Effect of Dexamethasone on Transport of α-Aminoisobutyric Acid and Sucrose Across the Blood-Brain Barrier

The effect of glucocorticoids on the blood-brain barrier (BBB) was studied in rats following a single injection or 3 days of dexamethasone administration. Tracers with a low permeability across the intact endothelium, [14C]sucrose and alpha-[3H]aminoisobutyric acid ([3H]AIB), were simultaneously injected intravenously in untreated rats or in rats treated with dexamethasone. Unidirectional blood-to-brain transfer constants (Ki) in 14 regions of the rat brain were determined. In regions of control brain, average Ki values for AIB and sucrose were approximately 0.0020 and 0.00060 ml g-1 min-1, respectively. The lowest transfer constants were found in caudate nucleus, hippocampus, white matter, and cerebellum. In dexamethasone-treated animals, Ki values for both sucrose and AIB markedly decreased by 30-50% in almost all brain regions. These results indicate that a single injection or 3 days of treatment with dexamethasone causes an apparent reduction in the normal BBB permeability, and dexamethasone may greatly interfere with drug delivery into brain. These observations may have an importance for the administration of drugs in brain disease in the presence of steroids.     

Blood-brain barrier dysfunctions following systemic injection of kainic acid in the rat.

Changes in blood-brain barrier (BBB) permeability and cerebral metabolic activity following intravenous injection of kainic acid (KA; 6, 12 mg/Kg) in rats were assessed by calculating respectively a blood-to-brain transfer constant (Ki) for [14C]alpha-aminoisobutyric acid and local cerebral glucose utilization (LCGU) values, at different times (1 h, or acute seizures phase, and 48 h, or chronic pathology phase) after the induction of seizures. A significant increase in the local permeability of the BBB was observed 1 h after the injection of KA 6 mg/Kg (eliciting no significant changes in cerebral metabolic activity, except within the frontal cortex and the hippocampus) and 12 mg/Kg (which induced a marked and widespread enhancement of LCGU). On the contrary, during the pathology phase, persistent regional increases in Ki values were evidenced in rats treated with the lowest dose of the convulsant, but not in rats injected with KA 12 mg/Kg (a dose able to cause extensive neuronal damage). Thus one can speculate that: 1) KA-induced regional changes in the permeability of the BBB are not correlated with changes in neuronal activity; 2) opening of the BBB is not reliably associated with neuronal injury.     

Effects of wheatgerm agglutinin and aging on the regional brain uptake of HIV-1GP120.

HIV-1 is associated with infection and altered functions of the CNS, especially in the elderly. Most studies indicate that HIV-1 is not evenly distributed throughout the CNS but is concentrated in deep brain nuclei. This study examined whether regional or age-related differences in the permeability of the blood-brain barrier to gp120, the viral coat of HIV-1, exist. The initial concentration of gp120 in 10 brain regions correlated with vascular content in young and old mice. Susceptibility to wheatgerm agglutinin (WGA)-induced uptake of gp120, which relates to endothelial cell internalization, varied regionally, with no induction of uptake into the striatum or hypothalamus but with large increases in the cerebellum, cortex, and midbrain. Transport across the BBB, as measured by the unidirectional influx rate (Ki), also varied regionally with the hypothalamus, hippocampus, and pons-medulla showing the highest values for Ki and the striatum the lowest. These regional variations in the permeability of the BBB to gp120 could contribute to the inhomogeneous distribution of HIV-1 within the CNS whereas the failure to see differences with aging suggests other causes underlie the susceptibility of the elderly to the CNS manifestations of AIDS.     

Sufficient virus-neutralizing antibody in the central nerve system improves the survival of rabid rats

Background

Rabies is known to be lethal in human. Treatment with passive immunity for the rabies is effective only when the patients have not shown the central nerve system (CNS) signs. The blood–brain barrier (BBB) is a complex functional barrier that may compromise the therapeutic development in neurological diseases. The goal of this study is to determine the change of BBB integrity and to assess the therapeutic possibility of enhancing BBB permeability combined with passive immunity in the late stage of rabies virus infection.

