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Sepsis is defined as a systemic inflammatory response to infection. This study is aimed to evaluate the effects of experimental sepsis on the proliferation and apoptosis of granulosa and theca cells in the rat ovary. 28-day-old immature Wistar-Albino female rats were treated with pregnant mare serum gonadotrophin to develop the first generation of preovulatory follicles. Sepsis was induced by cecal ligation and puncture (CLP). Following in vivo 5-Bromo-2-deoxyuridine (BrdU) labeling, animals were sacrificed and ovaries were embedded in paraffin and Epon. Besides electron microscopic evaluation, BrdU, cleaved caspase-3, p27 immunostaining, and TUNEL labeling were performed. In CLP-operated animals, cleaved caspase-3 immunoreactivity was significantly increased in Graafian follicles. TUNEL and BrdU labeling in the ovarian follicles were not statistically different between CLP and sham-operated rats. In septic animals, p27 immunoreactivity was increased significantly in the nuclei of oocytes and decreased in the cytoplasm of granulosa and theca cells in multilaminar primary follicles compared to the sham group. In ultrastructural evaluation, increased apoptosis was observed in theca interna and granulosa cells in both the early and late stages of follicles in the CLP group. In conclusion, experimentally-induced sepsis leads to apoptosis in ovarian follicles at advanced stages of development. Our data suggest that although sepsis may not cause a potential threat to developing follicles at least in the short term, more severe damage may occur during advanced stages of follicle development.

Most currently available antiepileptics are not fully effective in the prevention of seizures in absence epilepsy owing to the presence of blood-brain barrier (BBB). We aimed to test whether binding an antiepileptic drug, lacosamide (LCM), to glucose-coated gold nanoparticles (GNPs) enables efficient brain drug delivery to suppress the epileptic activity in WAG/Rij rats with absence epilepsy.In these animals, intracranial-EEG recording, behavioral test, in vivo imaging of LCM and LCM-GNP conjugate distribution in the brain, inductively coupled plasma mass spectrometry analysis, immunofluorescence staining of glucose transporter (Glut)- 1, glial fibrillary acidic protein (GFAP), and p-glycoprotein (P-gp) and electron microscopy were performed.Lacosamide-GNP conjugates decreased the amplitude and frequency of spike-wave-like discharges (SWDs) and alleviated the anxiety-like behavior as assessed by EEG and elevated plus-maze test, respectively (p 0.01). The in vivo imaging system results showed higher levels of fluorescein dye tagged to LCM-GNP in the brain during the 5-day injection period (p 0.01). Immunofluorescence staining displayed decreased P-gp, Glut-1, and GFAP expression by LCM-GNP conjugate treatment predominantly in the cerebral cortex suggesting a potential functionality of this brain region in the modulation of neuronal activity in our experimental setting (p 0.01).We suggest that the conjugation of LCM to GNPs may provide a novel approach for efficient brain drug delivery in light of the effectiveness of our strategy not only in suppressing the seizure activity but also in decreasing the need to use high dosages of the antiepileptics to reduce the frequently encountered side effects in drug-resistant epilepsy.

Gastrointestinal complications are frequent in renal transplant recipients. In this regard, renal ischemia/reperfusion injury (IRI)-induced gastric damage seems to be important and there is no data available on the mechanism of this pathology. Because of its anti-inflammatory and anti-oxidant properties, it can be suggested that prostaglandin-E1 (PGE1) protects cells from renal IRI-induced gastric damage. The aim of this study was to investigate the molecular mechanisms of gastric damage induced by renal IRI and the effect of PGE1 on these mechanisms. We set an experiment with four different animal groups: physiological saline-injected and sham-operated rats, PGE1 (20μg/kg)-administered and sham operated rats, renal IRI subjected rats, and PGE1-administered and renal IRI subjected rats. The protective effect of PGE1 on renal IRI-induced gastric damage was determined based on reduced histological damage and lactate dehydrogenase activity. Moreover, we demonstrated that PGE1 shows its protective effect through reducing the production of reactive oxygen species and malondialdehyde levels. During histological examination, we observed the presence of common mononuclear cell infiltration. Therefore, pro-inflammatory cytokines tumor necrosis factor-α and interleukin-1β levels were measured and it has been shown that PGE1 suppressed both cytokines. Furthermore, it was found that PGE1 reduced the number of NF-κB(+) and caspase-3(+) inflammatory cells, and also NF-κB DNA-binding activity, while increasing proliferating cell nuclear antigen(+) epithelial cells in the stomach tissue of rats subjected to renal IR. Our data showed that PGE1 has a protective effect on renal IRI-induced oxidative stress and inflammation mediated gastric damage in rats.

