Acid In Mouse Brain Research Articles

Ethanol concentration induces production of 3,4-dihydroxyphenylacetic acid and homovanillic acid in mouse brain through activation of monoamine oxidase pathway

First, we aimed to investigate ex vivo the effects of ethanol (EtOH) on levels of norepinephrine (NE), dopamine (DA), serotonin (5-HT), and their metabolites in the frontal cortex, hippocampus, and striatum of Aldh2-knockout (Aldh2-KO) and wild-type (WT) mice. Animals were treated intraperitoneally with saline (control) or EtOH (1.0, 2.0, or 3.0 g/kg). Brain samples were collected 60 and 120 min after EtOH injection, and monoamines and their metabolites were measured by HPLC-ECD. We found in both WT and Aldh2-KO mice that 3.0 g/kg EtOH increased the levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) and decreased the level of 3-methoxytyramine (3-MT). A 2.0 g/kg dose of EtOH also increased HVA, but there was not a consistent effect within the brain regions of Aldh2-KO and WT mice. There were inconsistent findings of genotype differences in the levels of DA, 5-HT, and their metabolites in the brain regions tested. None of the EtOH doses altered NE, DA, 5-HT, or 5-hydroxyindoleacetic acid contents in any of the brain regions studied. Second, we tested whether EtOH-induced increases in DOPAC and HVA are mediated by increased monoamine oxidase (MAO) or catechol-O-methyltransferase (COMT) activity. To test this, we used the MAO blocker clorgyline (2.0 and 4.0 mg/kg) and the COMT blocker tolcapone (15 and 30 mg/kg) alone or in combination with EtOH (3.0 g/kg). Clorgyline alone increased 3-MT and decreased DOPAC and HVA levels, whereas tolcapone alone increased DOPAC and decreased 3-MT and HVA levels. Surprisingly, the combination of EtOH with clorgyline (4.0 mg/kg) or tolcapone (30 mg/kg) further decreased 3-MT and increased DOPAC and HVA levels, an effect that reversed the inhibitor-induced decreases in HVA. These results suggest that a high concentration of EtOH can accelerate DA metabolism, as evidenced by the increase in DOPAC and HVA, and this effect is likely a consequence of increased degradation of DA by MAO.

X-ray Structure-Guided Discovery of a Potent, Orally Bioavailable, Dual Human Indoleamine/Tryptophan 2,3-Dioxygenase (hIDO/hTDO) Inhibitor That Shows Activity in a Mouse Model of Parkinson's Disease.

Human indoleamine 2,3-dioxygenase 1 (hIDO1) and tryptophan 2,3-dioxygenase (hTDO) have been closely linked to the pathogenesis of Parkinson's disease (PD); nevertheless, development of dual hIDO1 and hTDO inhibitors to evaluate their potential efficacy against PD is still lacking. Here, we report biochemical, biophysical, and computational analyses revealing that 1H-indazole-4-amines inhibit both hIDO1 and hTDO by a mechanism involving direct coordination with the heme ferrous and ferric states. Crystal structure-guided optimization led to 23, which manifested IC50 values of 0.64 and 0.04 μM to hIDO1 and hTDO, respectively, and had good pharmacokinetic properties and brain penetration in mice. 23 showed efficacy against the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse motor coordination deficits, comparable to Madopar, an anti-PD medicine. Further studies revealed that different from Madopar, 23 likely has specific anti-PD mechanisms involving lowering IDO1 expression, alleviating dopaminergic neurodegeneration, reducing inflammatory cytokines and quinolinic acid in mouse brain, and increasing kynurenic acid in mouse blood.

Pleiotropic effects of 5-aminolevulinic acid in mouse brain.

