Extracellular Glutamate Is Increased in Thalamus During Thiamine Deficiency-Induced Lesions and Is Blocked by MK-801

The current study measured extracellular fluid (ECF) levels of excitatory amino acids before and during the onset of thiamine deficiency-induced pathologic lesions. Male Sprague-Dawley rats were treated with daily pyrithiamine (0.25 mg/kg i.p.) and a thiamine-deficient diet (PTD). Microdialysates were simultaneously collected from probes inserted acutely via guide cannulae into right paracentral and ventrolateral nuclei of thalamus and left hippocampus of PTD and pair-fed controls. Hourly samples were collected from unanesthetized and freely moving animals. Basal levels obtained at a prelesion stage (day 12 of PTD treatment) were unchanged from levels in pairfed controls. In samples collected 4–5 h after onset of seizures (day 14 of PTD), the levels of glutamate were elevated an average 640% of basal levels in medial thalamus and 200% in hippocampus. Glutamine levels declined, taurine and glycine were elevated, and aspartate, GABA, and alanine were unchanged during this period. Within 7 h after seizure onset glutamine was undetectable in both areas, whereas glutamate had declined to ～200% in thalamus and 70% in hippocampus. No significant change in glutamate, aspartate, or other amino acids was observed in dialysates collected from probes located in undamaged dorsal-lateral regions of thalamus. Number of neurons within ventrolateral nucleus of thalamus was significantly greater in PTD animals in which the probe was dialyzed compared with nondialyzed, suggesting that removal of excitatory amino acids was protective. No significant pathologic damage was evident in hippocampus. Pretreatment with MK-801 completely blocked the rise of ECF glutamate and significantly reduced the pathologic damage within thalamus of PTD rats and produced a significant decrease in ECF glutamate in control rats.     

Protective effect of aspartate and glutamate on cardiac mitochondrial function during myocardial infarction in experimental rats

The present study investigates the effect of aspartate and glutamate on mitochondrial function during myocardial infarction (MI) in wistar rats. Male albino wistar rats were pretreated with aspartate [100 mg(kgbody weight)(-1) day(-1)] or glutamate [100 mg(kg body weight)(-1) day(-1)] intraperitoneally for a period of 7 days. Following amino acid treatment, MI was induced in rats by subcutaneous injection of isoproterenol [200 mg(kg body weight)(-1) day(-1)] for 2 days at an interval of 24 h. Isoproterenol (ISO) induction resulting in significant (P<0.05) increase in the levels of cardiac mitochondrial lipid peroxidation with a decrease in reduced glutathione level. The activities of glutathione peroxidase and glutathione reductase were significantly (P<0.05) decreased by ISO. ISO-induction also caused significant (P<0.05) decrease in the activities of mitochondrial tricarboxylic acid cycle enzymes (malate dehydrogenase, isocitrate dehydrogenase, succinate dehydrogenase, alpha-ketoglutarate dehydrogenase) and respiratory chain enzymes (NADH dehydrogenase and cytochrome-c-oxidase). ISO significantly (P<0.05) reduced the cytochrome contents, ATP production, ADP/O ratio and oxidation of succinate in state 3/state 4 whereas significantly (P<0.05) increased NADH oxidation. Pretreatment with aspartate or glutamate significantly (P<0.05) reduced the alterations induced by ISO and maintained normal mitochondrial function. The present findings reveal the protective effect of aspartate and glutamate on cardiac mitochondrial function in myocardial infarction-induced rats.     