Methods

The integrity of BBB permeability in rats was measured by quantitative ELISA for total IgG and albumin levels in the cerebrospinal fluid (CSF) and by exogenously applying Evans blue as a tracer. Western blotting of occludin and ZO-1, two tight junction proteins, was used to assess the molecular change of BBB structure.The breakdown of BBB with hypertonic arabinose, recombinant tumor necrosis factor-alpha (rTNF-γ), and focused ultrasound (FUS) were used to compare the extent of BBB disruption with rabies virus infection. Specific humoral immunity was analyzed by immunofluorescent assay and rapid fluorescent focus inhibition test. Virus-neutralizing monoclonal antibody (mAb) 8-10E was administered to rats with hypertonic breakdown of BBB as a passive immunotherapy to prevent the death from rabies.

Results

The BBB permeability was altered on day 7 post-infection. Increased BBB permeability induced by rabies virus infection was observed primarily in the cerebellum and spinal cord. Occludin was significantly decreased in both the cerebral cortex and cerebellum. The rabies virus-specific antibody was not strongly elicited even in the presence of clinical signs. Disruption of BBB had no direct association with the lethal outcome of rabies. Passive immunotherapy with virus-neutralizing mAb 8-10E with the hypertonic breakdown of BBB prolonged the survival of rabies virus-infected rats.

Conclusions

We demonstrated that the BBB permeability was altered in a rat model with rabies virus inoculation. Delivery of neutralizing mAb to the infected site in brain combined with effective breakdown of BBB could be an aggressive but feasible therapeutic mode in rabies when the CNS infection has been established.     

Effect of losartan on the blood-brain barrier permeability in diabetic hypertensive rats

Our previous publication has stressed the benefits of losartan, an angiotensin II receptor blocker, on the permeability of blood-brain barrier (BBB) and blood pressure during L-NAME-induced hypertension. This study reports the impacts of anti-hypertensive treatment by losartan on the brain endothelial barrier function and the arterial blood pressure, during acute hypertension episode, in experimentally diabetic hypertensive rats. Systolic blood pressure measurements were taken with tail cuff method before and during administration of L-NAME (0.5 mg/ml). We induced diabetes by using alloxan (50 mg/kg, i.p). Losartan (3 mg/kg, i.v) was given to rats following the L-NAME treatment. Acute hypertensive vascular injury was induced by epinephrine (40 microg/kg). The BBB disruption was quantified according to the extravasation of the Evans blue (EB) dye. L-NAME induced a significant increase in arterial blood pressure on day 14 in normoglycemic and hyperglycemic rats (p < 0.05). Losartan significantly reduced the increased blood pressure in hypertensive and diabetic hypertensive rats (p < 0.01). Epinephrine-induced acute hypertension in diabetic hypertensive rats increased the content of EB dye dramatically in cerebellum and diencephalon (p < 0.01) and slightly in both cerebral cortex (p < 0.05). Losartan treatment reduced the increased BBB permeability to EB dye in the brain regions of diabetic hypertensive rats treated with epinephrine (p < 0.05). This study indicates that, in diabetic hypertensive rats, epinephrine administration leads to an increase in microvascular-EB-albumin efflux to brain, however losartan treatment significantly attenuates this protein's transport to brain tissue.     

Effects of acute hyperosmolality on blood-brain barrier function in ovine fetuses and lambs

