Blood-Brain Barrier Permeability Is Exacerbated in Experimental Model of Hepatic Encephalopathy via MMP-9 Activation and Downregulation of Tight Junction Proteins

The present study was designed to investigate the mechanisms involved in blood-brain barrier (BBB) permeability in bile duct ligation (BDL) model of chronic hepatic encephalopathy (HE). Four weeks after BDL surgery, a significant increase was observed in serum bilirubin levels. Masson trichrome staining revealed severe hepatic fibrosis in the BDL rats. ^99mTc-mebrofenin retention was increased in the liver of BDL rats suggesting impaired hepatobiliary transport. An increase in permeability to sodium fluorescein, Evans blue, and fluorescein isothiocyanate (FITC)-dextran along with increase in water and electrolyte content was observed in brain regions of BDL rats suggesting disrupted BBB. Increased brain water content can be attributed to increase in aquaporin-4 mRNA and protein expression in BDL rats. Matrix metalloproteinase-9 (MMP-9) mRNA and protein expression was increased in brain regions of BDL rats. Additionally, mRNA and protein expression of tissue inhibitor of matrix metalloproteinases (TIMPs) was also increased in different regions of brain. A significant decrease in mRNA expression and protein levels of tight junction proteins, viz., occludin, claudin-5, and zona occluden-1 (ZO-1) was observed in different brain regions of BDL rats. VCAM-1 mRNA and protein expression was also found to be significantly upregulated in different brain regions of BDL animals. The findings from the study suggest that increased BBB permeability in HE involves activation of MMP-9 and loss of tight junction proteins.     

Blood-brain barrier disruption in the hypothalamus of young adult spontaneously hypertensive rats

Vascular permeability and endothelial glycocalyx were examined in young adult spontaneously hypertensive rats (SHR), stroke-prone SHR (SHRSP), and Wistar Kyoto rats (WKY) as a control, in order to determine earlier changes in the blood-brain barrier (BBB) in the hypothalamus in chronic hypertension. These rats were injected with horseradish peroxidase (HRP) as an indicator of vascular permeability. Brain slices were developed with a chromogen and further examined with cationized ferritin, a marker for evaluating glycocalyx. Staining for HRP was seen around vessels in the hypothalamus of SHR and SHRSP, but was scarce in WKY. The reaction product of HRP appeared in the abluminal pits of endothelial cells and within the basal lamina of arterioles, showing increased vascular permeability in the hypothalamus of SHR and SHRSP, whereas there were no leaky vessels in the frontal cortex of SHR and SHRSP, or in both areas of WKY. The number of cationized ferritin particles binding to the capillary endothelial cells was decreased in the hypothalamus of SHR and SHRSP, while the number decreased in the frontal cortex of SHRSP, compared with those in WKY. Cationized ferritin binding was preserved in some leaky arterioles, while it was scarce or disappeared in other leaky vessels. These findings suggest that BBB disruption occurs in the hypothalamus of 3-month-old SHR and SHRSP, and that endothelial glycocalyx is markedly damaged there without a close relationship to the early changes in the BBB.     

Adrenomedullin Improves the Blood–Brain Barrier Function Through the Expression of Claudin-5

Summary 1. Aims: Brain vascular endothelial cells secret Adrenomedullin (AM) has multifunctional biological properties. AM affects cerebral blood flow and blood–brain barrier (BBB) function. We studied the role of AM on the permeability and tight junction proteins of brain microvascular endothelial cells (BMEC).2. Methods: BMEC were isolated from rats and a BBB in vitro model was generated. The barrier functions were studied by measuring the transendothelial electrical resistance (TEER) and the permeability of sodium fluorescein and Evans’ blue albumin. The expressions of tight junction proteins were analyzed using immunocytochemistry and immunoblotting.3. Results: AM increased TEER of BMEC monolayer dose-dependently. Immunocytochemistry revealed that AM enhanced the claudin-5 expression at a cell–cell contact site in a dose-dependent manner. Immunoblotting also showed an overexpression of claudin-5 in AM exposure.4.Conclusions: AM therefore inhibits the paracellular transport in a BBB in vitro model through claudin-5 overexpression.     