5-Aminolevulinic acid (ALA) seems to be responsible for the neuropsychiatric manifestations of acute intermittent porphyria (AIP). Our aim was to study the effect of ALA on the different metabolic pathways in the mouse brain to enhance our knowledge about the action of this heme precursor on the central nervous system. Heme metabolism, the cholinergic system, the defense enzyme system, and nitric oxide metabolism were evaluated in the encephalon of CF-1 mice receiving a single (40 mg/kg body mass) or multiple doses of ALA (40 mg/kg, every 48 h for 14 days). We subsequently found ALA accumulation in the encephalon of the mice. ALA also altered the brain cholinergic system. After one dose of ALA, a decrease in superoxide dismutase activity and a reduction in glutathione levels were detected, whereas malondialdehyde levels and catalase activity were increased. Heme oxygenase was also increased as an antioxidant response to protect the encephalon against injury. All nitric oxide synthase isoforms were induced by ALA, these changes were more significant for the inducible isoform in glial cells. In conclusion, ALA affected several metabolic pathways in mouse encephalon. Data indicate that a rapid response to oxidative stress was developed; however, with long-term intoxication, the redox balance was probably restored, thereby minimizing oxidative damage.

Fucosterol, a sterol extracted from Sargassum fusiforme, shows antidepressant and anticonvulsant effects

We previously showed that extracts of Sargassum fusiforme significantly reduce immobility time in the forced swim test and tail suspension test, suggesting that these extracts possess antidepressant-like effects. Here, fucosterol extracted from S. fusiforme was evaluated for antidepressant and anticonvulsant activities in mice. Fucosterol (10, 20, 30 and 40mg/kg) significantly shortened immobility time in the forced swim test and tail suspension test for30min after treatment but had no effect on locomotor activity in the open field test. Fucosterol significantly increased serotonin, norepinephrine and the metabolite 5-hydroxyindoleacetic acid in mouse brain, suggesting that the effects of fucosterol may be mediated through these neurotransmitters. As assessed using maximal electroshock, fucosterol (20, 40, 100mg/kg) possessed anticonvulsant activity, whereas rotarod toxicity test results indicated that fucosterol did not induce neurotoxicity at the same dose levels in mice. Thus, fucosterol may be a useful antidepressant adjunct candidate for treating depression in patients with epilepsy. A significant increase in hippocampal brain-derived neurotrophic factor (BDNF) levels was found in the fucosterol 20mg/kg group (P<0.05). Our findings suggested that fucosterol may possess an antidepressant-like effect, which may be mediated by increasing central BDNF levels.

Practical Synthesis, Antidepressant, and Anticonvulsant Activity of 3‐Phenyliminoindolin‐2‐one Derivatives

Herein, a series of 3-phenyliminoindolin-2-one derivatives were designed, synthesized, and screened for their antidepressant and anticonvulsant activities. The IR spectra of the compounds afforded NH stretching (3340-3346 cm(-1)) bands and C=O stretching (1731-1746 cm(-1)). In the (1)H-NMR spectra of the compounds, N-H protons of indoline ring were observed at 10.65-10.89 ppm generally as broad bands, and (13)C-NMR spectra of the compounds C=O were seen at 161.72-169.27 ppm. Interestingly, compounds 3o, 3p and 3r significantly shortened immobility time in the The forced swimming test (FST) and The tail suspension test (TST) at 50 mg/kg dose levels. In addition, compound 3r exhibited higher levels of efficacy than the reference standard fluoxetine but had no effect on locomotor activity in the open-field test. Compound 3r significantly increased serotonin and norepinephrine and the metabolite 5-hydroxyindoleacetic acid in mouse brain, suggesting that the effects of compound 3r may be mediated through these neurotransmitters. In the seizure screen, 15 compounds showed some degree against PTZ-induced seizure at a dose of 100 mg/kg, and the tested compounds did not show any neurotoxicity at a dose of 300 mg/kg in the rotarod test.