We examined the effects of hyperosmolality on blood-brain barrier (BBB) permeability during development to test the vulnerability of the immature barrier to stress. The BBB response to hyperosmolality was quantified using the blood-to-brain transfer constant (Ki) with alpha-aminoisobutyric acid in fetuses at 60% and 90% gestation, premature, newborn, and older lambs. Ki plotted against osmolality increased as a function of increases in osmolality in all groups and brain regions. The relationship was described (P < 0.05) by a segmented regression model. At lower osmolalities, changes in Ki were minimal, but after a break point (threshold) was reached, the increase (P < 0.05) was linear. We examined the responses of Ki to hyperosmolality within each brain region by comparing the thresholds and slopes of the second regression segment. Lower thresholds and higher slopes imply greater vulnerability to hyperosmolality in the younger groups. Thresholds increased (P < 0.05) with development in the thalamus, superior colliculus, pons, and spinal cord, and slopes of the second regression segment decreased (P < 0.05) in the cerebellum, hippocampus, inferior colliculus, medulla, and spinal cord. BBB resistance to hyperosmolality increased (P < 0.05) with development in most brain regions. The pattern of the Ki plotted against osmolality was (P < 0.05) heterogenous among brain regions in fetuses and premature and newborn lambs, but not in older lambs. We conclude that 1) BBB permeability increased as a function of changes in osmolality, 2) the barrier becomes more resistant to hyperosmolality during development, and 3) the permeability response to hyperosmolality is heterogenous among brain regions in fetuses and premature and newborn lambs.     

Low concentrations of hydrogen sulphide alter monoamine levels in the developing rat central nervous system.

The central nervous system is one of the primary target organs for hydrogen sulphide (H2S) toxicity; however, there are limited data on the neurotoxic effects of low-dose chronic exposure on the developing nervous system. Levels of serotonin and norepinephrine in the developing rat cerebellum and frontal cortex were determined following chronic exposure to 20 and 75 ppm H2S during perinatal development. Both monoamines were altered in rats exposed to 75 ppm H2S compared with controls; serotonin levels were significantly increased at days 14 and 21 postnatal in both brain regions, and norepinephrine levels were significantly increased at days 7, 14, and 21 postnatal in cerebellum and at day 21 in the frontal cortex. Exposure to 20 ppm H2S significantly increased the levels of serotonin in the frontal cortex at day 21, whereas levels of norepinephrine were significantly reduced in the frontal cortex at days 14 and 21, and at day 14 in the cerebellum.     

Lead induced alterations in nitrite and nitrate levels in different regions of the rat brain

Nitric oxide (NO) is a free radical synthesized by nitric oxide synthase (NOS) during the conversion of l-arginine to citrulline. Lead (Pb) affects neuronal functioning in the rat brain. Nitric oxide, a neuronal messenger has a short half life and converts immediately into nitrite and nitrate. The present study is designed to determine lead-induced alterations in NO production by measuring nitrite and nitrate in the cerebellum, the hippocampus, the frontal cortex and the brain stem of the rat brain. Male Sprague–Dawley rats were treated with lead acetate (5 and 15 mg/kg body wt.) by intraperitoneal injection. The control and experimental rats were sacrificed at the end of 7 and 14 days after treatment and different regions of the brain were isolated. Nitrite and nitrate (NOx) levels were estimated by the chemiluminescent method using the NOA 280 (Sievers). The data suggested dose-dependent and region-specific responses to lead. Both treatments of lead reduced NOx levels in the cerebellum and the hippocampus. However, the frontal cortex and the brain stem responded differently to Pb exposure. NOx levels in the frontal cortex were significantly increased in rats treated with low and high doses of Pb for 7 days but not in rats treated for 14 days, whereas in the brain stem, NOx levels were increased in a dose- and time-dependent manner. Although, the response was time-dependent, the variation between 7- and 14-day treatment was not clearly delineated. These results provide additional evidence that Pb exposure alters NO-production in rat brain leading to neuronal dysfunction.     

Effects of radiofrequency radiation exposure on blood-brain barrier permeability in male and female rats

During the last several decades, numerous studies have been performed aiming at the question of whether or not exposure to radiofrequency radiation (RFR) influences the permeability of the blood-brain barrier (BBB). The objective of this study was to investigate the effect of RFR on the permeability of BBB in male and female Wistar albino rats. Right brain, left brain, cerebellum, and total brain were analyzed separately in the study. Rats were exposed to 0.9 and 1.8 GHz continuous-wave (CW) RFR for 20 min (at SARs of 4.26 mW/kg and 1.46 mW/kg, respectively) while under anesthesia. Control rats were sham-exposed. Disruption of BBB integrity was detected spectrophotometrically using the Evans-blue dye, which has been used as a BBB tracer and is known to be bound to serum albumin. Right brain, left brain, cerebellum, and total brain were evaluated for BBB permeability. In female rats, no albumin extravasation was found in in the brain after RFR exposure. A significant increase in albumin was found in the brains of the RF-exposed male rats when compared to sham-exposed male brains. These results suggest that exposure to 0.9 and 1.8 GHz CW RFR at levels below the international limits can affect the vascular permeability in the brain of male rats. The possible risk of RFR exposure in humans is a major concern for the society. Thus, this topic should be investigated more thoroughly in the future.     

