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PubMed1995

Reconsideration of the catalytic center and mechanism of mammalian paraoxonase/arylesterase.

For three decades, mammalian paraoxonase (A-esterase, aromatic esterase, arylesterase; PON, EC 3.1.8.1) has been thought to be a cysteine esterase demonstrating structural and mechanistic homologies with the serine esterases (cholinesterases and carboxyesterases). Human, mouse, and rabbit PONs each contain only three cysteine residues, and their positions within PON have been conserved. In purified human PON, residues Cys-41 and Cys-352 form an intramolecular disulfide bond and neither could function as an active-center cysteine. Highly purified, enzymatically active PON contains a single titratable sulfhydryl group. Thus, Cys-283 is the only probable candidate for an active-center cysteine. Through site-directed mutagenesis of the human cDNA, Cys-283 was replaced with either serine (C283S) or alanine (C283A). The expressed C283 (wild-type) enzyme was inactivated by para-hydroxymercuribenzoate, but the C283S and C283A mutant enzymes were not inactivated. C283A and C283S mutant enzymes retained both paraoxonase and arylesterase activities, and the Km values for paraoxon and phenyl acetate were similar to those of the wild type. Clearly, residue Cys-283 is free in active PON, but a free sulfhydryl group is not required for either paraoxonase or arylesterase activities. Consequently, it is necessary to examine other models for the active-site structure and catalytic mechanism of PON.

Amino Acid Sequence↗
PubMed2001

Lipid peroxidation is increased in paraoxonase L55 homozygotes compared with M-allele carriers.

Human serum paraoxonase (PON) is an antioxidative enzyme, which circulates on high-density lipoproteins and appears to use oxidized phospholipids as physiological substrates. PON M/L55 substitution changes the ability of PON to prevent lipid oxidation. Urinary 8-iso-PGF(2alpha) (one of F2 -isoprostanes) may represent a non-invasive in vivo index of free radical generation and we propose that PON might influence the biosynthesis of 8-iso-PGF(2alpha) in the vasculature. We studied the urinary excretion of 8-iso-PGF(2alpha) and related it to PON M/L55 genotypes in patients with type 2 diabetes mellitus (n = 55) and non-diabetic control subjects (n = 55). Urinary 8-iso-PGF(2alpha) was determined by competitive ELISA and the PON genotype by a PCR based restriction enzyme digestion method. LL homozygotes were compared to M-allele carriers (ML heterozygotes and MM homozygotes). The urinary excretion of 8-iso-PGF(2alpha) among non-diabetic non-smoking LL homozygotes was 3995.5 +/- 3352.8 ng/24-hour and among M-allele carriers 1689.8 +/- 1051.3 ng/24-hour (p = 0.017, ANCOVA; gender, hypertension, total cholesterol, triglycerides and LDL cholesterol as covariates). The excretion of 8-iso-PGF(2alpha), was increased in type 2 diabetes mellitus compared to non-diabetic control subjects. PON may thus protect against oxidative stress by destroying some biologically active lipids. Excretion of 8-iso-PGF(2alpha) is increased in type 2 diabetes, which may reflect oxidant injury.

Aryldialkylphosphatase↗
PubMed2004

Paraoxonase genotype, LDL-oxidation and carotid atherosclerosis in male life-long smokers.

Paraoxonase (PON-1) is a high-density lipoprotein (HDL) associated enzyme that hydrolyzes lipid peroxides in vitro, which may therefore protect against the onset of atherosclerosis. Heavy smokers are more exposed to oxidative stress and hence at high-risk for oxidative modification of LDL. Our hypothesis is that the anti-oxidative properties of PON-1 inhibit LDL oxidation, especially in populations exposed to high oxidative stress. We have studied the effects of PON-1 genotype and smoking to variation in oxidative status parameters and intima-media thickness (IMT), a surrogate marker of atherosclerosis. The contribution of two common polymorphisms in the PON-1 gene (Q192R and L55M) to LDL oxidizability, autoantibodies directed against oxLDL and IMT were studied in 207 male life-long smokers. Smokers were classified into average, heavy and excessive smokers based on pack years of cigarettes smoked. PON-1 genotype was not associated with autoantibodies to oxLDL, LDL oxidizability or IMT. Smoking was associated with IMT in subgroups with the high levels of LDL, but not in the population at large. The lack of association of PON-1 genotype with oxidative status parameters and IMT suggests that PON-1 is not a major inhibitor of LDL oxidation in a population of life-long smokers.

