Pharmacokinetics and distribution of fluvoxamine to the brain in rats under oxidative stress

Abstract

The effects of oxidative stress (OS) on the pharmacokinetics of fluvoxamine (FLV), particularly on FLV distribution in the plasma, were studied in ferric-nitrilotriacetate-induced OS rat models (OS rats). The study protocol involved a continuous FLV infusion (25.0 μg/kg/min). The resulting mean plasma FLV concentration measured in steady state OS rats was 0.13?±?0.01 μg/mL, which was significantly lower than plasma concentrations measured in control rats (0.19?±?0.01 μg/mL). Moreover, the mean FLV concentration in the OS rat brain (0.51?±?0.08 μg/g) was determined to be approximately half the concentration in control rat brains (0.95?±?0.11 μg/g). The FLV concentrations in both the unbound fraction of plasma and erythrocytes of OS rats were significantly greater than that of control rats. These results suggest the potential attenuation of FLV's pharmacological effects in patients under OS.     

Metabolism of polyamines and oxidative stress in the brain of cholestatic rats

In a recently published article in “Amino Acids” it was shown that obstructive jaundice of 9 days’ duration in rats induces significant alterations of polyamines’ metabolism in the brain, which might play an important pathogenetic role in cholestatic brain injury. The authors proposed that alterations of polyamines in cholestatic brain might induce neuronal toxicity through a mechanism that implicates the production of reactive oxygen species and oxidative stress, although this parameter was not evaluated in their study. This hypothesis is supported by our recent findings on brain oxidative status in rats with obstructive jaundice of 10 days’ duration. Potential interrelations of the two studies’ findings are discussed in this commentary.     

Aldosterone acts centrally to increase brain renin-angiotensin system activity and oxidative stress in normal rats

Aldosterone acts upon mineralocorticoid receptors in the brain to increase blood pressure and sympathetic nerve activity, but the mechanisms are still poorly understood. We hypothesized that aldosterone increases sympathetic nerve activity by upregulating the renin-angiotensin system (RAS) and oxidative stress in the brain, as it does in peripheral tissues. In Sprague-Dawley rats, aldosterone (Aldo) or vehicle (Veh) was infused for 1 wk via an intracerebroventricular (ICV) cannula, while RU-28318 (selective mineralocorticoid receptor antagonist), Tempol (superoxide dismutase mimetic), losartan [angiotensin II type 1 receptor (AT(1)R) antagonist], or Veh was infused simultaneously via a second ICV cannula. After 1 wk of ICV Aldo, plasma norepinephrine was increased and mean arterial pressure was slightly elevated, but heart rate was unchanged. These effects were ameliorated by ICV infusion of RU-28318, Tempol or losartan. Aldo increased expression of AT(1)R and angiotensin-converting enzyme (ACE) mRNA in hypothalamic tissue. RU-28318 minimized and Tempol prevented the increase in AT(1)R mRNA; RU-28318 prevented the increase in ACE mRNA. Losartan had no effect on AT(1)R or ACE mRNA. Immunohistochemistry revealed Aldo-induced increases in dihydroethidium staining (indicating oxidative stress) and Fra-like activity (indicating neuronal excitation) in neurons of the hypothalamic paraventricular nucleus (PVN). RU-28318 prevented the increases in superoxide and Fra-like activity in PVN; Tempol and losartan minimized these effects. Acute ICV infusions of sarthran (AT(1)R antagonist) or Tempol produced greater sympathoinhibition in Aldo-treated than in Veh-treated rats. Thus aldosterone upregulates key elements of brain RAS and induces oxidative stress in the hypothalamus. Aldosterone may increase sympathetic nerve activity by these mechanisms.     