Glycine modulates N-methyl-D-aspartic acid induced learning facilitation in rats

Summary Pretraining i.p. administration of N-methyl-D-aspartic acid (NMDA) at doses of 10 and 20mg/kg dose-dependently facilitated performance in a water T-maze learning task in rats. The effect of NMDA was inhibited by the competitive NMDA receptor antagonist CGP37849 [(DL)-E(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid] (CGP) at a dose of 6mg/kg, and by the NMDA receptor complex glycine site antagonist 1-hydroxy-3-amino-2-pyrrolidone (HA-966) at a dose of 10mg/kg. The NMDA site antagonist, when given alone, did not impair learning. The glycine precursor milacemide (2-N-pentylaminoacetamide HCl), at doses of 5 and 10mg/kg accelearted learning acquisition and its effect was antagonized by HA-966. The learning rate was impaired following the administration of NMDA 10mg/kg together with milacemide 5mg/kg when compared with the effect of 10mg/kg NMDA alone.The administration of 5mg/kg NMDA was associated with an elevated tissue concentration of aspartate in the hippocampus, an effect which was antagonized by 6mg/kg of CGP. NMDA at doses of 10 and 20mg/kg elevated the concentration of glycine but decreased the concentration of aspartate, glutamate and glutamine in the cortex and aspartate in the hippocampus. The cortical effects of NMDA 10mg/kg were antagonized by 6mg/kg of CGP. Milacemide at the dose of 10mg/kg elevated glycine, aspartate, glutamate and taurine concentrations. The coadministration of 5 mg/kg NMDA with 5mg/kg milacemide elevated the concentrations of glycine, glutamate and glutamine in the cortex and taurine in the hippocampus. These amino acid levels were higher than after administration of 5mg/kg either agent alone. The results demonstrate a dose-dependent facilitation effect on learning performance by NMDA and glycine receptor agonists. Antagonists at the NMDA and glycine sites counteracted the learning improvement of NMDA, and the glycine site antagonist the effect of milacemide.     

Effect of the Non-NMDA Receptor Antagonist GYKI 52466 on the Microdialysate and Tissue Concentrations of Amino Acids Following Transient Forebrain Ischaemia

Abstract: The effect of the non-N-methyl-D-aspartate (non-NMDA) receptor antagonist 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride (GYKI 52466) on ischaemia-induced changes in the microdialysate and tissue concentrations of glutamate, aspartate, and γ-aminobutyric acid (GABA) was studied in rats. Twenty minutes of four-vessel occlusion resulted in a transient increase in microdialysate levels of glutamate, aspartate, and GABA in striatum, cortex, and hippocampus. Administration of GYKI 52466 (10 mg/kg bolus + 10 mg/kg/60 min intravenously starting 20 min before onset of ischaemia) inhibited ischaemia-induced increases in microdialysate glutamate and GABA in striatum without affecting the increases in hippocampus or cortex. Twenty minutes of four-vessel occlusion resulted in immediate small decreases and larger delayed (72 h) decreases in tissue levels of glutamate and aspartate. Transient increases in tissue levels of GABA were shown in all three structures at the end of the ischaemic period. At 72 h, after the ischaemic period, significantly reduced GABA levels were observed in striatum and hippocampus. GYKI 52466, given under identical conditions as above, augmented the ischaemia-induced decrease in striatal tissue levels of glutamate and aspartate, without significantly affecting the decreases in hippocampus and cortex. Twenty minutes of ischaemia resulted in a large increase in microdialysate dopamine in striatum. GYKI 52466 failed to inhibit this increase. Kainic acid (500 μM infused through the probe for 20 min) caused increases in microdialysate glutamate and aspartate in the striatum. GYKI 52466 (10 mg/ kg bolus + 10 mg/kg/60 min) completely inhibited the kainic acid-induced glutamate release. In conclusion, the action of the non-NMDA antagonist, GYKI 52466, in the striatum is different from that in the cortex and hippocampus. The inhibition by GYKI 52466 of ischaemia-induced and kainate-induced increases in microdialysate glutamate concentration in the striatum may be related to the neuroprotection provided by GYKI 52466 in this region.     

