lowering effects. We investigated the effects of atorvastatin on the functional and structural properties of blood-brain barrier (BBB) and the activity of astrocytes during the N(omega)-nitro-L-arginine methyl ester (L-NAME) hypertension followed by angiotensin (ANG) II. We found that decreases in concentration of serum catalase and plasma nitric oxide (NO) induced by L-NAME were significantly ameliorated by atorvastatin, whereas L-NAME-induced serum malondialdehyde and cholesterol concentration increases were significantly reduced by atorvastatin. The content of Evans blue (EB) dye significantly increased in cerebellum, left cerebral cortex and diencephalon regions but atorvastatin markedly reduced the increased BBB permeability to EB in the brain regions of animals treated with L-NAME and L-NAME plus ANG II. Brain vessels of L-NAME-treated animals showed a considerable loss of immunoreactivity of tight junction proteins, zonula occludens (ZO)-1 and occludin. Immunoreactivity for ZO-1 and occludin increased in animals treated with atorvastatin and L-NAME plus atorvastatin. Glial fibrillary acidic protein (GFAP) immunoreactivity was seen in few astrocytes in the brain sections of L-NAME, but immunoreactivity for GFAP increased in L-NAME plus atorvastatin-treated animals. We suggest that long-term L-NAME treatment may affect BBB permeability through disruption of tight junction proteins, at least partly, via decreased NO concentration and increased oxidant capacity; the improvement of BBB integrity and astrocytic activity would be more closely associated with the action of atorvastatin favoring the increase in anti-oxidant capacity and expression of tight junction proteins and GFAP.

Effects of lipopolysaccharide on the radiation-induced changes in the blood-brain barrier and the astrocytes.

The use of radiation to improve the efficacy of chemotherapy on malignant brain tumors is also known to cause side effects on vascular endothelial cells and astrocytes in normal parts of the brain. We investigated the effects of lipopolysaccharide (LPS) on the functional and structural properties of blood-brain barrier (BBB) and the activity of astrocytes during whole-brain irradiation in rats. The permeability of the BBB to Evans blue (EB) dye significantly increased in the cerebral cortex, diencephalon and cerebellum regions of rats exposed to irradiation (P<0.01). In contrast, the BBB permeability in irradiated rats was significantly reduced by LPS (P<0.05). Tumor necrosis factor-alpha (TNF-alpha) levels were increased following LPS, irradiation and irradiation plus LPS (P<0.05, P<0.01). Irradiated brain vessels showed a considerable loss of staining intensity of tight junction proteins Zonula occludens-1 (ZO-1) and occludin. Staining for Zonula occludens-1 and occludin was intensive in animals treated with LPS and irradiation plus LPS. Glial fibrillary acidic protein (GFAP) immunoreactivity was seen in very few astrocytes of irradiated brains. However, this staining showed an increased positive intensity in the brain sections of LPS-treated as well as of irradiation plus LPS-treated animals. These results indicate that LPS reduces the passage of exogenous vascular tracer EB-binding albumin into the brain, at least partly, by increasing the expression of tight junction proteins and GFAP, following the irradiation. We suggest that irradiation may affect paracellular permeability through disruption of tight junction proteins, Zonula occludens-1 and occludin, and LPS could provide beneficial effects on the BBB integrity and the astrocytes against irradiation damage.

Effects of losartan on the blood-brain barrier permeability in long-term nitric oxide blockade-induced hypertensive rats.

Hypertension is closely associated with vascular endothelial dysfunction. The aim of this study was to investigate the effects of Angiotensin II (ANG II) receptor antagonist losartan on the blood-brain barrier (BBB) permeability in L-NAME-induced hypertension and/or in ANG II-induced acute hypertension in normotensive and hypertensive rats. Systolic blood pressure was measured by tail cuff method before, during and following L-NAME treatment (1 g/L). Losartan (3 mg/kg) was given to the animal for five days. Acute hypertension was induced by ANG II (60 microg/kg). Arterial blood pressure was directly measured on the day of the experiment. BBB disruption was quantified according to the extravasation of the albumin-bound Evans blue dye. Losartan significantly reduced the mean arterial blood pressure from 169 +/- 3.9 mmHg to 82 +/- 2.9 mmHg in L-NAME and from 171 +/- 2.9 mmHg to 84 +/- 2.9 in L-NAME plus losartan plus ANG II groups (p < 0.05). The content of Evans blue dye in the cerebral cortex significantly increased in L-NAME (p < 0.01). Moreover, the content of Evans blue dye markedly increased in the cerebellum (p < 0.001) and slightly increased in diencephalon region (p < 0.05) in L-NAME plus ANG II. Losartan reduced the increased BBB permeability to Evans blue dye in L-NAME (p < 0.01) and L-NAME plus ANG II (p < 0.001). These results indicate that L-NAME and L-NAME plus ANG II both lead to an increase in microvascular Evans blue dye efflux to brain, and losartan treatment attenuates this protein-bound dye transport into brain tissue presumably due to its protective effect on endothelial cells of brain vessels.