Red wine prevents brain oxidative stress and nephropathy in streptozotocin-induced diabetic rats

We have studied the effects of red wine on brain oxidative stress and nephropathy in streptozotocin (STZ)-induced diabetic rats. Diabetes was induced in Wistar rats with a single intraperitonally injection of STZ (50 mg/kg). Two weeks before and four weeks after injection, red wine was given orally in both normal and diabetic rats. Blood samples were taken from the neck vascular trunk in order to determine the glucose, triglycerides, total cholesterol, HDL-cholesterol (HDL-c), atherogenic index (AI), total protein, blood urea nitrogen (BUN), creatinine, insulin, lipid peroxidation products, reduced glutathione (GSH) and superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities. As well, we estimated the lipid peroxidtion, GSH and SOD, GSH-Px and catalase activities in brain and renal homogenates, and the excretion of albumin, proteins and glucose in urine over 24 h period. The administration of STZ caused significant increases in levels of glycosuria, proteinuria, albuminuria, glycemia, total cholesterol and AI, as well as in lipid peroxidation products in the brain, plasma and kidney, whereas it decreased the GSH content and SOD, GSH-Px and catalase activities. Treatment with red wine significantly prevented the changes induced by STZ. These data suggested that red wine has a protective effect against brain oxidative stress, diabetic nephropathy and diabetes induced by STZ, as well as it protects against hypercholesterolemia and atherogenic risk.     

Arsenic induced blood and brain oxidative stress and its response to some thiol chelators in rats

Chronic arsenic toxicity is a widespread problem, not only in India and Bangladesh but also in various other regions of the world. Exposure to arsenic may occur from natural or industrial sources. The treatment that is in use at present employs administration of thiol chelators, such as meso 2,3-dimercaptosuccinic acid (DMSA) and sodium 2,3-dimercaptopropane 1-sulfonate (DMPS), which facilitate its excretion from the body. However, these chelating agents are compromised with number of limitations due to their lipophobic nature, particularly for their use in cases of chronic poisoning. During chronic exposure, arsenic gains access into the cell and it becomes mandatory for a drug to cross cell membrane to chelate intracellular arsenic. To address this problem, analogs of DMSA having lipophilic character, were examined against chronic arsenic poisoning in experimental animals. In the present study, therapeutic efficacy of meso 2,3-dimercaptosuccinic acid (DMSA), sodium 2,3-dimercaptopropane 1-sulfonate (DMPS), monoisoamyl DMSA (MiADMSA) were compared in terms of reducing arsenic burden, as well as recovery in the altered biochemical variables particularly suggestive of oxidative stress. Adult male Wistar rats were given 100-ppm arsenic for 10 weeks followed by chelation therapy with the above chelating agents at a dose of 50 mg/Kg (orally) once daily for 5 consecutive days. Arsenic exposure resulted in marked elevation in reactive oxygen species (ROS) in blood, inhibition of ALAD activity and depletion of GSH. These changes were accompanied by significant decline in blood hemoglobin level. MiADMSA was the most effective chelator in reducing ROS in red blood cells, and in restoring blood ALAD compared to two other chelators. Brain superoxide dismutase (SOD) and glutathione peroxidase (GPx) decreased, while ROS and TBARS increased significantly following arsenic exposure. There was a significant increase in the activity of glutathione-S-transferase (GST) with a corresponding decline in its substrate i.e. glutathione. Among all the three chelators, MiADMSA showed maximum reduction in the level of ROS in brain. Additionally, administration of MiADMSA was most effective in counteracting arsenic induced inhibition in brain ALAD, SOD and GPx activity. Based on these results and in particular higher metal decorporation from blood and brain, we suggest MiADMSA to be a potential drug of choice for the treatment of chronic arsenic poisoning. However, further studies are required for the choice of appropriate dose, duration of treatment and possible effects on other major organs.     