Aim: To identify the localization of glucose-coated gold nanoparticles within cells of the brain after intravascular infusion which may point to the mechanism by which they cross the blood–brain barrier. Materials & methods: Tissue distribution of the nanoparticles was measured by inductively-coupled-mass spectrometry and localization within the brain by histochemistry and electron microscopy. Results & conclusion: Nanoparticles were identified within neurons and glial cells more than 10 μm from the nearest microvessel within 10 min of intracarotid infusion. Their distribution indicated movement across the endothelial cytosol, and direct transfer between cells of the brain. The rapid movement of this class of nanoparticle (

The blood-brain barrier (BBB) permeability primarily increases in cerebral venules during acute hypertension. Methyl-beta-cyclodextrin (M beta CD), a cholesterol-depleting agent, decreases the expression of caveolins disrupting caveolar structures. We aimed to determine the effects of M beta CD on the BBB permeability of angiotensin (ANG) II-induced hypertensive rats. Three minutes after M beta CD administration (5 mg/kg), acute hypertension was induced by ANG II (60 mu g/kg). Evans blue (EB) and horseradish peroxidase (HRP) tracers were used to assess BBB permeability. Immunohistochemistry for caveolin (Cav)-1 and tight junction protein claudin-5 was performed. EB dye content significantly increased in both cerebral cortices and left hippocampus in M beta CD (P < 0.05), right cerebral cortex and both hippocampi in ANG II (P < 0.05; P < 0.01), and both cerebral cortices and hippocampi in M beta CD plus ANG II groups compared with controls (P < 0.05; P < 0.01). A significant decrease in claudin-5 immunostaining intensity was observed in animals treated with M beta CD compared with controls (P < 0.05). Cav-1 immunostaining intensity increased in ANG II group (P < 0.05). Ultrastructurally, HRP reaction products were observed in endothelial cells of the microvessels in the hippocampus region in M beta CD group while the tracer was mainly localized in astrocytes and neurons in ANG II, and M beta CD plus ANG II groups. The endothelial cells of the venules in the cerebral cortex of the animals in the latter experimental groups also showed an abundance of caveolar vesicles devoid of HRP reaction products. Our results revealed that M beta CD did not provide overall protective effects on BBB integrity in acute hypertension and even led to BBB disruption in normotensive animals.

Preeclampsia is a disorder characterized by high blood pressure and often proteinuria during pregnancy. It is known that a subseptic dose of bacterial lipopolysaccharide (LPS) induces production of proinflammatory cytokines, and possibly increasing the risk for developing preeclampsia. We investigated the effects of LPS on the blood-brain barrier (BBB) integrity in pregnant rats with N(omega)-nitro-l-arginine methyl ester (L-NAME) induced preeclampsia.Starting from the 10th day of gestation, pregnant rats were given L-NAME for 10 days to produce hypertension and proteinuria. Animals were then treated with a single injection of LPS on the 19th day of pregnancy. Arterial blood pressure and proteinuria were measured on the day of the experiment, which was 24 hours after the LPS injection. The BBB integrity was assessed by using Evans blue (EB) and horseradish peroxidase (HRP) tracers.Proteinuria was observed in varying degrees, and the arterial blood pressure increased in L-NAME-treated pregnant rats (P.01). The overall brain EB content did not increase in these preeclamptic rats when compared to pregnant animals, and LPS treatment also did not change EB content. 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 (P.01). However, LPS did not change the amounts of HRP that mainly accumulated in brain capillary endothelial cells of these animals.Our results suggest that, in this experimental setting, LPS does not change the severity of BBB disruption observed in preeclamptic animals.