Anti-glycative and anti-inflammatory effects of protocatechuic acid in brain of mice treated by d-galactose

Protocatechuic acid (PCA) at 0.5%, 1% or 2% was supplied to d-galactose (DG) treated mice for 8week. PCA intake at 2% increased its deposit in brain. DG treatment increased brain level of reactive oxygen species, protein carbonyl, carboxymethyllysine, pentosidine, sorbitol, fructose and methylglyoxal (P<0.05). PCA intake, at 1% and 2%, lowered brain level of these parameters (P<0.05). DG treatments enhanced activity and protein expression of aldose reductase (AR) and sorbitol dehydrogenase, as well as declined glyoxalase I (GLI) activity and protein expression (P<0.05). PCA intake at 1% and 2% reduced activity and protein expression of AR (P<0.05), and at 2% restored GLI activity and expression (P<0.05). DG injection also elevated cyclooxygenase (COX)-2 activity and expression, and increased the release of interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha and prostaglandin E2 in brain (P<0.05). PCA intake decreased these cytokines (P<0.05), and at 1% and 2% suppressed COX-2 activity and expression (P<0.05). PCA intake at 1% and 2% also lowered DG-induced elevation in activity, mRNA expression and protein production of nuclear factor kappa B p65 (P<0.05). These findings suggest that the supplement of protocatechuic acid might be helpful for the prevention or alleviation of aging.

Anti-oxidative, anti-glycative and anti-apoptotic effects of oleanolic acid in brain of mice treated by d-galactose

Anti-oxidative, anti-glycative and anti-apoptotic effects of oleanolic acid in brain from d-galactose treated mice were examined. Oleanolic acid at 0.05%, 0.1% and 0.2% was supplied to mice for 10wk. d-Galactose treatment increased reactive oxygen species and protein carbonyl levels (P<0.05), and reduced activity and protein production of glutathione peroxide, superoxide dismutase and catalase in mice brain (P<0.05). Oleanolic acid intake dose-dependently lowered reactive oxygen species and protein carbonyl levels (P<0.05), and retained activity and expression of these enzymes (P<0.05). Brain levels of carboxymethyllysine, pentosidine and methylglyoxal were significantly increased in d-galactose treated mice (P<0.05). Oleanolic acid intake significantly decreased the level of these parameters (P<0.05). d-Galactose treatments enhanced brain activity and protein expression of aldose reducatse (AR); and declined glyoxalase I (GLI) activity and expression (P<0.05). Oleanolic acid intake dose-dependently diminished AR activity and expression (P<0.05), only at 0.2% retained GLI activity and expression (P<0.05). d-Galactose treatment up-regulated the activity, mRNA expression and protein production of nuclear factor-κB (NF-κB) p65, Bax and cleaved caspase-3 (P<0.05), as well as suppressed Bcl-2 production (P<0.05). Oleanolic acid intake at 0.1% and 0.2% suppressed NF-κB p65, Bax and cleaved caspase-3 production, and retained Bcl-2 expression (P<0.05). These findings support that oleanolic acid may be a potent neuro-protective agent against aging.

Effect of chlorpromazine and some of its metabolites on the accumulation of homovanilic acid in brain of mice.

Journal Article Effect of chlorpromazine and some of its metabolites on the accumulation of homovanillic acid in brain of mice Get access John Dailey, John Dailey Department of Pharmacology, Karolinska Institutet, S-104 01 Stockholm 60, Sweden Search for other works by this author on: Oxford Academic Google Scholar Göran Sedvall, Göran Sedvall Department of Pharmacology, Karolinska Institutet, S-104 01 Stockholm 60, Sweden Search for other works by this author on: Oxford Academic Google Scholar Birgitta Sjöquist Birgitta Sjöquist Department of Pharmacology, Karolinska Institutet, S-104 01 Stockholm 60, Sweden Search for other works by this author on: Oxford Academic Google Scholar Journal of Pharmacy and Pharmacology, Volume 24, Issue 7, July 1972, Pages 580–581, https://doi.org/10.1111/j.2042-7158.1972.tb09062.x Published: 12 April 2011 Article history Received: 17 April 1972 Published: 12 April 2011