Acute and Repeated Systemic Amphetamine Administration: Effects on Extracellular Glutamate, Aspartate, and Serine Levels in Rat Ventral Tegmental Area and Nucleus Accumbens

Abstract: Recent work indicates an important role for excitatory amino acids in behavioral sensitization to amphetamine. We therefore examined, using in vivo microdialysis in awake rats, the effects of amphetamine on efflux of glutamate, aspartate, and serine in the ventral tegmental area and nucleus accumbens, brain regions important for the initiation and expression of amphetamine sensitization, respectively. Water-pretreated and amphetamine-pretreated rats were compared to determine if sensitization altered such effects. In both brain regions, Ca²⁺-dependent efflux of glutamate accounted for ∼20% of basal glutamate efflux. A challenge injection of water or 2.5 mg/kg of amphetamine did not significantly alter glutamate, aspartate, or serine efflux in the ventral tegmental area or nucleus accumbens of water- or amphetamine-pretreated rats. However, 5 mg/kg of amphetamine produced a gradual increase in glutamate efflux in both regions that did not reverse, was observed in both water- and amphetamine-pretreated rats, and was prevented by haloperidol. Although increased glutamate efflux occurred with too great a delay to mediate acute behavioral responses to amphetamine, it is possible that repeated augmentation of glutamate efflux during repeated amphetamine administration results in compensatory changes in levels of excitatory amino acid receptors in the ventral tegmental area and nucleus accumbens that contribute to development or expression of amphetamine sensitization.     

A comparison of the glutamate release inhibition and anti-allodynic effects of gabapentin, lamotrigine, and riluzole in a model of neuropathic pain

The effects of treatment with the anti-convulsant agents, lamotrigine and riluzole were compared with gabapentin in a rat experimental model of neuropathic pain. Rats were treated intraperitoneally, with gabapentin (30, 100 and 300 mg/kg), lamotrigine (2, 10 and 50 mg/kg) or riluzole (6 and 12 mg/kg) prior to, and every 12 h for 4 days following chronic constriction injury (CCI) of the sciatic nerve. Mechanical and cold sensitivity were assessed prior to surgery (baseline) and then at 4, 8 and 12 days following CCI. The four-day treatment with each of the agents was effective at producing reductions in the development of mechanical and cold hypersensitivity for periods ranging from the fourth to 12th day. The highest doses of each of the agents were also assessed on formalin-induced nociceptive behaviors and on formalin-induced increases in extracellular glutamate (Glu) and aspartate (Asp) in the spinal cord dorsal horn (SCDH) of awake behaving rats using in vivo microdialysis. Nociceptive scores in formalin test were significantly decreased by gabapentin (300 mg/kg i.p.) and riluzole (12 mg/kg i.p.), but not by lamotrigine (50 mg/kg i.p.). Formalin-induced increases in glutamate levels in SCDH were lowered significantly, as compared with the controls, with all drugs both in the first phase and second phases, with the greatest effects for riluzole and gabapentin. Similar suppressive effects of the drugs were observed on formalin-induced increases in spinal aspartate, except that gabapentin and lamotrigine produced effects only during the second phase. Riluzole produced profound and prolonged reductions in the spinal levels of glutamate and aspartate both for basal and formalin-stimulated release. In conclusion, the results suggest that the anti-convulsant agents gabapentin, lamotrigine and riluzole may reduce the development of hyperalgesia in a rat model of neuropathic pain by reducing the spinal release of glutamate. Riluzole's pronounced suppressive effects on spinal EAA levels is attributed to its established role as a glutamate release inhibitor and an enhancer of glutamate transporter activity.     