Transforming Growth Factor-β1 Upregulates the Tight Junction and P-glycoprotein of Brain Microvascular Endothelial Cells

1. The present study was aimed at elucidating effects of transforming growth factor-beta (TGF-beta) on blood-brain barrier (BBB) functions with mouse brain capillary endothelial (MBEC4) cells. 2. The permeability coefficients of sodium fluorescein and Evans blue albumin for MBEC4 cells and the cellular accumulation of rhodamine 123 in MBEC4 cells were dose-dependently decreased after a 12-h exposure to TGF-beta1 (0.01-10 ng/mL). 3. The present study demonstrates that TGF-beta lowers the endothelial permeability and enhances the functional activity of P-gp, suggesting that cellular constituents producing TGF-beta in the brain may keep the BBB functioning.     

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.     

Tissue Plasminogen Activator Enhances the Hypoxia/reoxygenation-induced Impairment of the Blood–brain Barrier in a Primary Culture of Rat Brain Endothelial Cells

Hemorrhagic transformation is a major complication associated with tissue plasminogen activator (tPA) therapy for ischemic stroke. We studied the effect of tPA on the blood–brain barrier (BBB) function with our in vitro monolayer model generated using rat brain microvascular endothelial cells subjected either to normoxia or to hypoxia/reoxygenation (H/R) with or without the administration of tPA. The barrier function was evaluated by the transendothelial electrical resistance (TEER), the permeability of sodium fluorescein and Evans’ blue-albumin (EBA), and the uptake of lucifer yellow (LY). The permeability of sodium fluorescein and EBA was used as an index of paracellular and transcellular transport, respectively. The administration of tPA increased the permeability of EBA and the uptake of LY under normoxia. It enhanced the increase in the permeability of both sodium fluorescein and EBA, the decrease in the TEER, and the disruption in the expression of ZO-1 under H/R conditions. Administration of tPA could cause an increase in the transcellular transport under normoxia, and both the transcellular and paracellular transport of the BBB under H/R conditions in vitro. Even in humans, tPA may lead to an opening of the BBB under non-ischemic conditions and have an additional effect on the ischemia-induced BBB disruption.     

Immunogold study of effects of prenatal exposure to lipopolysaccharide and/or valproic acid on the rat blood-brain barrier vessels

The involvement of blood microvessels, representing the anatomic site of the blood-brain barrier (BBB), in brain damage induced by prenatal exposure to lipopolysaccharide (LPS) and/or valproic acid (VPA) was studied in four-week-old rats. The immunogold procedure was applied for localization at the ultrastructural level of endogenous albumin and glucose transporter (GLUT-1) in three brain regions: cerebral cortex, cerebellum and hippocampus. Four groups of rats were used: (1) untreated control, (2) prenatally VPA-treated, (3) prenatally LPS-treated, and (4) prenatally LPS- and VPA-treated. The functional state of the BBB was evaluated as follows: (a) by its tightness, i.e., permeability to blood-borne albumin, and (b) by the expression of GLUT-1 in the endothelial cells (ECs). Using morphometry, the labelling density for GLUT-1 was recorded over luminal and abluminal plasma membranes of the ECs, also providing information on their functional polarity. No extensive increase of vascular permeability and/or any considerable dysfunction of the BBB in experimental groups nos. 2 and 3 were observed, although in solitary vascular profiles, increased endocytosis or even transcytosis of albumin by ECs was noted. In experimental group no. 4, some vascular profiles showed scanty leakage (microleakage), manifested by the presence of immunosignals for albumin in the perivascular area. Although some fluctuations in the expression of GLUT-1 occurred in all experimental groups, especially in group no. 3, a most pronounced and significant diminution of the labelling density, in all three regions of the brain, was observed in group no. 4. This finding suggests the synergistic action of prenatally applied LPS and VPA that affects specific transport functions of glucose in the microvascular endothelium. The diminished or disturbed supply of glucose to selected brain regions can be one of the factors leading to previously observed behavioral disturbances in similarly treated rats.     