Age Factors↗
PubMed2000

Promoter polymorphisms of human paraoxonase PON1 gene and serum paraoxonase activities and concentrations.

Paraoxonase (PON) is a serum enzyme with a wide species distribution. It protects lipoproteins from toxic oxidative modifications and is an antiatherogenic mechanism of major potential. Activity levels of PON are major determinants of the protective function; consequently, factors that influence PON levels are of particular relevance. The present study has identified 3 polymorphisms in the promoter region of the human PON1 gene. Cell transfection studies have revealed their variable impact on promoter activity, with up to 2-fold differences in reporter gene expression. Genotyping studies have established that the polymorphisms are frequent in the population, a finding that is consistent with a major impact on PON concentrations. The physiological relevance of the polymorphisms was underlined by showing that they are associated with highly significant differences in serum concentrations and activities of PON. The study thus firmly establishes a genetic basis for variations in serum PON levels and, consequently, serum PON activity. It is consistent with the suggestion that variations in a major antioxidant function of high density lipoprotein are, to an important degree, genetically determined.

Aryldialkylphosphatase↗
PubMed1995

Protective effect of high density lipoprotein associated paraoxonase. Inhibition of the biological activity of minimally oxidized low density lipoprotein.

Our group has previously demonstrated that oxidized phospholipids in mildly oxidized LDL (MM-LDL) produced by oxidation with lipoxygenase, iron, or cocultures of artery wall cells increase monocyte-endothelial interactions and this sequence of events is blocked by HDL. To obtain further insight into the mechanism by which HDL abolishes the activity of MM-LDL we investigated the effect of the HDL-associated ester hydrolase paraoxonase (PON). Treatment of MM-LDL with purified PON significantly reduced the ability of MM-LDL to induce monocyte-endothelial interactions. Inactivation of PON by pretreating HDL with heat or EDTA reduced the ability of HDL to inhibit LDL modification. HPLC analysis of phospholipids isolated from MM-LDL before and after treatment with purified PON showed that the 270 nm absorbance of phospholipids was decreased, while no effect was observed on 235 nm absorbance. Oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (Ox-PAPC) and specific fractions of Ox-PAPC isolated by HPLC induced the same monocyte-endothelial interactions as did MM-LDL. Biologically active and inactive HPLC fractions of Ox-PAPC were compared by fast atom bombardment-mass spectrometry which revealed that active fractions possessed ions with a mass to charge [correction of change] ratio greater than native PAPC by multiples of 16 D suggesting the addition of 3 and 4 oxygen atoms to PAPC. Comparison of Ox-PAPC by fast atom bombardment-mass spectrometry before and after PON treatment showed that PON destroyed these multi-oxygenated molecules found in biologically active fractions of Ox-PAPC. These results suggest that PON in HDL may protect against the induction of inflammatory responses in artery wall cells by destroying biologically active lipids in mildly oxidized LDL.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed2004

Effect of short term treatment with simvastatin and atorvastatin on lipids and paraoxonase activity in patients with hyperlipoproteinaemia.