Effects of radiofrequency radiation exposure on blood-brain barrier permeability in male and female rats

During the last several decades, numerous studies have been performed aiming at the question of whether or not exposure to radiofrequency radiation (RFR) influences the permeability of the blood-brain barrier (BBB). The objective of this study was to investigate the effect of RFR on the permeability of BBB in male and female Wistar albino rats. Right brain, left brain, cerebellum, and total brain were analyzed separately in the study. Rats were exposed to 0.9 and 1.8?GHz continuous-wave (CW) RFR for 20?min (at SARs of 4.26?mW/kg and 1.46?mW/kg, respectively) while under anesthesia. Control rats were sham-exposed. Disruption of BBB integrity was detected spectrophotometrically using the Evans-blue dye, which has been used as a BBB tracer and is known to be bound to serum albumin. Right brain, left brain, cerebellum, and total brain were evaluated for BBB permeability. In female rats, no albumin extravasation was found in in the brain after RFR exposure. A significant increase in albumin was found in the brains of the RF-exposed male rats when compared to sham-exposed male brains. These results suggest that exposure to 0.9 and 1.8?GHz CW RFR at levels below the international limits can affect the vascular permeability in the brain of male rats. The possible risk of RFR exposure in humans is a major concern for the society. Thus, this topic should be investigated more thoroughly in the future.     

Dissimilar Aluminum and Gallium Permeation of the Blood-Brain Barrier Demonstrated by In Vivo Microdialysis

Aluminum (Al) and gallium (Ga) permeations of the blood-brain barrier (BBB) were assessed in rats. Unbound extracellular Al and Ga concentrations were ascertained at the two potential sites of BBB permeation, cerebral capillaries and choroid plexuses, by implantation of microdialysis probes in the frontal cortex and lateral ventricle, respectively. A microdialysis probe implanted in the jugular vein revealed unbound blood Al or Ga concentrations. Al or 67Ga citrate was administered via the femoral vein. Peak Al and Ga concentrations were seen within the first 10 min at all three sites. Area under the curve (concentration vs. time to final sample) values were calculated using RSTRIP. Within-rat overall frontal cortical/blood and lateral ventricular/blood ratios [brain/blood ratios (oBBRs)] were calculated from area under the curve values. Aluminum frontal cortical oBBRs were significantly higher than those for the lateral ventricle. Ga oBBRs were not significantly different between the two sites. Al and Ga oBBRs were significantly different in the lateral ventricle. These results suggest that the primary site of A1 permeation across the BBB is at cerebral capillaries, whereas Ga permeation across the BBB does not significantly differ between cerebral capillaries and choroid plexuses. The use of Ga as a model to study Al pharmacokinetics may not be appropriate in the elucidation of the site or mechanism of Al entry into the brain.     

Effects of Metabotropic Glutamate Receptor Stimulation on Blood–Brain Barrier Permeability During Focal Cerebral Ischemia