Distinct Patterns of Cerebral Extravasation by Evans Blue and Sodium Fluorescein in Rats

The Evans blue dye (EBD; 961 Da) and the sodium fluorescein dye (NaF; 376 Da) are commonly used inert tracers in blood-brain barrier (BBB) research. They are both highly charged low molecular weight (LMW) tracers with similar lipophobic profiles. Nevertheless, the EBD binds to serum albumin (69,000 Da) to become a high molecular weight (HMW) protein tracer when injected into the circulation, whereas the NaF remains an unbound small molecule in the circulation. In this study, rats were injected with equal doses of either EBD or NaF to monitor their blood and tissue distribution. The EBD was largely confined to the circulation with little accumulation in the peripheral organ and even less accumulation in the central tissue, whereas the NaF distributed more evenly between the blood and the peripheral organ but was also largely excluded from the central tissue. Importantly, the EBD crossed the BBB most effectively at the prefrontal cortex and the cerebellum, and most poorly at the striatum. In marked contrast, the NaF was evenly distributed throughout the brain. Finally, the EBD exhibited this same peculiar tissue distribution profile when administered by either bolus injection or slow infusion. Our study suggests that different regions of the brain are equally permeable to LMW inert dyes like the NaF, but are markedly different in permeability to HMW proteins such as EBD-labelled serum albumin.     

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.     

Increased permeability of primary cultured brain microvessel endothelial cell monolayers following TNF-alpha exposure.

TNF-alpha is a cytokine that produces increased permeability in the peripheral vasculature; however, little is known about the effects of TNF-alpha on the blood-brain barrier (BBB). Using primary cultured bovine brain microvessel endothelial cells (BBMEC) as an in vitro model of the BBB, this study shows that TNF-alpha produces a reversible increase in the permeability of the brain microvessel endothelial cells. The BBMEC monolayers were pre-treated with 100 ng/ml of TNF-alpha for periods ranging from 2 to 12 hours. Permeability was assessed using three molecular weight markers, fluorescein (376 MW), fluorescein-dextran (FDX-4400; 4400 MW), and FDX-70000 (MW 70000). The permeability of BBMEC monolayers to all three fluorescent markers was increased two-fold or greater in the TNF-alpha treatment group compared to control monolayers receiving no TNF-alpha. Significant changes in permeability were also observed with TNF-alpha concentrations as low as 1 ng/ml. These results suggest that TNF-alpha acts directly on the brain microvessel endothelial cells in a dynamic manner to produce a reversible increase in permeability. Exposure of either the lumenal or ablumenal side of BBMEC monolayers to TNF-alpha resulted in similar increases in permeability to small macromolecules, e.g. fluorescein. However, when a higher molecular weight marker was used (e.g. FDX-3000), there was a greater response following lumenal exposure to TNF-alpha. Together, these studies demonstrate a reversible and time dependent increase in brain microvessel endothelial cell permeability following exposure to TNF-alpha. Such results appear to be due to TNF's direct interaction with the brain microvessel endothelial cell.     

Effect of middle cerebral artery occlusion on the passage of pituitary adenylate cyclase activating polypeptide across the blood-brain barrier in the rat

Pituitary adenylate cyclase-activating polypeptide (PACAP) has been shown to be a potent neuroprotective agent in global and focal ischemia. We demonstrated that PACAP could cross the blood-brain barrier (BBB) by a saturable transport system, and a systemic administration of PACAP reduced the infarct induced by unilateral middle cerebral artery occlusion (MCAO). Therefore, we studied whether this transport system is affected by MCAO in the rat. The entry of PACAP38 into the brain was compared in five groups: control, 4, 6, 24, and 48 h after MCAO. [(125)I]PACAP38 was injected intravenously and serum and various brain regions were collected 3 min later. The rate of entry into the brain of PACAP38 was also determined. We showed that PACAP entered the rat brain via a rapid transport system when the BBB is intact. After transient (2 h) unilateral MCAO, all regions of the brain, showed a selective increase in the passage of PACAP38 across the BBB after 4 h after the occlusion, which was not related to any generalized change in the permeability of the BBB, as measured with albumin. A significant decrease in the amount of PACAP38 entering the brain was observed in the 6- and 24-h groups, but it returned to the baseline level in the 48-h group. These results suggest that focal cerebral ischemia can selectively modify the passage of PACAP38 across the BBB, in both damaged and undamaged sides of the brain, and that these changes in influx are not solely due to the disruption of BBB. These findings imply the necessity of adjusting the dose of intravenously administered PACAP38 in order to maximize its therapeutic effect on the brain damage resulting from focal ischemia     

Potential Role of Cerebral Glutathione in the Maintenance of Blood-Brain Barrier Integrity in Rat