NAAG peptidase inhibitor increases dialysate NAAG and reduces glutamate, aspartate and GABA levels in the dorsal hippocampus following fluid percussion injury in the rat

Traumatic brain injury (TBI) produces a rapid and excessive elevation in extracellular glutamate that induces excitotoxic brain cell death. The peptide neurotransmitter N-acetylaspartylglutamate (NAAG) is reported to suppress neurotransmitter release through selective activation of presynaptic group II metabotropic glutamate receptors. Therefore, strategies to elevate levels of NAAG following brain injury could reduce excessive glutamate release associated with TBI. We hypothesized that the NAAG peptidase inhibitor, ZJ-43 would elevate extracellular NAAG levels and reduce extracellular levels of amino acid neurotransmitters following TBI by a group II metabotropic glutamate receptor (mGluR)-mediated mechanism. Dialysate levels of NAAG, glutamate, aspartate and GABA from the dorsal hippocampus were elevated after TBI as measured by in vivo microdialysis. Dialysate levels of NAAG were higher and remained elevated in the ZJ-43 treated group (50 mg/kg, i.p.) compared with control. ZJ-43 treatment also reduced the rise of dialysate glutamate, aspartate, and GABA levels. Co-administration of the group II mGluR antagonist, LY341495 (1 mg/kg, i.p.) partially blocked the effects of ZJ-43 on dialysate glutamate and GABA, suggesting that NAAG effects are mediated through mGluR activation. The results are consistent with the hypothesis that inhibition of NAAG peptidase may reduce excitotoxic events associated with TBI.     

Homocysteine-induced alterations in extracellular amino acids in rat hippocampus.

The effects of DL-homocysteine, and DL-homocysteate, on extracellular levels of amino acids in the rat hippocampus have been studied using brain microdialysis. Hippocampal electroencephalogram activity was monitored simultaneously using an electrode attached to the dialysis probe. DL-Homocysteine (1200 mg/kg; i.p. injection) produced epileptic activity in hippocampus in an inconsistent manner. Alterations in electroencephalogram activity were not observed in urethane anaesthetized animals, whereas 50% of Hypnorm anaesthetized animals exhibited epileptic activity. DL-Homocysteate (2 mu mol; i.c.v.) induced epileptic activity in a majority of animals anaesthetized using urethane. Dialysate levels of aspartate were significantly elevated by homocysteine in both groups of animals. Conversely, dialysis levels of GABA were reduced. Dialysate levels of other amino acids measured (glutamate, glutamine, taurine, alanine and valine) were not affected significantly. Dialysate levels of taurine were increased significantly in animals injected with homocysteate. These data suggest that the imbalance in excitatory:inhibitory neurotransmission in the hippocampus caused by these alterations in extracellular levels of neuroexcitatory (i.e. aspartate) and neuroinhibitory (i.e. GABA) transmitters could underly the epileptic effect of homocysteine.     

Toxicity of aromatic hydrocarbons. VII. Hepatotoxicity of 9-nitrophenanthrene, and protection against it by beta-naphthoflavone

Male Sprague-Dawley rats were treated with a single i.p. injection of DMSO (3.0 ml/kg) or 9-nitrophenanthrene (9-NP, mg/kg) in DMSO. 9-NP produced a significant elevation of serum aspartate aminotransferase, alanine aminotransferase, sorbitol dehydrogenase, and gamma-glutamyl transpeptidase (GGTP) levels relative to DMSO-injected rats 24 hr after injection. With the exception of GGTP, the increase in enzyme activities induced by 9-NP was significantly reduced by a 3-day pretreatment with beta-naphthoflavone (BNF; 40 mg/kg/day) in DMSO. The effect of 9-NP on GGTP levels was enhanced by BNF pretreatment.     

GABA involvement in naloxone induced reversal of respiratory paralysis produced by thiopental

No agent is yet available to reverse respiratory paralysis produced by CNS depressants, such as general anesthetics. In this study naloxone reversed respiratory paralysis induced by thiopental in rats. 25 mg/kg, i.v. thiopental produced anesthesia without altering respiratory rate, increased GABA, decreased glutamate, and had no effect on aspartate or glycine levels compared to controls in rat cortex and brain stem. Pretreatment of rats with thiosemicarbazide for 30 minutes abolished the anesthetic action as well as the respiratory depressant action of thiopental. 50 mg/kg, i.v. thiopental produced respiratory arrest with further increase in GABA and decrease in glutamate again in cortex and brain stem without affecting any of the amino acids studied in four regions of rat brain. Naloxone (2.5 mg/kg, i.v.) reversed respiratory paralysis, glutamate and GABA levels to control values in brain stem and cortex with no changes in caudate or cerebellum. These data suggest naloxone reverses respiratory paralysis produced by thiopental and involves GABA in its action.     