Pharmacokinetics and cerebral distribution of glycine administered to rats

High doses of glycine have been reported to improve negative schizophrenic symptoms, suggesting that ingested glycine activates glutamatergic transmission via N-methyl-d-aspartate (NMDA) receptors. However, the pharmacokinetics of administered glycine in the brain has not been evaluated. In the present study, the time- and dose-dependent distributions of administered glycine were investigated from a pharmacokinetic viewpoint. Whole-body autoradiography of radiolabeled glycine was performed, and time–concentration curves for glycine and serine in plasma, cerebrospinal fluid (CSF), and brain tissues were obtained. Furthermore, pharmacokinetic parameters were calculated. For a more detailed analysis, the amount of glycine uptake in the brain was evaluated using the brain uptake index method. Radiolabeled glycine was distributed among periventricular organs in the brain. Oral administration of 2?g/kg of glycine significantly elevated the CSF glycine concentration above the ED₅₀ value for NMDA receptors. The glycine levels in CSF were 100 times lower than those in plasma. Glycine levels were elevated in brain tissue, but with a slower time-course than in CSF. Serine, a major metabolite of glycine, was elevated in plasma, CSF, and brain tissue. Glycine uptake in brain tissue increased in a dose-dependent manner. Time–concentration curves revealed that glycine was most likely transported via the blood–CSF barrier and activated NMDA receptors adjacent to the ventricles. The pharmacokinetic analysis and the brain uptake index for glycine suggested that glycine was transported into brain tissue by passive diffusion. These results provide further insight into the potential therapeutic applications of glycine.     

Intracerebroventricular injection of streptozotocin in rats produces both oxidative stress in the brain and cognitive impairment

Recent reports suggest the involvement of free radicals in the pathophysiology of Alzheimer's disease [AD]. Streptozotocin [STZ] injection in the brain is known to cause cognitive impairment in rats and is likened to sporadic AD in humans. Though STZ is known to cause impairment in glucose and energy metabolism, it is not known whether this is associated with free radical generation. The present study was designed to investigate if the changes in learning and memory by intracerebroventricular administration of STZ are associated with changes in the markers of oxidative stress. Adult male Wistar rats [330-340 g] were injected with intracerebroventricular STZ [3 mg/kg] bilaterally stereotaxically under ketamine anesthesia [70 mg/kg]. The rats were treated with STZ twice, on day 1 and on day 3. The learning and memory behavior was analyzed using passive avoidance paradigms, elevated plus maze and the closed field activity test while the parameters of oxidative stress assessed were malondialdehyde [MDA] and glutathione. The behavioral tests were performed on day 17, 18 and 19. The rats developed significant deficits in learning, memory and cognitive behavior, indicated by deficits in passive avoidance paradigm and elevated plus maze as compared to sham rats. On day 21, the rats were sacrificed under ether anesthesia and the brains were analyzed for biochemical studies. There was a development of oxidative stress in the brain as indicated by significant elevations in malondialdehyde [MDA] levels and decreased levels of glutathione. The study demonstrates that intracerebroventricular STZ may be appropriate model for investigations of antioxidants as potential treatment in Alzheimer's dementia.     

Effect of chronic exposure to aspartame on oxidative stress in brain discrete regions of albino rats

This study was aimed at investigating the chronic effect of the artificial sweetener aspartame on oxidative stress in brain regions of Wistar strain albino rats. Many controversial reports are available on the use of aspartame as it releases methanol as one of its metabolite during metabolism. The present study proposed to investigate whether chronic aspartame (75 mg/kg) administration could release methanol and induce oxidative stress in the rat brain. To mimic the human methanol metabolism, methotrexate (MTX)-treated rats were included to study the aspartame effects. Wistar strain male albino rats were administered with aspartame orally and studied along with controls and MTX-treated controls. The blood methanol level was estimated, the animal was sacrificed and the free radical changes were observed in brain discrete regions by assessing the scavenging enzymes, reduced glutathione, lipid peroxidation (LPO) and protein thiol levels. It was observed that there was a significant increase in LPO levels, superoxide dismutase (SOD) activity, GPx levels and CAT activity with a significant decrease in GSH and protein thiol. Moreover, the increases in some of these enzymes were region specific. Chronic exposure of aspartame resulted in detectable methanol in blood. Methanol per se and its metabolites may be responsible for the generation of oxidative stress in brain regions.     