The effects of magnesium sulfate on blood-brain barrier disruption caused by intracarotid injection of hyperosmolar mannitol in rats.

The study was performed to evaluate whether magnesium sulfate could alter the degree of disruption of the blood-brain barrier (BBB) caused by hyperosmotic mannitol. Wistar adult female rats were infused with 25% mannitol into the left internal carotid artery. Each animal received intraperitoneally a 300 mg/kg loading dose of magnesium sulfate, dissolved in 0.9% saline, followed by a further 100 mg/kg dose. In the other group, intracarotid infusion of magnesium sulfate was performed at a dose of 150 mg/kg 10 min before mannitol administration. Evans blue (EB) dye was used as a marker of BBB disruption. The measured serum glucose and magnesium levels increased after mannitol and/or magnesium administration when compared with their initial values before treatment (P < 0.01). Water content of the left hemisphere was significantly increased by hyperosmotic mannitol (P < 0.01). The increased water content in the mannitol-perfused hemisphere was significantly decreased by magnesium treatment (P < 0.05). The content of EB dye in the mannitol-perfused hemisphere markedly increased when compared with the right hemisphere of the same brain (P < 0.01). The EB dye content in the mannitol-perfused hemisphere following both intraperitoneal and intraarterial administration of magnesium decreased when compared with mannitol alone (P < 0.01). We conclude that although magnesium sulfate administration by both intracarotid arterial and intraperitoneal routes attenuates BBB disruption caused by hyperosmolar mannitol, particularly intraperitoneal route of magnesium sulfate administration may provide a useful strategy to limit the transient osmotic opening of the BBB.

Effects of magnesium administration on brain edema and blood-brain barrier breakdown after experimental traumatic brain injury in rats.

In this study, we examined the effects of magnesium sulfate administration on brain edema and blood-brain barrier breakdown after experimental traumatic brain injury in rats. Seventy-one adult male Sprague-Dawley rats were anesthetized, and experimental closed head trauma was induced by allowing a 450-g weight to fall from a 2-m height onto a metallic disk fixed to the intact skull. Sixty-eight surviving rats were randomly assigned to receive an intraperitoneal bolus of either 750 micromol/kg magnesium sulfate (group 4; n = 30) or 1 mL of saline (group 2; n = 30) 30 minutes after induction of traumatic brain injury; 39 nontraumatized animals received saline (group 1; n = 21) or magnesium sulfate (group 3; n = 18) with an identical protocol of administration. Brain water content and brain tissue specific gravity, as indicators of brain edema, were measured 24 hours after traumatic brain injury. Blood-brain barrier integrity was evaluated quantitatively 24 hours after injury by spectrophotometric assay of Evans blue dye extravasations. In the magnesium-treated injured group, brain water content was significantly reduced (left hemisphere: group 2, 83.2 +/- 0.8; group 4, 78.4 +/- 0.7 [P <.05]; right hemisphere: group 2, 83.1 +/- 0.7; group 4, 78.4 +/- 0.5. [P <.05]) and brain tissue specific gravity was significantly increased (left hemisphere: group 2, 1.0391 +/- 0.0008; group 4, 1.0437 +/- 0.001 [P <.05]; right hemisphere, group 2, 1.0384 +/- 0.001; group 4, 1.0442 +/- 0.005 [P <.05]) compared with the saline-treated injured group. Evans blue dye content in the brain tissue was significantly decreased in the magnesium-treated injured group (left hemisphere: group 2, 0.0204 +/- 0.03; group 4, 0.0013 +/- 0.0002 [P <.05]; right hemisphere: group 2, 0.0064 +/- 0.0009; group 4, 0.0013 +/- 0.0003 [P <.05]) compared with the saline-treated injured group. The findings of the present study support that beneficial effects of magnesium sulfate exist after severe traumatic brain injury in rats. These results also indicate that a blood-brain barrier permeability defect occurs after this model of diffuse traumatic brain injury, and magnesium seems to attenuate this defect.