Dichloroacetate (DCA) reduces brain lactate but increases brain glutamine in experimental cerebral malaria: a 1H-NMR study

Recent findings that levels of brain lactate and alanine were elevated in murine cerebral malaria led us to investigate the effect of dichloroacetate (DCA; 60 mg/kg), an activator of pyruvate dehydrogenase, on the levels of brain metabolites, and on the survival of mice infected with Plasmodium berghei ANKA which normally causes lethal cerebral malaria. DCA significantly reduced brain lactate and alanine levels when administered to infected mice, had no effect on the TCA cycle-related metabolites glutamate, GABA and aspartate and was associated with increased brain glutamine levels: 40% of mice thus treated survived the normally lethal infection.     

Excitatory Transmitter Amino Acid Release from the Ischemic Rat Cerebral Cortex: Effects of Adenosine Receptor Agonists and Antagonists

The effects of selective adenosine receptor agonists [N6-cyclopentyladenosine (CPA) and N-ethylcarboxamidoadenosine (NECA)] and antagonists [8-cyclopentyl-1,3-dipropylxanthine (DPCPX) and 9-chloro-2-(2-furanyl)-5,6-dihydro-1,2,4-triazolo[1,5-c]quinazoline-5-im ine (CGS-15943A)] on aspartate and glutamate release from the ischemic rat cerebral cortex were studied with the cortical cup technique. Cerebral ischemia (for 20 min) was elicited by four-vessel occlusion. Excitatory amino acid releases were compared from control ischemic rats and drug-treated rats. Basal levels of aspartate and glutamate release were not greatly affected by pretreatment with the adenosine receptor agonists or antagonists. However, CPA (10(-10) M) and NECA (10(-9) M) significantly inhibited the ischemia-evoked release of aspartate and glutamate into cortical superfusates. The ability to block ischemia-evoked release of excitatory amino acids was not evident at higher concentrations of CPA (10(-6) M) or NECA (10(-5) M). The selective A1 receptor antagonist DPCPX also had no effect on release when administered at a low dosage (0.01 mg/kg, i.p.) but blocked the ischemia-evoked release of aspartate and glutamate at a higher dosage (0.1 mg/kg). Evoked release was inhibited by the selective A2 receptor antagonist CGS-15943A (0.1 mg/kg, i.p.). Thus, adenosine and its analogs may suppress ischemia-evoked release of excitatory neurotransmitter amino acids via high-affinity A1 receptors, whereas coactivation of lower-affinity A2 receptors may block (or reverse) the A1-mediated response.     

Hesperidin, a flavanone glycoside, on lipid peroxidation and antioxidant status in experimental myocardial ischemic rats

Myocardial infarction continues to be a leading cause of mortality world-wide. Novel therapies are needed to treat the myocardial ischemia. This study was undertaken to evaluate the cardioprotective role of hesperidin on isoproterenol-induced myocardial ischemia in rats. Myocardial ischemia was induced by subcutaneous injection of isoproterenol hydrochloride (85 mg/kg body weight), for two consecutive days. Isoproterenol-administered rats showed elevated levels of cardiac markers (aspartate transaminase, alanine transaminase, lactate dehydrogenase, creatine kinase, creatine kinase-MB, cardiac troponins T and I) when compared with control and hesperidin treatment groups (100, 200 and 400 mg/kg body weight). The serum levels of cardiac markers were significantly reduced at the doses of 200 mg and 400 mg. All further experiments were carried out at the 200 mg dose. Lipid peroxidation markers (thiobarbituric acid reactive substances, lipid hydroperoxides and conjugated dienes) were elevated significantly in the plasma and heart whereas non-enzymic antioxidants (vitamin C, vitamin E and reduced glutathione) were decreased significantly. Activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase and glutathione reductase declined significantly in the heart of ischemic rats. However, after hesperidin treatment, all the above parameters reverted to normal levels. This study demonstrated that the cardioprotective effect of hesperidin on ischemic rats could be due to its anti-lipid peroxidative and antioxidant properties.     