Rapid β-oxidation of eicosapentaenoic acid in mouse brain: An in situ study

Analyses of brain phospholipid fatty acid profiles reveal a selective deficiency and enrichment in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), respectively. In order to account for this difference in brain fatty acid levels, we hypothesized that EPA is more rapidly β-oxidized upon its entry into the brain. Wild-type C57BL/6 mice were perfused with either 14C-EPA or 14C-DHA via in situ cerebral perfusion for 40 s, followed by a bicarbonate buffer to wash out the residual radiolabeled polyunsaturated fatty acid (PUFA) in the capillaries. 14C-PUFA-perfused brains were extracted for chemical analyses of neutral lipid and phospholipid fatty acids. Based on the radioactivity in aqueous, total lipid, neutral lipid and phospholipid fractions, volume of distribution ( V D, μl/g) was calculated. The V D between 14C-EPA- and 14C-DHA-perfused samples was not statistically different for total lipid, neutral lipids or total phospholipids. However, the V D of 14C-EPA in the aqueous fraction was 2.5 times higher than that of 14C-DHA ( p=0.025), suggesting a more extensive β-oxidation than DHA. Furthermore, radiolabeled palmitoleic acid, a fatty acid that can be synthesized de novo, was detected in brain phospholipids from 14C-EPA but not from 14C-DHA-perfused mice suggesting that β-oxidation products of EPA were recycled into endogenous fatty acid biosynthetic pathways. These findings suggest that low levels of EPA in brain phospholipids compared to DHA may be the result of its rapid β-oxidation upon uptake by the brain.

Influence of growth environment on the ganglioside composition of an experimental mouse brain tumor

Ganglioside composition was examined in an experimental mouse brain tumor growing as a solid tumor in vivo and as a cultured cell line in vitro. Gangliosides were also studied in the solid tumor rederived from the cultured tumor cell line. Although GM3-NeuAc was the major ganglioside in both the solid tumor and cultured tumor cells, several gangliosides expressed in the solid tumors (e.g., GM2-NeuGc, GM1, and GM1b) were not expressed in the cultured tumor cells. These gangliosides, however, are major components of mouse macrophages. Furthermore, significant amounts of gangliosides containing N-glycolylneuraminic acid (NeuGc) were found in the solid tumor growing in vivo, but only trace amounts were present in the cultured tumor cells. NeuGc is a common ganglioside sialic acid in mouse nonneural cells, whereas N-acetylneuraminic (NeuAc) is the predominant sialic acid in mouse brain. The trace amounts of NeuGc in the cultured cells are attributed to contamination from the fetal bovine serum. Radiolabeling of the cultured tumor cell gangliosides with [14C]galactose revealed that GM3-NeuAc was the only ganglioside synthesized by the tumor cells. The results suggest that nontumor-infiltrating cells, e.g., macrophages, lymphocytes, and endothelial cells, may contribute significantly to the total ganglioside composition of solid tumors growing in vivo.

O-152 - Induction of c-fos expression by intracerebro- ventricular administration of ethacrynic acid in mouse brain.

O-152 - Induction of c-fos expression by intracerebro- ventricular administration of ethacrynic acid in mouse brain.

Early and late increases of c- fos expression by intracerebroventricular administration of ethacrynic acid in mouse brain

Early and late increases of c- fos expression by intracerebroventricular administration of ethacrynic acid in mouse brain

Determination of m-nitrophenol and nipecotic acid in mouse tissues by high-performance liquid chromatography after administration of the anticonvulsant m-nitrophenyl-3-piperidinecarboxylate hydrochloride