This investigation was performed to evaluate whether ACPD [(1S, 3R)-1-aminocyclopentane-1, 3-dicarboxylic acid], a metabotropic glutamate receptor agonist, would enhance the degree of increase in blood-brain barrier (BBB) permeability caused by focal cerebral ischemia. In this study, male Wistar rats were placed in control (n = 7) and ACPD (n = 7) groups under isoflurane anesthesia. Twenty minutes after middle cerebral artery (MCA) occlusion, patches of 10(-5) M ACPD or normal saline were placed on the ischemic cortex (IC) for a period of 40 min. Patches were changed every 10 min. One hour after MCA occlusion, BBB permeability was determined by measuring the transfer coefficient (Ki) of [alpha-14C] aminoisobutyric acid. There were no statistical differences in systemic blood pressures and heart rates between these groups. Blood gases were within normal limits. In the control group, the Ki of ischemic cortex (IC) was 2.1 times that of the contralateral cortex (CC) (3.7+/-0.9 vs. 1.8+/-0.3 microl/g/min). In the ACPD group, the Ki of the IC was 3.3 times that of the CC (5.0+/-0.7 vs. 1.5+/-0.4 microl/g/min). The increase in Ki of the ACPD group in the ischemic cortex was significantly greater than that in the control group. There was no significant difference in the Ki of the CC between these groups. Our data suggest that activation metabotropic glutamate receptors in the cortex can further augment the increase in BBB permeability caused by focal ischemia.     

Increased brain uptake and brain to blood efflux transport of 14C-GABA in spontaneously hypertensive rats

The brain uptake and brain to blood efflux transport of (14)C-GABA were studied in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats using 20 min bilateral in situ brain perfusion in rats anesthetized using urethane. The volume of distribution (Vd) of (14)C-GABA into cerebrospinal fluid (CSF) and brain regions (cortex, diencephalon, cerebellum, and brain stem) was significantly greater in SHR than in the corresponding regions in WKY rats (p<0.05). The estimated Vd value of (14)C-GABA in CSF of SHR was 3.4 fold greater than that in WKY. Also compared to WKY, the Vd of (14)C-GABA into cerebellum and cortex of SHR was 15.3 fold and 19.4 fold greater, respectively. Although the study of blood-brain barrier (BBB) integrity using (3)H-mannitol revealed increased paracellular permeability at the brain capillaries of SHR when compared to WKY rats, this was found to be only partially responsible for the increased (14)C-GABA uptake. The study of brain to blood efflux transport of (14)C-GABA (after loading of brain with (14)C-GABA by vascular perfusion) revealed that the half-time of elimination was significantly shorter in SHR (5.35+/-0.66 min) than in WKY rats (14.83+/-1.94 min), (p<0.001). HPLC analysis revealed that GABA concentrations in brain extracts and CSF of SHR were similar to those in WKY rats (p>0.05). The faster efflux in SHR might be, at least partially, responsible to compensate for increased uptake of this neurotransmitter and to preserve the protective function of BBB towards GABA. The protective function of the BCSFB towards GABA appears to be also preserved, since systemic infusion of GABA within a wide range of administered doses (0.004-5.00 mg/kg) produced an increase in GABA CSF concentration from around 0.5 microM to only 11 microM, and the obtained pattern of CSF GABA concentrations under these conditions did not differ between SHR and WKY rats, as revealed by HPLC.     

Bicuculline Up-Regulation of GABAA Receptors in Rat Brain

Effects of acute and subacute administration of bicuculline on [3H]muscimol, [3H]flunitrazepam, and t-[35S]butylbicyclophosphorothionate ([35S]TBPS) binding to various brain regions were studied in Sprague-Dawley rats. Acute administration of bicuculline affected neither the KD nor the Bmax of the three receptor sites. In rats treated subacutely with bicuculline (2 mg/kg, i.p., daily for 10 days), [3H]muscimol binding was increased in the frontal cortex, cerebellum, striatum, and substantia nigra. Scatchard analysis revealed that subacute treatment of rats with bicuculline resulted in a significantly lower KD of high-affinity sites in the striatum and in a significantly lower KD of high- and low-affinity sites in the frontal cortex. In the cerebellum, two binding sites were apparent in controls and acutely treated animals; however, only the high-affinity site was defined in subacutely treated animals, with an increase in the Bmax value. Triton X-100 treatment of frontal cortical membranes eliminated the difference in [3H]muscimol binding between control and subacute bicuculline treatments. On the other hand, [3H]muscimol binding was significantly increased in the cerebellum from bicuculline-treated animals even after Triton X-100 treatment. The apparent Ki of bicuculline for the GABAA receptor was also decreased in the frontal cortex and the striatum following the treatment. However, subacute administration of bicuculline affected neither the KD nor the Bmax of [3H]flunitrazepam and [35S]TBPS binding in the frontal cortex and the cerebellum. These results suggest that GABAA receptors are up-regulated after subacute administration of bicuculline, with no change in benzodiazepine and picrotoxin binding sites.     