Antihyperglycemic and antioxidant effects of a flavanone, naringenin, in streptozotocin–nicotinamide-induced experimental diabetic rats

In the present study, the putative antihyperglycemic and antioxidant effects of a flavanone, naringenin, were evaluated in comparison with those of glyclazide, a standard drug for therapy of diabetes mellitus. Diabetes was induced experimentally in 12-h-fasted rats by intraperitoneal injections of first streptozotocin (50 mg/kg b.w.) and then of nicotinamide (110 mg/kg b.w.) after a 15-min interval. Untreated diabetic rats revealed the following in comparison with normal rats: significantly higher mean levels of blood glucose and glycosylated hemoglobin, significantly lower mean levels of serum insulin, significantly lower mean activities of pancreatic antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase), significantly lower mean levels of plasma non-enzymatic antioxidants (reduced glutathione, vitamin C , vitamin E), significantly elevated mean levels of pancreatic malondialdehyde (MDA) and significantly elevated mean activities of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH). Following oral administration of naringenin (50 mg/kg b.w./day) to diabetic rats for 21 days, the following observations were made in comparison with untreated diabetic rats: significantly lower mean levels of fasting blood glucose and glycosylated hemoglobin, significantly elevated serum insulin levels, significantly higher mean activities of pancreatic enzymatic antioxidants, significantly higher mean levels of plasma non-enzymatic antioxidants, lower mean pancreatic tissue levels of MDA and lower mean activities of ALT, AST, ALP and LDH in serum. The values obtained in the naringenin-treated animals approximated those observed in glyclazide-treated animals. Histopathological studies appeared to suggest a protective effect of naringenin on the pancreatic tissue in diabetic rats. These results suggest that naringenin exhibits antihyperglycemic and antioxidant effects in experimental diabetic rats.     

Repeated Cocaine Administration Alters Extracellular Glutamate in the Ventral Tegmental Area

Abstract: The present study determined if repeated cocaine injections alter the effect of cocaine on extracellular glutamate in the ventral tegmental area (VTA). All rats were treated with daily cocaine (15 mg/kg i.p. × 2 days, 30 mg/kg i.p. × 5 days) or saline for 7 days. At 21 days after discontinuing the daily injections, a dialysis probe was placed into the VTA and the extracellular levels of glutamate were estimated. A systemic injection of cocaine (15 mg/kg i.p.) elevated extracellular glutamate in the VTA of rats pretreated with daily cocaine but not in the daily saline-pretreated subjects. No significant change in glutamate was produced by a saline injection in either pretreatment group. In a group of rats pretreated with daily cocaine, the D₁ antagonist SCH-23390 (30 µ M ) was infused through the dialysis probe prior to the acute injections of saline and cocaine. SCH-23390 prevented the increase in extracellular glutamate associated with the acute administration of cocaine. Behavioral data were collected simultaneously with the measures of extracellular glutamate. The behavioral stimulant effect of cocaine was greater in cocaine-pretreated than saline-pretreated subjects, and the behavioral augmentation in cocaine-pretreated rats was partly blocked by SCH-23390. These data support the hypotheses that repeated cocaine administration produces an increase in the capacity of D₁ receptor stimulation to release glutamate in the VTA and that this mechanism partly mediates behavioral sensitization produced in rats treated with daily cocaine injections.     