High‐fat diet and hydrochlorothiazide increase oxidative stress in brain of rats

This study evaluated the effect of possible synergic interaction between high fat diet (HF) and hydrochlorothiazide (HCTZ) on biochemical parameters of oxidative stress in brain. Rats were fed for 16 weeks with a control diet or with an HF, both supplemented with different doses of HCTZ (0.4, 1.0, and 4.0 g kg⁻¹ of diet). HF associated with HCTZ caused a significant increase in lipid peroxidation and blood glucose levels. In addition, HF ingestion was associated with an increase in cerebral lipid peroxidation, vitamin C and non‐protein thiol groups (NPSH) levels. There was an increase in vitamin C as well as NPSH levels in HCTZ (1.0 and 4.0 g kg⁻¹ of diet) and HF plus HCTZ groups. Na⁺–K⁺‐ATPase activity of HCTZ (4.0 g kg⁻¹ of diet) and HCTZ plus HF‐fed animals was significantly inhibited. Our data indicate that chronic intake of a high dose of HCTZ (4 g kg⁻¹ of diet) or HF change biochemical indexes of oxidative stress in rat brain. Furthermore, high‐fat diets consumption and HCTZ treatment have interactive effects on brain, showing that a long‐term intake of high‐fat diets can aggravate the toxicity of HCTZ. Copyright © 2009 John Wiley & Sons, Ltd.     

Effect of taurine on gastric oxidative stress and hemorrhagic erosion in brain ischemic rats

The effect of taurine on gastric hemorrhage and mucosal erosion in the brain ischemia (BI) is unknown. The aim of the research was to study the involvement of gastric oxidative stress in hemorrhagic erosion produced in BI rats. The protective effect of taurine on this erosion model was evaluated. Male Wistar rats were deprived of food for 24 h. Under chloral hydrate -anesthesia, bilateral carotid artery ligation (BCAL) was performed 12, 18 and 21 h after removal of food to obtain 12, 6 and 3 h of BI duration. The pylorus and carotid esophagus of rats also were ligated. The stomachs were then irrigated for 3 h with normal saline or simulated gastric juice containing 100 mM HCl plus 17.4 mM pepsin and 54 mM NaCl. The stomach was dissected. Gastric samples were harvested. The rat brain was dissected for examination of ischemia by using triphenyltetrazolium chloride staining method. Changes in gastric ulcerogenic parameters, such as decreased mucosal GSH level as well as enhanced gastric acid back-diffusion, mucosal lipid peroxide generation, histamine concentration, luminal hemoglobin content and mucosal erosion in gastric samples were measured. The results indicated that BCAL could produce severe BI in rats. Moreover, a BI- duration-dependent exacerbation of various ulcerogenic parameters also was observed in these rats. Intraperitoneal taurine (0-300 mg/kg) dose-dependently ameliorated gastric oxidative stress and hemorrhagic erosion in BI rats. Taken together, BI could produce gastric oxidative stress and hemorrhagic erosions that was ameliorated by taurine through stimulation of GSH biosynthesis and inhibition of oxidative stress.     

Pharmacokinetics and brain uptake of lactoferrin in rats

Lactoferrin (Lf) is an iron-binding glycoprotein belonging to the transferrin (Tf) family. Lf was reported to cross the blood brain barrier (BBB) via receptor-mediated transcytosis in an in vitro model of the BBB. In the present study, we compared the in vivo brain uptake of Lf with that of OX26, an anti-Tf receptor antibody, and Tf. These three proteins were radiolabeled with 125I and administered to rats by i.v. injection. We found that Lf was more rapidly eliminated from the blood compared with OX26 and Tf (The half-life of Lf was approximately 8 and 6 times shorter than that of OX26 and Tf, respectively; the area under the blood concentration-time curve of Lf was approximately 15 and 17 times smaller than that of OX26 and Tf, respectively), and mainly accumulated in the liver, spleen, and kidney. Markedly high brain uptake was observed for Lf relative to Tf and OX26. Lf might be useful as a ligand for facilitating drug delivery into the brain.     