Hyperbaric oxygen (HBO) treatment yields conflicting results on blood-brain barrier (BBB) integrity under various pathological conditions and the effects of HBO on healthy brain is poorly understood. In this experimental study, the effects of HBO on BBB integrity were investigated in comparison with hyperbaric air (HBA) in intact rats. Four sessions of HBA or HBO were applied to intact rats in 24h. BBB integrity was functionally and structurally evaluated by determining extravasation of Evans blue (EB) dye and horseradish peroxidase (HRP) tracers. In immunohistochemical evaluation, relative staining intensity for occludin, a tight junction (TJ) protein, and aquaporin 4 (AQP4), a water-channel protein, was detected in the barrier type of microvessels of brain by image analysis. BBB permeability to EB dye significantly increased in animals in HBO treatment group compared to those in HBA and control groups (p

Background Intravenous (IV) immunoglobulin (Ig) treatment is known to alleviate behavioral deficits and increase survival in the experimentally induced model of sepsis. To delineate the mechanisms by which IVIg treatment prevents neuronal dysfunction, an array of immunological and apoptosis markers was investigated. Methods Sepsis was induced by cecal ligation perforation (CLP) in rats. The animals were divided into five groups: sham, control, CLP + saline, CLP + immunoglobulin G (IgG) (250 mg/kg, iv), and CLP + immunoglobulins enriched with immunoglobulin M (IgGAM) (250 mg/kg, iv). Blood and brain samples were taken in two sets of experiments to see the early (24 h) and late (10 days) effects of treatment. Total complement activity, complement 3 (C3), and soluble complement C5b-9 levels were measured in the sera of rats using ELISA-based methods. Cerebral complement, complement receptor, NF-κB, Bax, and Bcl-2 expressions were analyzed by western blot and/or RT-PCR methods. Immune cell infiltration and gliosis were examined by immunohistochemistry using CD3, CD4, CD8, CD11b, CD19, and glial fibrillary acidic protein antibodies. Apoptotic neuronal death was investigated by TUNEL staining. Results IVIgG and IgGAM administration significantly reduced systemic complement activity and cerebral C5a and C5a receptor expression. Likewise, both treatment methods reduced proapoptotic NF-κB and Bax expressions in the brain. IVIgG and IgGAM treatment induced considerable amelioration in glial cell proliferation and neuronal apoptosis which were increased in non-treated septic rats. Conclusions We suggest that IVIgG and IgGAM administration ameliorates neuronal dysfunction and behavioral deficits by reducing apoptotic cell death and glial cell proliferation. In both treatment methods, these beneficial effects might be mediated through reduction of anaphylatoxic C5a activity and subsequent inhibition of inflammation and apoptosis pathways. Electronic supplementary material The online version of this article (doi:10.1186/s40635-016-0114-1) contains supplementary material, which is available to authorized users.

This study investigated the effects of cortical dysplasia (CD) on electrophysiology and blood-brain barrier (BBB) permeability in WAG/Rij rats with genetic absence epilepsy.Pregnant WAG/Rij rats were exposed to 145cGy of gamma-irradiation on embryonic day 17 to induce CD. An electroencephalogram was recorded from cortices subdurally in the offspring of the pregnant animals. Horseradish peroxidase (HRP) was used as determinant of BBB permeability.A massive tissue loss in the cerebral cortex was seen in WAG/Rij rats with CD (p0.05). There was a significant decrease in the number and duration of spike-and-wave discharges (SWDs) and an increase in the frequency of SWDs in the WAG/Rij rats with CD when compared with the properties of SWDs in intact WAG/Rij rats (p0.01). Ultrastructurally, the accumulation of HRP reaction products in the cerebral cortex and thalamus of WAG/Rij rats was significantly higher than that of control values (p0.01). The accumulation of HRP reaction products in the cerebral cortex and thalamus regions of WAG/Rij rats with CD increased and was higher than that of the control and WAG/Rij animals (p0.01).In our study, we showed that number and duration of SWDs decreased and SWD frequency increased in WAG/Rij rats with CD, suggesting a shift in seizure pattern. The association of these alterations with significant loss of cortical thickness and increased BBB permeability to HRP tracer may represent a causal relation of the EEG abnormalities with cerebral structural changes in these animals.

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.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.Seizure scores and mortality rates were decreased by LEV during hyperthermia-induced seizures in rats with CD (P0.01). Increased NaFlu extravasation into brain by hyperthermia-induced seizures in animals with CD was decreased by LEV (P0.01). 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.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.