Using the model of glutathione (GSH) depletion, possible role of GSH in the maintenance of blood-brain barrier (BBB) integrity was evaluated in rats. Administration (ip) of GSH depletors, diethyl maleate (DEM, 1–4 mmol/kg), phorone (2–3 mmol/kg) and 2-cyclohexene-1-one (CHX, 1 mmol/kg), to male adults was found to deplete brain and liver GSH and increase the BBB permeability to micromolecular tracers (sodium fluorescein and [¹⁴C]sucrose) in a dose-dependent manner at 2h. However, BBB permeability to macromolecular tracers such as horseradish peroxidase and Evan's blue remained unaltered. It was also shown that observed BBB permeability dysfunction was associated with brain GSH depletion. A lower magnitude of BBB increase in rat neonates, as compared to adults, indicated a possible bigger role of GSH in the BBB function of mature brain. The treatment with N-acetylcysteine, methionine and GSH provided a partial to full protection against DEM-induced brain (microvessel) GSH depletion and BBB dysfunction; however, the treatment with -tocopherol, ascorbic acid and turmeric were not effective. Our studies showed that cerebral GSH plays an important role in maintaining the functional BBB integrity.     

Blood Pressure-Independent Factors Determine the Susceptibility to Delayed Neuronal Death in the Stroke-Prone Spontaneously Hypertensive Rats

The stroke-prone spontaneously hypertensive rat (SHRSP) is vulnerable to delayed neuronal death (DND) in the CA1 subfield of the hippocampus after the transient forebrain ischemia by the occlusion of the bilateral carotid arteries. The present study was designed to show that the genetic factors independent of high blood pressure contributed to the high incidence of DND in SHRSP. Male rats of the four strains, SHRSP/Izm, SHRSP/Ngsk, SHR/Izm and a congenic strain for the blood pressure quantitative trait locus on chromosome 1 [SHRSP.WKY-(D1Wox29-D1Arb21)/Izm]were used in the experiments. At 13 weeks of age, the bilateral carotid arteries of rats were occluded for 10 min under anesthesia with their body temperature kept at 37°C. Seven days after the transient ischemia, the loss of the pyramidal cells in the CA1 was evaluated histologically. In some experiments, the blood flow was monitored with a laser Doppler flowmeter during the transient ischemia. The blood pressure in SHRSP/Izm was significantly greater than that in the other three strains. The incidence of DND, however, was not significantly different among SHRSP/Izm, SHRSP/Ngsk and the congenic strain (82, 74 and 65%, respectively), while SHR/Izm showed a significantly lower incidence (20%). Neither a significant correlation between the incidence of DND and the blood flow reduction during the occlusion, nor a significant inter-strain difference in the blood flow reduction was observed. The genetic factors independent of high blood pressure may contribute to the greater susceptibility to DND in SHRSP.     

Quantitative Analysis of Delayed Neuronal Death in the Hippocampal Subfields of SHRSP and SHR

Transient forebrain ischemia and reperfusion induces delayed neuronal death (DND) in the hippocampal Cornu Ammonis 1 (CA1) subfield of stroke-prone spontaneously hypertensive rat (SHRSP). The vulnerability to DND is potentially related to the genetic susceptibility to stroke in this strain. To elucidate the mechanism of DND in SHRSP, however, it is essential to establish a method for quantitative evaluation of DND, which is not available yet. Male SHRSPs and spontaneously hypertensive rats (SHRs) at 12 weeks of age were used in the experiment. The bilateral common carotid arteries were surgically occluded with aneurysmal clips for 10 min. The brain was taken out 7 days after the experiment of the transient ischemia, and was sliced into serial coronal sections. Quantitative estimation of the number of viable pyramidal cells in the CA1 and CA2/3 subfields was performed based on the stereology with a random and systematic sampling. The transient ischemia and reperfusion (TIR) significantly reduced the number of viable pyramidal cells in CA1 of SHRSP (61000 ± 20100 in TIR vs. 128500 ± 21900 in the sham-operation, P < 0.000001 by Student’s t-test), while no significant difference was observed in SHR (140300 ± 30800 in TIR vs. 128200 ± 16700 in the sham-operation, P = 0.35). Further analysis revealed a dorsal-ventral gradient in the distribution of DND in CA1 of SHRSP with the most severe change in the dorsal area. The quantitative measurement using a stereological method is useful in the precise evaluation of DND in SHRSP. This method can be applied in the studies of effects of medical treatments on the ‘ischemia/reperfusion’ insult.     