Antioxidant DL-alpha lipoic acid as an attenuator of adriamycin induced hepatotoxicity in rat model

Protective efficacy of DL-alpha lipoic acid on adriamycin induced hepatotoxicity was evaluated in rats. Adriamycin toxicity, induced by a single injection (ip; 15 mg/kg body wt), was expressed by an elevation in alanine transaminase, aspartate transaminase, bilirubin levels in serum and alkaline phosphatase, lactate dehydrogenase, alanine transaminase, aspartate transaminase activity in hepatic tissue. Adriamycin produced significant increase in malondialdehyde levels indicating tissue lipid peroxidation and potentially inhibiting the activity of antioxidant, reduced glutathione and antioxidant enzymes, catalase, superoxide dismutase, glutathione peroxidase, glutathione reductase, glutathione-S-transferase, glucose-6-phosphate dehydrogenase. The present results showed that pretreatment with lipoic acid [75 mg/kg body wt/day (ip), 24 h prior to administration of adriamycin] significantly restored various cellular activity suggesting the antioxidant potential of lipoic acid in ameliorating the hepatotoxicity induced by adriamycin.     

Vinpocetine ameliorates acute hepatic damage caused by administration of carbon tetrachloride in rats

Vinpocetine is a widely used drug for the treatment of cerebrovascular and memory disorders. This study aimed to investigate the effect of vinpocetine on the acute hepatic injury caused in the rat by the administration of CCl4 in vivo. Vinpocetine (2.1, 4.2, 8.4 mg/kg) or silymarin (30 mg/kg) was given once daily orally simultaneously with CCl4 and for 15 days thereafter. Liver damage was assessed by determining serum enzyme activities and hepatic histopathology. Stained sections were subjected to morphometric evaluation using computerized image analyzer. The results showed that vinpocetine administered to CCl4-treated rats decreased the elevated alanine aminotransferase (ALT) by 49.3, 58.1 and 63.6%, aspartate aminotransferase (AST) by 10.5, 22.6 and 27.2% and alkaline phosphatase (ALP) by 52.5, 59.6 and 64.9%, respectively, and in a dose-dependent manner. Meanwhile, silymarin reduced elevated ALT, AST and ALP levels by 53.1, 26.9 and 66%, respectively. Histological examination of liver specimens revealed a marked reduction in liver cell necrosis in vinpocetine and silymarin-treated rats compared with vehicle-treated CCl4-treated rats. Quantitative analysis of the area of damage showed 85.3% reduction in the area of damage after silymarin and 72.2, 78.9 and 82.6% reduction after vinpocetine treatment at 2.1, 4.2, 8.4 mg/kg, respectively. It is concluded that administration of vinpocetine in a model of CCl4-induced liver injury in rats reduced liver damage. The reduction obtained by 4.2 mg/kg of vinpocetine was similar to that obtained by 30 mg/kg silymarin. Therefore, it is suggested that vinpocetine might be a good pharmacological agent in the treatment of liver disease besides its neuroprotective effects.     

Studies on the effects of lactate transport inhibition, pyruvate, glucose and glutamine on amino acid, lactate and glucose release from the ischemic rat cerebral cortex