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

There is growing evidence of partial etiological overlap between schizophrenia (SZ) and bipolar I disorder (BD-I) from linkage analysis, genetic epidemiology and molecular genetics studies. SZ and BD-I are neurodevelopmental disorders with genetic and environmental etiologies. Recent studies have demonstrated that matrix metalloproteinase 3 (MMP3) is a key event in associative memory formation, learning and synaptic plasticity, which are important in psychiatric disorders. In the light of these findings, we analyzed the genetic variations in the MMP3-1171 5A/6A in patients with SZ, patients with BD-I and healthy controls. To the best of our knowledge, this is the first study to report an association of variation in gene encoding MMP3 with SZ. Our study group consisted of 111 unrelated patients with SZ, 141 unrelated patients with BD-I, and 121 unrelated healthy controls. The frequencies of 6A6A genotype and 6A allele distributions of MMP3 in patients with SZ were significantly decreased when compared with controls. In contrast, in patients with SZ, the distributions of 5A5A genotype and 5A allele of MMP3 gene were significantly increased as compared with healthy controls. When the frequencies of genotypes or alleles in schizophrenic patients and bipolar patients were compared, 6A6A genotype and 6A allele in patients with BD-I were significantly higher than patients with SZ. In contrast, 5A5A genotype and 5A allele distributions of MMP3 gene were significantly frequent in patients with SZ. On the other hand, no significant differences were found in the allele or genotype distribution in patients with BD-I compared with controls. In conclusion, our data have supported the hypothesis that there is a possible relationship between − 1171 5A/6A polymorphism of MMP3 gene and SZ. A larger sample group is needed to confirm the potential role of this gene in the pathophysiology of psychiatric disorders.

Oxidative stress and free radical-induced toxicity have been implicated in the pathophysiology of schizophrenia. In this study, we examined paraoxonase (PON1)-55/192 polymorphisms and PON1 activity in patients with schizophrenia, first-degree relatives of schizophrenic patients, and healthy controls.This study consisted of 292 healthy participants, 267 unrelated patients with schizophrenia and 311 first-degree relatives of schizophrenic patients. PON1 55 (rs 854560) and PON1 192 (rs 662) polymorphisms were performed by restriction fragment length polymorphism.The frequencies of the QQ and LL genotypes were significantly overpresented in controls compared with those of schizophrenic patients and their relatives. In contrast, the RR genotype was more prevalent in patients than their relatives and healthy controls. The frequencies of the LM and QR genotypes in relatives were higher than controls. Serum PON1 activities of controls were significantly higher when compared with both schizophrenic patients and their relatives. The RR and LL genotypes were associated with a significantly increased PON1 activity as compared with QR or QQ and MM or LM genotypes, respectively, in all groups.This is the first study that shows the association between PON1-55/192 polymorphisms and schizophrenia. Our data suggest that the subjects carrying R allele or RR genotype might be susceptible to schizophrenia and subjects with QQ or LL might be protected against schizophrenia. First-degree relatives of schizophrenic patients have higher heterozygote genotypes, suggesting that this group can shift either to patient or control group depending on their allele types and environmental factors. PON1 genetic variations are also associated with PON1 activities. Reduced PON1 activity in patients and their relatives might result from the combined effects of more than one polymorphic variant in PON1 or other genes and/or increased oxidative stress, supporting the hypothesis that reactive oxygen species-mediated cellular damage might contribute to the neuropathology of schizophrenia.

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. (C) 2008 Elsevier B.V. All Tights reserved.

Migraine is a primary headache disorder which involves both genetic and environmental components. Since angiotensin-converting enzyme (ACE) and matrix metalloproteinase (MMP) share the same homology, we investigated whether the MMP-3 and ACE I/D gene variants are involved in migraine risk and whether the ACE variant might act in combination with the MMP-3 genetic variant in patients with migraine. This is the first study to evaluate the association between MMP-3 and ACE polymorphisms, and migraine. Genotypes were determined by polymerase chain reaction. The frequencies of 5A5A genotypes of the MMP-3 and D allele of ACE were significantly elevated, but II genotypes of the ACE and 6A allele of MMP-3 significantly decreased in all patients. The combined DD/5A5A and ID/5A5A genotypes increased the risk of migraine. Individuals who were homozygous for the deletion (D) allele showed increased ACE activity. Subjects with the 5A5A genotype and/or D allele or with the combined DD/5A5A or ID/5A5A might be more susceptible to migraine development. In contrast, subjects with the II and/or 6A6A genotypes may be protected from migraine development. The greater activity of the 5A5A and DD genotypes might result in vascular reactivity that is more pronounced in migraine. Taken together, our data suggest that numerous genes may influence ACE activity. Discovery of new genes might better clarify the pathogenesis of migraine and open an avenue to therapeutic strategies against migraine.