Pentosan polysulfate protects brain endothelial cells against bacterial lipopolysaccharide-induced damages

Peripheral inflammation can aggravate local brain inflammation and neuronal death. The blood-brain barrier (BBB) is a key player in the event. On a relevant in vitro model of primary rat brain endothelial cells co-cultured with primary rat astroglia cells lipopolysaccharide (LPS)-induced changes in several BBB functions have been investigated. LPS-treatment resulted in a dose- and time-dependent decrease in the integrity of endothelial monolayers: transendothelial electrical resistance dropped, while flux of permeability markers fluorescein and albumin significantly increased. Immunostaining for junctional proteins ZO-1, claudin-5 and beta-catenin was significantly weaker in LPS-treated endothelial cells than in control monolayers. LPS also reduced the intensity and changed the pattern of ZO-1 immunostaining in freshly isolated rat brain microvessels. The activity of P-glycoprotein, an important efflux pump at the BBB, was also inhibited by LPS. At the same time production of reactive oxygen species and nitric oxide was increased in brain endothelial cells treated with LPS. Pentosan polysulfate, a polyanionic polysaccharide could reduce the deleterious effects of LPS on BBB permeability, and P-glycoprotein activity. LPS-stimulated increase in the production of reactive oxygen species and nitric oxide was also decreased by pentosan treatment. The protective effect of pentosan for brain endothelium can be of therapeutical significance in bacterial infections affecting the BBB.     

Different vascular permeability between the sensory and secretory circumventricular organs of adult mouse brain

The blood-brain barrier (BBB) prevents free access of circulating molecules to the brain and maintains a specialized brain environment to protect the brain from blood-derived bioactive and toxic molecules; however, the circumventricular organs (CVOs) have fenestrated vasculature. The fenestrated vasculature in the sensory CVOs, including the organum vasculosum of lamina terminalis (OVLT), subfornical organ (SFO) and area postrema (AP), allows neurons and astrocytes to sense a variety of plasma molecules and convey their information into other brain regions and the vasculature in the secretory CVOs, including median eminence (ME) and neurohypophysis (NH), permits neuronal terminals to secrete many peptides into the blood stream. The present study showed that vascular permeability of low-molecular-mass tracers such as fluorescein isothiocyanate (FITC) and Evans Blue was higher in the secretory CVOs and kidney as compared with that in the sensory CVOs. On the other hand, vascular permeability of high-molecular-mass tracers such as FITC-labeled bovine serum albumin and Dextran 70,000 was lower in the CVOs as compared with that in the kidney. Prominent vascular permeability of low- and high-molecular-mass tracers was also observed in the arcuate nucleus. These data demonstrate that vascular permeability for low-molecular-mass molecules is higher in the secretory CVOs as compared with that in the sensory CVOs, possibly for large secretion of peptides to the blood stream. Moreover, vascular permeability for high-molecular-mass tracers in the CVOs is smaller than that of the kidney, indicating that the CVOs are not totally without a BBB.     

自发性高血压大鼠中枢血管紧张素Ⅱ的变化对中枢肾上腺素...

The content of norepinephrine (NE) and epinephrine (E) in the brain of spontaneously hypertensive rats has proved abnormal, but the cause remained unknown. It was shown in the recent work that NE content in pons, posterior hypothalamus, nucleus caudatus and E concentration in medulla oblongata, anterior and posterior hypothalamus of 12-week old stroke-prone spontaneously hypertensive rats (SHRSP) were much higher than those of age-matched Wister-Kyoto rats (WKY). SHRSP also showed higher levels of systolic blood pressure (SBP) and brain angiotensin II (A II) than WKY. Intracerebroventricular (icv) perfusion of angiotensin-converting enzyme inhibitor captopril (20 micrograms for each time and three times for each day for four weeks) inhibited the synthesis of brain A II and reduced SBP and NE, E contents in all examined brain areas in SHRSP and WKY. However, the effects of chronically perfused captopril on SBP and brain NE, E levels in SHRSP were much more significant than in WKY. The results indicate that the modulatory effects of central renin-angiotensin system (RAS) on central adrenergic and noradrenergic system might be overactivated in SHRSP, which might partially responsible for the abnormally high levels of NE, E in some of the brain areas of SHRSP.     

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.