Effects of acute cold exposure on blood-brain barrier permeability in acute and chronic hyperglycemic rats.

These experiments were carried out to study, the effects of cold exposure on the permeability of blood-brain barrier (BBB) in hyperglycemic rats. The integrity of the BBB was investigated using Evans blue albumin (EBA) extravasation. Serum glucose levels in hyperglycemic rats were significantly higher than that obtained from normoglycemic rats (P < 0.05). Mean arterial blood pressure in hypothermic groups significantly dropped into lower levels, than that obtained in normothermic groups (P < 0.05). The EBA extravasation to the cerebellum in the group of cold exposure+acute hyperglycemia significantly increased compared with the values obtained from the cold exposure group (P < 0.05). The EBA extravasation to the brain regions of diabetic rats exposed to cold increased more than that in normotermic control rats (P < 0.05), but did not exceed the levels in cold controls. The result of this study suggests that, acute hyperglycemia superimposed upon the permeability of BBB in the rat exposed to cold, only in selected regions of the brain, especially the cerebellum, and this result could be an important factor to explain the mechanisms of death related with hyperglycemia+cold exposure in forensic medicine.

The effects of superoxide dismutase mimetic MnTMPyP on the altered blood-brain barrier integrity in experimental preeclampsia with or without seizures in rats.

We investigated the effects of a cell-permeable superoxide dismutase mimetic, manganese(III) tetrakis(1-methyl-4-pyridyl)porphyrin (MnTMPyP) on blood-brain barrier (BBB) integrity following pentylenetetrazole (PTZ)-induced seizures in experimental preeclampsia symptoms induced by N(omega)-nitro-l-arginine methyl ester (l-NAME) in pregnant rats. To show the functional and morphological alterations in BBB integrity, quantitative analysis of sodium fluorescein (NaFlu) extravasation, immunohistochemistry and electron microscopic assessment of horseradish peroxidase (HRP) permeability were performed. Varying degrees of proteinuria were seen and arterial blood pressure increased in l-NAME-treated pregnant rats (p<0.01). MnTMPyP pretreatment and convulsive PTZ challenge significantly decreased the immunoreactivity of occludin in hippocampal capillaries in l-NAME-treated pregnant rats (p<0.01). BBB permeability to NaFlu significantly increased in pregnant rats treated with l-NAME plus PTZ (p<0.01), but MnTMPyP pretreatment did not significantly decrease NaFlu penetration into the brain parenchyma in these animals. Ultrastructurally, frequent vesicles containing HRP reaction products were observed in the capillary endothelial cells in the cerebral cortex and hippocampus of pregnant rats treated with l-NAME and l-NAME plus PTZ with the abundance being more in the latter group. MnTMPyP pretreatment caused a marked reduction in the frequency of HRP reaction product containing vesicles in both experimental settings. In conclusion, the results of the present study provide evidence that MnTMPyP plays an important role in limiting the enhanced vesicle-mediated transcellular transport in BBB endothelium in a rat model of preeclampsia and the differences in the way of transports of NaFlu and HRP might be responsible for the different effects of MnTMPyP on the BBB permeability to these two tracers.

Effects of levetiracetam on blood-brain barrier disturbances following hyperthermia-induced seizures in rats with cortical dysplasia.