Background: We aim to demonstrate behavioral alterations in a sepsis model using intravenous (IV) immunoglobulin G (IgG) and immunoglobulins enriched with IgA and IgM (IgGAM). Methods: We divided 48 Wistar albino rats into five groups: control group, sham-operated group (only antibiotic treatment), cecal ligation and puncture (CLP) group (CLP plus antibiotic treatment), IgG group (250 mg/kg IV IgG) and IgGAM group (250 mg/kg IV IgGAM). Intravenous immunoglobulins were given 5 min after the CLP procedure. Experimental animals put into three behavioral tasks 10, 30 and 60 days after the surgery; to evaluate the locomotor activity, an open field test was performed, elevated plus maze test was used to measure anxiety levels, and depressive state was assessed by forced swimming test. The effects of therapy which were acquired from the results of these tests were used to estimate the behavioral changes after CLP. Results: The mortality rate of 50% in the septic rats decreased to 30 and 20% with the administration of IgG and IgGAM, respectively. Significant changes on locomotor activity and depressive-like behavior were reported in the sepsis group; on the other hand, the treatment with immunoglobulins reduced the symptoms. Treatment with immunoglobulins attenuated the sepsis-related anxiogenic-like responses. Behavioral alterations returned to normal on day 60 in all groups., NA

This study investigates the effect of beta-hydroxybutyrate (BHB) on blood-brain barrier (BBB) integrity during traumatic brain injury (TBI) in rats. Evans blue (EB) and horseradish peroxidase (HRP) were used as determinants of BBB permeability. Glutathione (GSH) and malondialdehyde (MDA) levels were estimated in the right (injury side) cerebral cortex of animals. The gene expression levels for occludin, glucose transporter (Glut)-1, aquaporin4 (AQP4) and nuclear factor-kappaB (NF-κB) were performed, and Glut-1 and NF-κB activities were analyzed. BHB treatment decreased GSH and MDA levels in intact animals and in those exposed to TBI (P

For the purposes of the present study, the protective effect of prostaglandin E1 (PGE1) on lung injury following renal ischemia–reperfusion (RIR) was investigated. Adult male rats were divided into four groups, namely, (I) control rats given physiological saline; (II) rats given PGE1 (20 μg/kg, intravenously); (III) rats subjected to RIR; and (IV) rats subjected to RIR given PGE1 30 min prior to ischemia and just before reperfusion. The right nephrectomy was performed in the RIR model. The left renal pedicle was occluded for 60 min to induce ischemia and then the left kidney was subjected to reperfusion for 60 min. The lungs of rats were used for microscopic and biochemical analyses. Although rats subjected to RIR did not exhibit heavy degenerative alterations in the lung structure, they possessed pulmonary interstitial edema. Lung glutathione levels and catalase, superoxide dismutase, glutathione peroxidase, and tissue factor (TF) activities were decreased in rats subjected to RIR, while lung lipid peroxidation, myeloperoxidase (MPO), xanthine oxidase and serum lactate dehydrogenase (LDH) activities, and blood urea and serum creatinine levels were increased in these rats when compared with the control group. PGE1 treatments resulted in the regression of oxidative stress via induction of antioxidant system, the decreased MPO and LDH activities, the reduced urea and creatinine levels, and the induced TF activity in rats subjected to RIR, while edema still remained permanent. We conclude that PGE1 may be useful in preventing lung injury with the exception of edema that occurred as a result of RIR in rats.

Bipolar disorder (BD) has a complex genetic etiology, with multiple unidentified genes and environmental factors playing important roles in its pathogenesis. A growing body of evidence suggests that reactive oxygen species (ROS) may be crucially involved in the pathogenesis of psychiatric diseases, including BD. The association between paraoxonase 1 (PON1), an important antioxidant enzyme, and development of BD has been scarcely investigated. We thus attempted to examine genetic variants in the PON1 gene, a putative BD susceptibility gene, in patients with bipolar disease and their first-degree relatives.The study population consisted of 292 healthy individuals, 199 patients with BD, and 280 unaffected first-degree relatives of the patients. Genotyping of PON1 L55M and Q192R polymorphisms was performed by polymerase chain reaction and restriction enzyme digestion.Patients mostly shared the same PON1 genotypes with their first-degree relatives. The frequency of MM genotype of PON1 L55M polymorphism was lower and that of LM genotype was higher in patients and relatives than healthy controls. PON1 enzyme activities did not differ between patient, relative and healthy control groups but were influenced by PON1 genotype.Our findings indicate an association between the genetic variants of PON1 and BD. The PON1 L55M MM genotype seems to be protective against the development of BD.