Aluminum overload increases oxidative stress in four functional brain areas of neonatal rats

Background

Higher aluminum (Al) content in infant formula and its effects on neonatal brain development are a cause for concern. This study aimed to evaluate the distribution and concentration of Al in neonatal rat brain following Al treatment, and oxidative stress in brain tissues induced by Al overload.

Methods

Postnatal day 3 (PND 3) rat pups (n =46) received intraperitoneal injection of aluminum chloride (AlCl₃), at dosages of 0, 7, and 35 mg/kg body wt (control, low Al (LA), and high Al (HA), respectively), over 14 d.

Results

Aluminum concentrations were significantly higher in the hippocampus (751.0 ± 225.8 ng/g v.s. 294.9 ± 180.8 ng/g; p < 0.05), diencephalon (79.6 ± 20.7 ng/g v.s. 20.4 ± 9.6 ng/g; p < 0.05), and cerebellum (144.8 ± 36.2 ng/g v.s. 83.1 ± 15.2 ng/g; p < 0.05) in the HA group compared to the control. The hippocampus, diencephalon, cerebellum, and brain stem of HA animals displayed significantly higher levels of lipid peroxidative products (TBARS) than the same regions in the controls. However, the average superoxide dismutase (SOD) activities in the cerebral cortex, hippocampus, cerebellum, and brain stem were lower in the HA group compared to the control. The HA animals demonstrated increased catalase activity in the diencephalon, and increased glutathione peroxidase (GPx) activity in the cerebral cortex, hippocampus, cerebellum, and brain stem, compared to controls.

Conclusion

Aluminum overload increases oxidative stress (H₂O₂) in the hippocampus, diencephalon, cerebellum, and brain stem in neonatal rats.     

The role of anthocyanins as an antioxidant under oxidative stress in rats

Cyanidin 3-O-beta-D-glucoside (C3G) is included in anthocyanins, and expected to have a potency to scavenge active oxygen species in vivo. Rats were fed a diet containing C3G (2 g/kg diet) for 14 days, and then subjected to hepatic ischemia-reperfusion (I/R) as an oxidative stress model. I/R treatment elevated the liver thiobarbituric acid-reactive substance concentration and the serum activities of marker enzymes for liver injury, and lowered the liver reduced glutathione concentration. Feeding C3G significantly suppressed these changes caused by hepatic I/R. These results indicate that C3G functions as a potent antioxidant in vivo under oxidative stress. To clarify the mechanism of action of C3G, we investigated the absorption and metabolism of C3G in rats. C3G appeared in the plasma immediately after the oral administration of C3G. Protocatechuic acid, which seems to be produced by the degradation of cyanidin, was also present in the plasma. In the liver and kidneys, C3G was metabolized to methylated form.     

Identification of the oxidative stress proteome in the brain

The redox proteomics technique normally combines two-dimensional gel electrophoresis, mass spectrometry, and protein databases to analyze the cell proteome from various samples, thereby leading to the identification of specific targets of oxidative modification. Oxidative stress that occurs because of increased levels of reactive oxygen species and reactive nitrogen species can target most biomolecules, consequently leading to altered physiological function of the cells. Redox proteomics has identified oxidatively modified protein targets in various pathological conditions, consequently providing insight into the pathways involved in the pathogenesis of these conditions. This approach also can be used to identify possible protective mechanisms to prevent or delay these disorders.     

Glycine nano-selenium prevents brain oxidative stress and neurobehavioral abnormalities caused by MPTP in rats