The Effects of Zinc Treatment on the Blood–Brain Barrier Permeability and Brain Element Levels During Convulsions

We evaluated the effect of zinc treatment on the blood–brain barrier (BBB) permeability and the levels of zinc (Zn), natrium (Na), magnesium (Mg), and copper (Cu) in the brain tissue during epileptic seizures. The Wistar albino rats were divided into four groups, each as follows: (1) control group, (2) pentylenetetrazole (PTZ) group: rats treated with PTZ to induce seizures, (3) Zn group: rats treated with ZnCl₂ added to drinking water for 2 months, and (4) Zn?+?PTZ group. The brains were divided into left, right hemispheres, and cerebellum?+?brain stem regions. Evans blue was used as BBB tracer. Element concentrations were analyzed by inductively coupled plasma optical emission spectroscopy. The BBB permeability has been found to be increased in all experimental groups (p?<?0.05). Zn concentrations in all brain regions in Zn-supplemented groups (p?<?0.05) showed an increase. BBB permeability and Zn level in cerebellum?+?brain stem region were significantly high compared to cerebral hemispheres (p?<?0.05). In all experimental groups, Cu concentration decreased, whereas Na concentrations showed an increase (p?<?0.05). Mg content in all the brain regions decreased in the Zn group and Zn?+?PTZ groups compared to other groups (p?<?0.001). We also found that all elements’ levels showed hemispheric differences in all groups. During convulsions, Zn treatment did not show any protective effect on BBB permeability. Chronic Zn treatment decreased Mg and Cu concentration and increased Na levels in the brain tissue. Our results indicated that Zn treatment showed proconvulsant activity and increased BBB permeability, possibly changing prooxidant/antioxidant balance and neuronal excitability during seizures.     

Effect of Vitamin E on Blood-Brain Barrier Permeability in Aged Rats with PTZ-Induced Convulsions

The effect of vitamin E on blood-brain barrier (BBB) permeability was studied under conditions of pentylenetetrazole (PTZ)-induced convulsions in aged (23- to 24-month-old) male albino rats; Evans Blue was used as a tracer. The BBB permeability was found to increase considerably in rats with PTZ-evoked seizures; the Evans Blue contents in the left and right hemispheres and cerebellum + brainstem region were significantly higher than those in the control. Vitamin E at a dose of 70 mg/kg exerted practically no beneficial effect on the increased BBB permeability in rats with seizures, while a greater dose of vitamin E (700 mg/kg) exerted a significant protective effect, especially with respect to the cerebellum + brainstem regions (P < 0.01). The seizure-related rise in the arterial blood pressure was also smaller in the latter experimental group. Thus, our observations confirm the importance of the vitamin E dose as a protective factor for BBB permeability and demonstrate that the dose dependence of this antioxidant in aged animals differs from that in younger organisms.     

A Method for the In Vivo Investigation of the Serotonergic 5-HT2 Receptors in the Human Cerebral Cortex Using Positron Emission Tomography and 18F-Labeled Setoperone