The pathophysiological mechanisms underlying blood-brain barrier (BBB) disruption in preeclampsia/eclampsia have not been elucidated. This study investigated the effect of pentylenetetrazole (PTZ)-induced seizures on the functional and structural properties of the BBB during N (omega)-nitro-L-arginine methyl ester (L-NAME)-induced hypertension and proteinuria in pregnant rats. Animals were treated with L-NAME for 10 days, beginning on day 10 of pregnancy. The BBB permeability was determined by measurements of sodium fluorescein (NaFlu) extravasation into the brain. Occludin and aquaporin (AQP)-4 immunoreactivities were evaluated in brain sections. Severe proteinuria and significantly increased arterial blood pressure were observed following L-NAME treatment. PTZ-induced seizures in pregnant rats treated with L-NAME increased NaFlu levels in all of the brain regions analyzed (P < 0.01). A significant increase in the extravasation of NaFlu was also observed in the diencephalon of intact pregnant rats treated with PTZ. PTZ-induced seizures in both L-NAME-treated and untreated pregnant rats significantly decreased occludin immunoreactivity in the hippocampal capillaries. L-NAME administration significantly increased AQP-4 immunoreactivity in the astrocytic endfeet surrounding the parietal cortex microvessels of PTZ-treated and untreated pregnant rats. These findings suggest that PTZ-induced seizures lead to a severe disruption of the BBB in preeclampsia and that the paracellular pathway may play an important role in increased BBB permeability in this context.

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

The blood-brain barrier (BBB) is highly restrictive of the transport of substances between blood and the central nervous system. Lipopolysaccharide (LPS) from Gram-negative bacteria was reported to affect the permeability of the BBB. BBB disruption using a LPS is used as a model of septic encephalopathy in mice. The present study was designed to investigate the effects of different doses and serotypes of LPS on BBB integrity in Sprague-Dawley rats.

This study investigates the effects of vagus nerve stimulation (VNS) on seizure severity and blood-brain barrier (BBB) integrity in kindled rats with cortical dysplasia (CD).Pregnant rats were exposed to 145 cGy of gamma-irradiation on day 17 of pregnancy. In offsprings, kindling was induced by giving subconvulsive doses of pentylenetetrazole. Left VNS was performed for 48 h at output currents of 0.5 or 1 mA. Horseradish peroxidase (HRP) was used to study the BBB permeability. Immunohistochemistry for occludin and P-glycoprotein (P-gp) was also performed.Kindled rats with CD exhibited seizures with mean Racine's scores of 3.57 ± 1.2 during video EEG recording. Kindled animals with CD receiving VNS at 0.5 and 1.0 mA did not exhibit either clinical or electrophysiological signs of seizure. Immunostaining for occludin, a tight junction protein, in hippocampus remained relatively intact in all groups. VNS-treated and -untreated kindled animals with CD revealed intense immunostaining for P-gp in hippocampal formation (P0.01). Electron microscopic observations revealed frequent transport vesicles containing electron-dense HRP reaction products in the cytoplasm of brain capillary endothelial cells in both cerebral cortex and hippocampus of kindled animals with CD. Those which were exposed to 1 mA VNS were observed to have brain capillary endothelial cells largely devoid of HRP reaction products in both cerebral cortex and hippocampus.The results of this study suggest that VNS therapy at 1 mA inhibits seizure activity and protects BBB integrity by limiting the enhancement of transcellular pathway in kindled animals with CD.

We investigated the effects of topiramate (TPM), a novel broad spectrum anticonvulsant, on seizure severity, survival rate and blood-brain barrier (BBB) integrity during hyperthermic seizures in rats with cortical dysplasia (CD). Offsprings of irradiated mothers were used in this study. To show the functional and morphological alterations in BBB integrity, quantitative analysis of Evans blue (EB) extravasation, immunohistochemistry and electron microscopic assessment of horseradish peroxidase (HRP) permeability were performed. Rats with CD exposed to hyperthermia exhibited seizures with mean Racine's scores of 3.92 ± 1.2. Among the rats with CD pretreated with TPM, 21 of 24 rats showed no sign of seizure activity upon exposure to hyperthermia (p0.01). The immunoreactivity of occludin, a tight junction protein, remained essentially unaltered in capillaries of hippocampus in all groups. In animals with CD exposed to hyperthermia, the significantly increased p-glycoprotein immunoreactivity in hippocampus (p0.01) was slightly decreased by TPM pretreatment. Hyperthermic seizures increased BBB permeability to EB in animals with CD, but TPM pretreatment decreased the penetration of the tracer into the brain in these animals (p0.01). Ultrastructurally frequent vesicles containing HRP reaction products were observed in capillary endothelial cells in cerebral cortex and hippocampus of rats with CD subjected to hyperthermia-induced seizures, and TPM pretreatment prevented the development of HRP reaction products in these animals. The results of this study suggest that TPM inhibits seizure activity and maintains BBB integrity in the course of febrile seizures in the setting of CD.