BackgroundParkinson's disease (PD) is a common degenerative disease of the central nervous system in the elderly. In recent years, the results of clinical and experimental studies have shown that oxidative stress is one of the important pathogenesis of PD. Selenium is one of the minor elements reported to possess antioxidant properties. Thus, the purpose of this study was to investigate the recovery effect of glycine nano-selenium on neurobehavioral abnormalities and oxidative stress caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in rat.Materials and methodsSD male rats weighing 280−310 g were purchased from the Chengdu Dossy Experimental Animals Company, China. All rats were housed in a temperature-controlled room, with a 12 h light–dark cycles and had free access to food and water ad libitum. Rats were randomly divided into 4 groups with 8 animals in each group: the control group (normal saline), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine group (MPTP), MPTP + 0.05 mg/kg glycine nano-selenium (MPTP + 0.05 Se), MPTP + 0.1 mg/kg glycine nano-selenium (MPTP + 0.1 Se). Behavioral assessment, clinical symptoms, Immunohistochemistry analysis of tyrosine hydroxylase (TH) and antioxidant activity were accessed to determine the protective effects glycine nano-selenium have on PD rats.ResultsFrom the results, Rats showed a decrease in spontaneous motor behavior and an increase in pole test score. Also, the number of TH⁺ neurons were also significantly decreased (P < 0.05) after treated with MPTP for 7 days indicating that MPTP could successfully induce neurobehavioral abnormalities in rats. Furthermore, the lipid peroxide (MDA) levels of the PD model group were significantly increased and the antioxidant activities (SOD and GSH-PX) were significantly inhibited (P < 0.05) compared to the control group indicating the important role oxidative stress played in dopaminergic neuron death and neurobehavioral abnormalities in PD rats. Compared with the PD model group, glycine nano-selenium administration could significantly improve behavior and increase the number of TH⁺ neurons (P < 0.05) to protect against the loss of dopaminergic neurons. At the same time, glycine nano-selenium could decrease the MDA levels and increase the activities of SOD and GSH-PX significantly (P < 0.05).ConclusionIn conclusion, PD rat model was successfully developed by intraperitoneal injection of MPTP and the intragastric administration of glycine nano-selenium reduced neurobehavioral abnormalities by decreasing oxidative stress in rat brain.     

Intermittent hypoxia conditioning prevents behavioral deficit and brain oxidative stress in ethanol-withdrawn rats.

Intermittent hypoxia (IH) has been found to protect brain from ischemic injury. We investigated whether IH mitigates brain oxidative stress and behavioral deficits in rats subjected to ethanol intoxication and abrupt ethanol withdrawal (EW). The effects of IH on overt EW behavioral signs, superoxide generation, protein oxidation, and mitochondrial permeability transition pore (PTP) opening were examined. Male rats consumed dextrin or 6.5% (wt/vol) ethanol for 35 days. During the last 20 days, rats were treated with repetitive (5-8 per day), brief (5-10 min) cycles of hypoxia (9.5-10% inspired O2) separated by 4-min normoxia exposures. Cerebellum, cortex, and hippocampus were biopsied on day 35 of the diet or at 24 h of EW. Superoxide and protein carbonyl contents in tissue homogenates and absorbance decline at 540 nm in mitochondrial suspensions served as indicators of oxidative stress, protein oxidation, and PTP opening, respectively. Although IH altered neither ethanol consumption nor blood ethanol concentration, it sharply lowered the severity of EW signs including tremor, tail rigidity, and startle response. Compared with dextrin and ethanol per se, in the three brain regions, EW increased superoxide and protein carbonyl contents and accelerated PTP opening in a manner ameliorated by IH. Administration of antioxidant N-acetylcysteine throughout the IH program abrogated the reductions in EW signs and superoxide content, implicating IH-induced ROS as mediators of the salutary adaptations. We conclude that IH conditioning during chronic ethanol consumption attenuates oxidative damage to the brain and mitigates behavioral abnormalities during subsequent EW. IH-induced ROS may evoke this powerful protection.     

Subcellular distribution of glutathione and its dynamic changes under oxidative stress in the yeast Saccharomyces cerevisiae

Glutathione is an important antioxidant in most prokaryotes and eukaryotes. It detoxifies reactive oxygen species and is also involved in the modulation of gene expression, in redox signaling, and in the regulation of enzymatic activities. In this study, the subcellular distribution of glutathione was studied in Saccharomyces cerevisiae by quantitative immunoelectron microscopy. Highest glutathione contents were detected in mitochondria and subsequently in the cytosol, nuclei, cell walls, and vacuoles. The induction of oxidative stress by hydrogen peroxide (H(2) O(2) ) led to changes in glutathione-specific labeling. Three cell types were identified. Cell types I and II contained more glutathione than control cells. Cell type II differed from cell type I in showing a decrease in glutathione-specific labeling solely in mitochondria. Cell type III contained much less glutathione contents than the control and showed the strongest decrease in mitochondria, suggesting that high and stable levels of glutathione in mitochondria are important for the protection and survival of the cells during oxidative stress. Additionally, large amounts of glutathione were relocated and stored in vacuoles in cell type III, suggesting the importance of the sequestration of glutathione in vacuoles under oxidative stress.     