AbstractThe nipecotic acid ester m-nitrophenyl-3-piperidinecarboxylate (MNPC) possesses anticonvulsant activity. In the present study, the metabolites m-nitrophenol and nipecotic acid were determined in mouse blood and brain tissue after administration of MNPC. This determination was used as an indication of the distribution of the parent compound MNPC and to provide information regarding the differences in distribution between the enantiomers of MNPC, the times of onset, and effectiveness when (±)MNPC was administered by subcutaneous (sc) and intraperitoneal (ip) routes. m-Nitrophenol was determined by a previously reported high-performance liquid chromatography (HPLC) method. There was no significant difference in m-nitrophenol distribution after sc administration of (+)MNPC and (−)MNPC (400 mg/kg each). This similar pattern of distribution is in agreement with the earlier reported equi-effectiveness of the enantiomers of anticonvulsants. Peak m-nitrophenol levels in blood, which occurred at 15min, were three times greater when (±)MNPC was administered by ip injection as compared with sc injection. This significant difference is most likely due to enhanced absorption and the peripheral metabolism of MNPC by the liver when the ip route is employed. A novel HPLC assay for the determination of nipecotic acid in mouse brain was developed, based on a modification of a reported amino acid analysis procedure. The results of the brain distribution studies showed that nipecotic acid brain levels peaked at 30min after sc administration of (−)MNPC. These findings correlate with m-nitrophenol distribution in the blood and the previously reported onset of the anticonvulsant effect of MNPC. The HPLC assays used in this study are simple, rapid, and sensitive. Furthermore, the HPLC brain assay for nipecotic acid can be used to examine the distribution of other esters of nipecotic acid reported to possess anticonvulsant activity.

Ontogeny of aromatase messenger ribonucleic acid in mouse brain: fluorometrical quantitation by polymerase chain reaction

Ontogeny of aromatase messenger ribonucleic acid in mouse brain: fluorometrical quantitation by polymerase chain reaction

Ontogeny of aromatase messenger ribonucleic acid in mouse brain: fluorometrical quantitation by polymerase chain reaction.

A sensitive method was developed for the determination of trace amounts of aromatase mRNA in various tissues. Aromatase mRNA was quantitated by subjecting it to reverse transcription in the presence of an internal standard RNA and then amplifying the resulting cDNA by polymerase chain reaction with a fluorescent primer. The tissue distribution of aromatase mRNA in mice was examined by this polymerase chain reaction method. Results showed that aromatase mRNA is expressed in the brain, testis, and ovary, but scarcely at all in other tissues, including the placenta. In mouse brain, aromatase is mainly located in the forebrain, especially the diencephalon. In adult male and female diencephala, aromatase mRNA levels were 0.022 +/- 0.004 and 0.014 +/- 0.003 attomoles/micrograms total RNA, respectively. Aromatase in the diencephalon is known to participate in brain differentiation and sexual behavior, so changes in its mRNA levels in the brain during development were examined. Aromatase mRNA was first detected in the 12-day-old fetus and was found to increase rapidly during the fetal and neonatal periods. Its mRNA levels in male and female brains reached maxima of 0.068 +/- 0.008 and 0.059 +/- 0.006 attomoles/micrograms total RNA, respectively, 3-4 days after birth and then gradually decreased to adult levels. These observations are consistent with previous data indicating that the marginal period of neonatal imprinting of sexual differences is within a week after birth and suggest that brain aromatase may be important in sexual differentiation and behavior.

Platelet‐Activating Factor Antagonist BN52021 Decreases Accumulation of Free Polyunsaturated Fatty Acid in Mouse Brain During Ischemia and Electroconvulsive Shock