The effects of immunoglobulin G and immunoglobulins enriched with immunoglobulin A and immunoglobulin M on blood-brain barrier integrity and survival rates in septic rats were comparatively investigated.Sepsis was induced by cecal ligation and perforation in Sprague-Dawley rats. The animals were divided into the following groups: Sham, cecal ligation and perforation, cecal ligation and perforation plus immunoglobulin G (250 mg/kg, intravenous), and cecal ligation and perforation plus immunoglobulins enriched with immunoglobulin A and immunoglobulin M (250 mg/kg, intravenous). Immunoglobulins were administered 5 mins before cecal ligation and perforation and the animals were observed for behavioral changes for 24 hrs following cecal ligation and perforation. Blood-brain barrier permeability was functionally and structurally evaluated by determining the extravasation of Evans Blue and horseradish peroxidase tracers, respectively. Immunohistochemistry and Western blotting for occludin were performed.The high mortality rate (34%) noted in the septic rats was decreased to 15% and 3% by immunoglobulin G and immunoglobulins enriched with immunoglobulin A and immunoglobulin M, respectively (p.01). Both immunoglobulin G and immunoglobulins enriched with immunoglobulin A and immunoglobulin M alleviated the symptoms of sickness behavior in the septic rats, with the animals becoming healthy and active. Increased extravasation of Evans Blue into the brain tissue of the septic rats was markedly decreased with the administration of both immunoglobulin G and immunoglobulins enriched with immunoglobulin A and immunoglobulin M (p.01). Occludin expression remained essentially unchanged in all groups, including the cecal ligation and perforation group. In the cecal ligation and perforation group, increased luminal and abluminal vesicles containing electron-dense horseradish peroxidase-reaction product were noted in the cytoplasm of endothelial cells located in the hippocampus and the cerebral cortex. Tight junction was ultrastructurally intact, suggesting that the transcellular pathway is responsible for the blood-brain barrier breakdown in sepsis. Following immunoglobulin G or immunoglobulins enriched with immunoglobulin A and immunoglobulin M treatment, no ultrastructural evidence of leaky capillaries in the brain was observed in the septic rats, indicating the blockade of the transcellular pathway by immunoglobulins administration.Our study suggests that immunoglobulin G and immunoglobulins enriched with immunoglobulin A and immunoglobulin M improve the integrity of the blood-brain barrier and inhibits cecal ligation and perforation-induced symptoms of sickness behavior in rats.

Obsessive compulsive disorder is a common psychiatric disorder defined by the presence of obsessive thoughts and repetitive compulsive actions. The mutations or polymorphic variants in mitochondrial DNA-encoded genes or nuclear genes result in oxidative stress, which has recently been associated with various psychiatric disorders. In order to understand the association of mitochondrial disorders with oxidative stress in obsessive compulsive disorder, we examined genetic variants of manganese superoxide dismutase and uncouple-2 antioxidant genes and malondialdehyde and glutathione, markers of oxidative stress. The study sample comprised 104 patients with OCD and 110 healthy controls. For manganese superoxide dismutase, the frequencies of CT (Ala/Val) genotype (p < 0.01) in patients were significantly lower than those of controls. In contrast, CC (Ala/Ala) genotype was significantly more frequent in patients than controls (p < 0.05). For uncouple-2 I/D, the frequencies of ID genotype (p < 0.01) and I allele (p < 0.05) were lower in patients as compared with controls. In contrast, DD genotype was more prevalent in patients than controls (p < 0.01). While whole blood glutathione was significantly diminished (p < 0.0001), serum malondialdehyde was significantly elevated in patients compared with controls (p < 0.0001). Malondialdehyde levels were significantly elevated in subjects with DD genotype of UCP-2 I/D (p < 0.05) and CC genotype of manganese superoxide dismutase (p < 0.05) as compared with II or ID and TT or CT genotype, respectively. Malondialdehyde levels in patients carrying CC (p < 0.05) or CT (p < 0.05) genotype were significantly higher than those of carrying TT genotype. In conclusion, CC genotype of manganese superoxide dismutase or DD genotype of UCP-2 might result in mitochondrial disorders by increasing oxidative stress in obsessive compulsive disorders.