Following previous validation in baboons, we have studied the characteristics of [18F]setoperone as a radioligand for investigating serotonergic 5-hydroxytryptamine2 (5-HT2) receptors in the normal, unmedicated human brain with positron emission tomography (PET); subjects orally pretreated with therapeutic amounts of ketanserin, sulpiride, or prazosin were also studied to evaluate the specificity and sensitivity of [18F]setoperone brain specific binding. In controls (n = 10), the tracer showed a clear-cut retention in both frontal cortex and striatum (known to contain a high density of 5-HT2 receptors) relative to cerebellum (known to be devoid of 5-HT2 receptors). In the seven young controls (20-39 years old), the frontal cortex/cerebellum and striatum/cerebellum ratios increased during the first hour to reach similar values of 2.53 +/- 0.12 and 2.38 +/- 0.11 (mean +/- SEM), respectively, and were essentially stable during the second hour. Pretreatment with ketanserin (a 5-HT2 blocker) significantly reduced the frontal cortex/cerebellum ratio to 0.7-1.0 at 65 min, whereas the striatum/cerebellum ratio was significantly, but only partially, reduced. During sulpiride treatment (a D2 blocker), the frontal cortex/cerebellum ratio was not altered, whereas the striatum/cerebellum ratio was significantly, but only partially, reduced. With prazosin pretreatment (an alpha 1-adrenergic blocker), neither the frontal cortex/cerebellum nor the striatum/cerebellum ratio was modified. These data in humans with PET demonstrate that [18F]setoperone labels with high sensitivity and selectivity 5-HT2 receptors in the frontal cortex; in striata, however, binding is to both 5-HT2 and D2 receptors. The deproteinated-to-whole plasma radio-activity concentration ratio increased with time following injection. The mean percentage of intact [18F]setoperone, in deproteinated plasma, was 82, 74, 53, 45, 30, and 22% at 5, 10, 20, 30, 60, and 110 min following injection, respectively. These data indicate that [18F]setoperone (a) is significantly bound to plasma proteins and (b) is significantly metabolized into several labeled metabolites that are much more hydrophilic than setoperone and, hence, presumably do not cross the blood-brain barrier. These results suggest the suitability of [18F]setoperone data for modeling of 5-HT2 receptor binding in brain.     

Alterations in soluble guanylate cyclase content and modulation by nitric oxide in liver disease

Hyperammonemia is the main responsible for the neurological alterations in hepatic encephalopathy in patients with liver failure. We studied the function of the glutamate-nitric oxide (NO)-cGMP pathway in brain in animal models of hyperammonemia and liver failure and in patients died with liver cirrhosis. Activation of glutamate receptors increases intracellular calcium that binds to calmodulin and activates neuronal nitric oxide synthase, increasing nitric oxide, which activates soluble guanylate cyclase (sGC), increasing cGMP. This glutamate-NO-cGMP pathway modulates cerebral processes such as circadian rhythms, the sleep-waking cycle, and some forms of learning and memory. These processes are impaired in patients with hepatic encephalopathy. Activation of sGC by NO is significantly increased in cerebral cortex and significantly reduced in cerebellum from cirrhotic patients died in hepatic coma. Portacaval anastomosis in rats, an animal model of liver failure, reproduces the effects of liver failure on modulation of sGC by NO both in cerebral cortex and cerebellum. In vivo brain microdialisis studies showed that sGC activation by NO is also reduced in vivo in cerebellum in hyperammonemic rats with or without liver failure. The content of alpha but not beta subunits of sGC are increased both in frontal cortex and cerebellum from patients died due to liver disease and from rats with portacaval anastomosis. We assessed whether determination of activation of sGC by NO-generating agent SNAP in lymphocytes could serve as a peripheral marker for the impairment of sGC activation by NO in brain. Chronic hyperammonemia and liver failure also alter sGC activation by NO in lymphocytes from rats or patients. These findings show that the content and modulation by NO of sGC are strongly altered in brain of patients with liver disease. These alterations could be responsible for some of the neurological alterations in hepatic encephalopathy such as sleep disturbances and cognitive impairment.     

Pentylenetetrazol-induced seizures and kindling: changes in free fatty acids,superoxide dismutase,and glutathione peroxidase activity

The whole brain free fatty acid (FFA) level, as well as the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPX) were determined in the frontal cortex, cerebellum, hippocampus, and pons-medulla region of the single pentylenetetrazol (PZT)-treated and PZT-kindled Hannover-Wistar rats. PZT administration in the convulsive dose caused significant increase of the brain FFA content. Decreased SOD activity was detected in the frontal cortex of PZT-kindled rats, whereas decreased GPX activity was found in the frontal cortex and cerebellum of all treated rats, as well as in the hippocampus and pons-medulla of PZT-kindled rats. Kindling caused distinctive change of antioxidative defense in the frontal cortex, hippocampus, and pons-medulla region.