We have investigated the effects of the specific platelet-activating factor (PAF; 1-alkyl-2-acetyl-glycerophosphocholine) antagonist BN52021 on free fatty acid (FFA) and diacylglycerol (DG) accumulation and on the loss of fatty acids from phosphatidylinositol-4,5-bisphosphate (PIP2) in mouse brain. Mice were pretreated with BN52021 (10 mg/kg, i.p.) 30 min before electroconvulsive shock (ECS) or postdecapitation ischemia. These procedures cause rapid breakdown of PIP2 and accumulation of FFA and DG. Lipid extracts were prepared from microwave-fixed cerebrum and fractionated by TLC, and the fatty acid methyl esters were prepared by methanolysis and quantified by capillary GLC. In saline or vehicle (dimethyl sulfoxide)-treated mice, ECS caused marked accumulation of FFA and DG and loss of mainly stearic (18:0) and arachidonic (20:4) acids from PIP2. BN52021 pretreatment of ECS-treated mice decreased the accumulation of free palmitic (16:0), 18:0, 20:4, and docosahexaenoic (22:6) acids with no effect on the fatty acids in DG or the loss of PIP2. BN52021 had no effect on basal levels of FFA, DG, or PIP2. One minute of postdecapitation ischemia induced PIP2 loss and accumulation of FFA and DG. BN52021 attenuated the accumulation of free 20:4 and 22:6 acids, decreased the content of oleic (18:1), 20:4, and 22:6 acids in DG, but had no effect on PIP2 loss. These data indicate that BN52021 reduces the injury-induced activation of phospholipase A2 and lysophospholipase, which mediate the accumulation of FFA in brain, while having a negligible effect on phospholipase C-mediated degradation of PIP2.

Effect of immobilization stress on pipecolic acid transport in mouse brain areas and peripheral tissues

Transport activity of d-pipecolic acid and of l-pipecolic acid in mouse brain and peripheral tissues were tested, and the effect of immobilization stress was described, along with the method for preparative, enantiomeric resolution and purification of d,l-pipecolic acid using high performance liquid chromatography equipped with a chiral column. It was found that l-isomer, an endogenous substance, was more rapidly transported to brain and liver than the d-isomer, non-endogenous one, which was more rapidly eliminated into the kidney. Immobilization stress caused acceleration of transport of l-pipecolic acid into the brain region, liver and heart, but not that of d-pipecolic acid. From these results it was suggested that the elevation of pipecolic acid concentration caused by stress might be exerted through its stimulatory effect on the transport of l-pipecolic acid into the tissues.

Estimation of the p and m isomers of hydroxyphenylacetic acid in mouse brain by a gas chromatographic procedure: their regional distribution and the effects of some drugs.

The mouse brain contains 12.5 and 4.1 ng/g of p- and m-hydroxyphenylacetic acids, respectively. The hydroxyphenylacetic acids were isolated by chromatography on DEAE-Sephadex A-25 and quantitated as their pentafluoropropionyl and hexafluoropropanol esters by use of a gas chromatograph equipped with an electron-capture detector. The highest concentrations of p- or m-hydroxyphenylacetic acids were observed in the caudate nuclei (27.9 and 8.7 ng/g, respectively) and olfactory tubercles (20.2 and 5.3 ng/g, respectively). The identities of the p- and m-hydroxyphenylacetic acids were further confirmed as a consequence of the reductions observed following monoamine oxidase inhibition or the increases observed in the appropriate acid following the parenteral administration of p- or m-tyramine.

O-9 - Accumulation, elimination and metabolism of pipecolic acid in mouse brain

O-9 - Accumulation, elimination and metabolism of pipecolic acid in mouse brain

Postmortem changes of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in mouse brain and their prevention by pargyline and microwave irradiation.

Postmortem (pm) manipulations of brain tissue of decapitated mice produced a maximum decline in 5-HT and a maximum rise in 5-HIAA of 20 and 40%, respectively. The pm treatments included freezing and thawing, mincing, and leaving over. Microwave irradiation or pretreatment of the animals with the enzymatic inhibitors NSD 1015 or pargyline suppressed the pm effects. The possible role of pm effects in the initial accumulation of 5-HT and decline of 5-HIAA in the brain following administration of pargyline was studied. Out data suggest that, when MAO inhibitors are used, 5-HT turnover might be overestimated by pm changes.