替米沙坦及吡哆胺对自发性高血压大鼠脑组织氧化应激的影响

目的:探讨替米沙坦及吡哆胺对自发性高血压大鼠脑组织氧化应激的影响。方法:自发性高血压大鼠24只随机分为4组(n=6):高血压对照组(HC组);替米沙坦组(T组);吡哆胺组(P组);联合治疗组(TP组)。同龄WKY大鼠作为正常对照组(NC组)。药物干预16周,测定各组脑组织中丙二醛(MDA)含量、超氧化物歧化酶(SOD)活性及烟酰胺腺嘌呤二核苷酸磷酸(NADPH)氧化酶p47phox mRNA表达。结果:与NC组比较,HC组脑组织中MDA含量明显升高、SOD活性明显减低(P<0.05);与HC组比较T组、P组、TP组MDA含量明显减低,SOD活性明显升高(P<0.05);与NC组比较HC组(NADPH)氧化酶p47phox mRNA表达显著上调(P<0.01);与HC组比较T组、TP组NADPH氧化酶p47phox mRNA表达明显下调(P<0.01);HC组与P组比较NADPH氧化酶p47phox mRNA表达无统计学差异(P>0.05)。结论:自发性高血压大鼠脑组织处于氧化应激状态,替米沙坦及吡哆胺可抑制自发性高血压大鼠脑组织的氧化应激水平,联合治疗并不优于替米沙坦单药治疗。     

Opioid peptide content of the brain and blood of rats under immobilization stress

A study was made of the influence of acute and repeated immobilization on the content of immunoreactive metenkephalin (ME), leu-enkephalin (LE) and beta-endorphine (beta-E) in different regions of rat brain and that of beta-E in rat blood. Acute immobilization for 30 min led to a decrease in the content of the enkephalins in the hypothalamus. Meanwhile 150-min immobilization caused a remarkable increase in the opioid concentration in the hypothalamus and of the enkephalins in the pituitary. At the same time the beta-E content in the pituitary dropped to 38% of the control (P less than 0.001), that in the blood was twice as increased (P less than 0.05). Repeated immobilization for 7 days abolished these changes in the hypothalamus and pituitraty. The next day following immobilization for 39 days the content of LE and beta-E in the hypothalamus, medulla oblongata, midbrain and blood plasma was noticeably lowered. However, after successive immobilization it rose to the control level. The data obtained are discussed in the light of the involvement of opiate systems in the realization of antinociceptive and emotional effects of stress.     

Acrolein induces oxidative stress in brain mitochondria

Acrolein, a byproduct of lipid peroxidation, has been shown to inflict significant structural and functional damage to isolated guinea pig spinal cord. Reactive oxygen species (ROS) are thought to mediate such detrimental effects. The current study demonstrates that acrolein can directly stimulate mitochondrial oxidative stress. Specifically, exposure of purified brain mitochondria to acrolein resulted in a dose-dependent increase of ROS and decreases in glutathione content and aconitase activity. This effect was not accompanied by significant intramitochondrial calcium influx or mitochondrial permeability transition, but rather by impaired function of the mitochondrial electron transport system. As well, we detected a significant inhibition of mitochondrial adenine nucleotide translocase (ANT) in the presence of acrolein. This inhibition of ANT likely contributes to acrolein-induced ROS elevation since application of atractyloside, a specific ANT inhibitor, induced significant increase of ROS. We hypothesize that inhibition of ANT may mediate, in part, the acrolein-induced ROS increase in mitochondria.