AIMS: The mechanisms underlying the changes in blood-brain barrier (BBB) integrity and the generation of seizures in childhood associated with preexisting brain lesions like cortical dysplasia (CD) are poorly understood. We investigated the effects of levetiracetam (LEV) on BBB integrity and the survival during hyperthermic seizures in rats with CD. MAIN METHODS: Pregnant rats were exposed to 145 cGy of gamma-irradiation on embryonic day 17. On postnatal day 28, hyperthermia-induced seizures were evoked in offspring with CD. To show the functional and morphological alterations in BBB integrity, quantitative analysis of sodium fluorescein (NaFlu) extravasation, immunohistochemistry and electron microscopy were performed. KEY FINDINGS: Seizure scores and mortality rates were decreased by LEV during hyperthermia-induced seizures in rats with CD (P<0.01). Increased NaFlu extravasation into brain by hyperthermia-induced seizures in animals with CD was decreased by LEV (P<0.01). While glial fibrillary acidic protein (GFAP) immunoreactivity slightly increased in brain sections of animals with CD during hyperthermia-induced seizures, LEV led to GFAP immunoreactivity comparable to that of controls. Decreased occludin immunoreactivity and expression in CD plus hyperthermia-induced seizures was increased by LEV. Opening of tight junctions and abundance of pinocytotic vesicles representing ultrastructural evidences of BBB impairment and severe perivascular edema were observed in animals with CD exposed to hyperthermia-induced seizures and LEV treatment led to the attenuation of these findings. SIGNIFICANCE: These results indicate that LEV may present a novel approach for the protection of the BBB besides its antiepileptic impact on hyperthermic seizures in the setting of CD.

Levetiracetam decreases the seizure activity and blood-brain barrier permeability in pentylenetetrazole-kindled rats with cortical dysplasia.

This study investigates the effects of levetiracetam (LEV) on the functional and structural properties of blood-brain barrier (BBB) in pentylenetetrazole (PTZ)-kindled rats with cortical dysplasia (CD). Pregnant rats were exposed to 145 cGy of gamma-irradiation on embryonic day 17. In offsprings, kindling was induced by giving subconvulsive doses of PTZ three times per week for 45 days. While all kindled rats with CD died during epileptic seizures evoked by the administration of a convulsive dose of PTZ in 15 to 25 min, one week LEV (80 mg/kg) pretreatment decreased the mortality to 38% in the same setting. LEV caused a remarkable decrease (p<0.01) in extravasation of sodium fluorescein dye into the brain tissue of kindled animals with CD treated with convulsive dose of PTZ. Occludin immunoreactivity and expression remained essentially unchanged in all groups. Immunoreactivity for glial fibrillary acidic protein (GFAP) was observed to be slightly increased by acute convulsive challenge in kindled rats with CD while LEV pretreatment led to GFAP immunoreactivity comparable to that of controls. An increased c-fos immunoreactivity in kindled rats with CD exposed to convulsive PTZ challenge was also observed with LEV pretreatment. Tight junctions were ultrastructurally intact, whereas LEV decreased the increased pinocytotic activity in brain endothelium of kindled rats with CD treated with convulsive dose of PTZ. The present study showed that LEV decreased the increased BBB permeability considerably by diminishing vesicular transport in epileptic seizures induced by convulsive PTZ challenge in kindled animals with CD.

Catalase and alpha-tocopherol attenuate blood-brain barrier breakdown in pentylenetetrazole-induced epileptic seizures in acute hyperglycaemic rats.

Experimental data indicate that acute hyperglycaemia can aggravate the consequences of epileptic seizures on the permeability of the blood-brain barrier (BBB). The purpose of this study was to examine the effects of chronic administration of alpha -tocopherol (vitamin E) and acute catalase administration on the disrupted BBB during experimentally pentylenetetrazole-induced status epilepticus in acute hyperglycaemic rats. The integrity of the BBB was tested using the Evans Blue (EB) dye extravasation. The concentration of EB dye was measured in four regions of the brain. Epileptic seizures induced a significant increase in EB dye extravasation in the brain regions compared with that of the groups of rats treated with saline, glucose, catalase and alpha -tocopherol (P< 0.01). The content of EB dye in the brain regions of animals in the acute hyperglycaemia plus epileptic group was higher than that of the saline, glucose, catalase, alpha -tocopherol and epileptic groups (P< 0.01). The increased EB dye transfer from blood to the brain in status epilepticus and acute hyperglycaemia plus status epilepticus was attenuated by the treatment with catalase and alpha -tocopherol. These data suggest that a partial reduction in the production of reactive oxygen species by catalase and alpha -tocopherol contributes to decreases in the content of EB dye across the BBB during pentylenetetrazole-induced status epilepticus in acute hyperglycaemic rats.