The mechanisms underlying the changes in blood-brain barrier (BBB) integrity in septic encephalopathy are poorly understood. The present study was designed to examine whether hyperbaric oxygen therapy (HBOT) influences the response of BBB to sepsis induced by cecal ligation and puncture (CLP) in rats. Cerebral cortical and hippocampal tissue levels of tumor necrosis factor-alpha (TNF-α), malondialdehyde (MDA) and glutathione (GSH) levels were measured. BBB permeability was functionally and structurally evaluated by determining extravasation of Evans blue (EB) and horseradish peroxidase (HRP) tracers, respectively. Immunohistochemistry and western blotting for occludin were performed. HBOT did not alter TNF-α levels in CLP operated rats while a significant decrease was noted when the therapy was subjected to intact rats. MDA levels in animals subjected to CLP plus HBOT were significantly decreased. In septic rats, the decreased GSH levels were significantly increased by HBOT. While HBOT attenuated the increased BBB permeability to EB in rats subjected to CLP (P

We investigated the effect of polymorphic variants of c.1298A>C (Glu429Ala) and c.677C>T (Ala222Val) in methylenetetrahydrofolate (MTHFR) gene on the total homocysteine (tHcy), folate and B12 levels in patients with bipolar disorder, first-degree relatives of patients, and controls. The c.677C>T and c.1298A>C polymorphisms in MTHFR were determined by polymerase chain reaction-restriction fragment length polymorphism in 197 bipolar patients, 278 relatives and 238 controls. tHcy and folate and vitamin B12 levels were measured by Fluorescence Polarization Immunoassay and Electrochemiluminescence, respectively. The tHcy was significantly increased in patients and relatives. In contrast, folate and B12 were significantly lower in patients and relatives. Gender was not considered as a significant determinant in the multivariate analysis. Genotypes of c.1298A>C and c.677C>T were correlated with tHcy, folate and B12. Patients and relatives carrying TT and/or AA and AC genotypes had elevated tHcy and reduced folate and B12 levels. High tHcy but low folate and vitamin B12 levels may be a risk factor for development of bipolar disorder.

We examined whether the GRIK3 (T928G) polymorphic variants in patients with schizophrenia are different from those of their first-degree relatives and healthy controls. The study population was composed of 256 patients with schizophrenia, 305 first-degree relatives of schizophrenia patients and 242 healthy control subjects. The GRIK3 (T928G) polymorphism was determined by restriction fragment length polymorphism. The frequency of the TT genotype was predominant, whereas the GG genotype was rare among all groups. The frequencies of GRIK3 (T928G) genotype distributions in the patients with schizophrenia were similar to those of their relatives. The frequency of the GG genotype was significantly higher in patients than in healthy controls. Similarly, GG genotype distribution in relatives was elevated compared with that in controls, but this value did not reach statistical significance. On the other hand, the subgroups of schizophrenia patients did not show a significant association with the GRIK3 (T928G) gene. It appears that the patients share the same (GRIK3) T928G gene variants with their relatives. One interpretation of our findings is that the relatives are at risk for the development of schizophrenia in the future.

The present study investigated the effects of a single dose of intraperitoneal (i.p.) IgG and IgGAM administration on various behavioral alterations in a cecal ligation perforation (CLP)-induced sepsis model in rats.

The effect of intravenous immunoglobulin preparations - immunoglobulin G (IgG), immunoglobulin G enriched with IgA and IgM (IgGAM) - on blood-brain barrier (BBB) integrity and survival rate was comparatively investigated in septic rats.

This study aimed to explore the effects of hyperbaric oxygen (HBO2) on blood-brain barrier (BBB) integrity in rats, when administered for one (at 2.5 ATA, 3 HBO2 sessions a day) and five days (at 2.5 ATA, 3 HBO2 sessions a day for the first two days, and twice a day for the last three days). Horseradish peroxidase (HRP) was used to evaluate the BBB permeability. Superoxide dismutase (SOD) activity, glutathione (GSH) andmalondialdehyde (MDA) levels were measured in the cerebral cortex and hippocampus regions. Frequent vesicles containing HRP reaction products were observed in capillary endothelial cells in the cerebral cortex and hippocampus of rats subjected to HBO2. The accumulation of HRP reaction products in these brain regions was significantly higher than that of control animals (P