A rat four vessel occlusion model was utilized to examine the effects of ischemia/reperfusion on cortical window superfusate levels of amino acids, glucose, and lactate. Superfusate aspartate, glutamate, phosphoethanolamine, taurine, and GABA were significantly elevated by cerebral ischemia, then declined during reperfusion. Other amino acids were affected to a lesser degree. Superfusate lactate rose slightly during the initial ischemic period, declined during continued cerebral ischemia and then was greatly elevated during reperfusion. Superfusate glucose levels declined to near zero levels during ischemia and then rebounded beyond basal levels during the reperfusion period. Inhibition of neuronal lactate uptake with alpha-cyano-4-hydroxycinnamate dramatically elevated superfusate lactate levels, enhanced the ischemia/reperfusion evoked release of aspartate but reduced glutamine levels. Topical application of an alternative metabolic fuel, glutamine, had a dose dependent effect. Glutamine (1 mM) elevated basal superfusate glucose levels, diminished the decline in glucose during ischemia, and accelerated its recovery during reperfusion. Lactate levels were elevated during ischemia and reperfusion. These effects were not evident at 5 mM glutamine. At both concentrations, glutamine significantly elevated the superfusate levels of glutamate. Topical application of sodium pyruvate (20 mM) significantly attenuated the decline in superfusate glucose during ischemia and enhanced the levels of both glucose and lactate during reperfusion. However, it had little effect on the ischemia-evoked accumulation of amino acids. Topical application of glucose (450 mg/dL) significantly elevated basal superfusate levels of lactate, which continued to be elevated during both ischemia and reperfusion. The ischemia-evoked accumulations of aspartate, glutamate, taurine and GABA were all significantly depressed by glucose, while phosphoethanolamine levels were elevated. These results support the role of lactate in neuronal metabolism during ischemia/reperfusion. Both glucose and glutamine were also used as energy substrates. In contrast, sodium pyruvate does not appear to be as effectively utilized by the ischemic/reperfused rat brain since it did not reduce ischemia-evoked amino acid efflux.     

Tenoxicam Exerts a Neuroprotective Action after Cerebral Ischemia in Rats

In this study we investigated the effects of Tenoxicam, a type 2 cyclooxygenase (COX-2) inhibitor, on brain damage induced by ischemia-reperfusion. Male Wistar rats (18-month old average) were anesthetized and submitted to ischemia occlusion of both common carotid arteries (BCAO) for 45 min. After 24 h of reperfusion, rats were decapitated and hippocampi removed for further assays. Animals were divided into sham-operated, ischemia, ischemia + Tenoxicam 2.5 mg/kg, and ischemia + Tenoxicam 10 mg/kg groups. Tenoxicam was administered intraperitoneally immediately after BCAO. Histological analyses show that ischemia produced significant striatal as well as hippocampal lesions which were reversed by the Tenoxicam treatment. Tenoxicam also significantly reduced, to control levels, the increased myeloperoxidase activity in hippocampus homogenates observed after ischemia. However, nitrite concentrations showed only a tendency to decrease in the ischemia + Tenoxicam groups, as compared to that of ischemia alone. On the other hand, hippocampal glutamate and aspartate levels were not altered by Tenoxicam. In conclusion, we showed that ischemia is certainly related to inflammation and to increased free radical production, and selective COX-2 inhibitors might be neuroprotective agents of potential benefit in the treatment of cerebral brain ischemia.     

Effects of pycnogenol treatment on oxidative stress in streptozotocin-induced diabetic rats

Free radicals and oxidative stress have been implicated in the etiology of diabetes and its complications. This in vivo study has examined whether subacute administration of pycnogenol, a French pine bark extract containing procyanidins that have strong antioxidant potential, alters biomarkers of oxidative stress in normal and diabetic rats. Diabetes was induced in female Sprague-Dawley rats by a single injection of streptozotocin (90 mg/kg body weight, ip), resulting (after 30 days) in subnormal body weight, increased serum glucose concentrations, and an increase in liver weight, liver/body weight ratios, total and glycated hemoglobin, and serum aspartate aminotransferase activity. Normal and diabetic rats were treated with pycnogenol (10 mg/kg body weight/day, ip) for 14 days. Pycnogenol treatment significantly reduced blood glucose concentrations in diabetic rats. Biochemical markers for oxidative stress were assessed in the liver, kidney, and heart. Elevated hepatic catalase activity in diabetic rats was restored to normal levels after pycnogenol treatment. Additionally, diabetic rats treated with pycnogenol had significantly elevated levels of reduced glutathione and glutathione redox enzyme activities. The results demonstrate that pycnogenol alters intracellular antioxidant defense mechanisms in streptozotocin-induced diabetic rats.