OBJECTIVE: High-density lipoprotein (HDL)-associated paraoxonase (PON) activity may play an important role in the inhibition of low-density lipoprotein (LDL) oxidation. Previous studies have demonstrated that serum PON activity is decreased in patients with hyperlipoproteinaemia and coronary heart disease. The study presented here examined the effect of short-term treatment with simvastatin and atorvastatin on lipids and PON activity in patients with hyperlipoproteinaemia. RESEARCH DESIGN AND METHODS: A prospective, non-blinded, single-group, cross-over, comparative trial was performed. Following an 8-week dietary run-in period, 49 patients (23 men and 26 women, mean age: 59.8 +/- 7.9 years) with Fredrickson type IIa. and IIb. hyperlipoproteinaemias were randomized to receive either simvastatin 20 mg/day or atorvastatin 10 mg/day for 3 months. Following an 8-week washout period, patients were crossed-over to receive the other drug for a further 3 months. Serum lipids were measured and serum PON activity was determined spectrophotometrically using paraoxon as a substrate. RESULTS: Simvastatin treatment significantly reduced serum cholesterol, LDL-cholesterol (LDL-C) and apolipoprotein (apo) B levels (p < 0.001). Atorvastatin had a more pronounced cholesterol, LDL-C- and apo B-lowering effect (p < 0.001) compared with simvastatin. Both statins also significantly reduced serum triglyceride levels (p < 0.01). Simvastatin and atorvastatin caused no significant change in the levels of HDL-cholesterol (HDL-C) and apo A1. HDL-associated PON activity did not change significantly after simvastatin therapy, but significantly increased after atorvastatin treatment (p < 0.05). CONCLUSIONS: Short-term administration of simvastatin did not increase PON activity. Atorvastatin treatment had a favourable effect on lipid profile and increased the activity of HDL-associated PON.

Adult↗
PubMed2004

Paraoxonase activity in high-density lipoproteins: a comparison between healthy and obese females.

Paraoxonase, an enzyme associated with high-density lipoprotein (HDL-PON), exerts a protective effect against oxidative damage of circulating cells and lipoproteins, modulates the susceptibility of HDL to atherogenic modifications such as glycation and homocysteinylation, and even exerts an antiinflammatory role. The aim of the present study was to investigate the relationship between lipoprotein oxidative stress and the activity of HDL-PON in healthy and obese subjects. Therefore, the activity of HDL-PON and the levels of lipid hydroperoxides in HDL and low-density lipoprotein (LDL) isolated from plasma of obese females (n = 12) and age-sex-matched controls (n = 31) were compared. Our results demonstrated for the first time that the activity of HDL-PON in obese subjects was significantly lower compared with that in controls (P < 0.001). Moreover, our results showed a significant increase in the levels of lipid hydroperoxides in HDL and LDL isolated from obese subjects (P < 0.001). The negative correlations established between HDL-PON activity and the levels of lipid hydroperoxides associated with HDL and LDL confirm the relationship between paraoxonase activity and lipid peroxidation of lipoproteins. Plasma levels of leptin correlated negatively with HDL-PON activity and positively with levels of lipid hydroperoxides in HDL and LDL of obese subjects, suggesting a relationship between leptin and oxidative damage of lipoproteins. In conclusion, our study demonstrated that the increase in oxidative stress in LDL and HDL of obese subjects is associated with a decrease in HDL-PON activity. The lower paraoxonase activity and the compositional changes in HDL and LDL could contribute to the greater risk of cardiovascular disease associated with obesity.

Adult↗
PubMed1999

Targeted disruption of the murine lecithin:cholesterol acyltransferase gene is associated with reductions in plasma paraoxonase and platelet-activating factor acetylhydrolase activities but not in apolipoprotein J concentration.

Lecithin:cholesteryl acyltransferase (LCAT) deficiency resulting from targeted disruption of the Lcat gene in the mouse is associated with dramatic decreases in HDL concentration and the accumulation of nascent HDL in the plasma. We examined whether LCAT deficiency in mice is associated with a concomitant decrease in two antioxidative enzymes, paraoxonase (PON) and platelet-activating factor acetylhydrolase (PAF-AH). In control Lcat (+/+) mice both these enzymes are transported on HDL. Compared to Lcat (+/+) mice, HDL-cholesterol is reduced 94% and apoA-I, 90%, in Lcat (-/-) mice; this reduction in HDL is paralleled by a 71% decrease in PAF-AH activity and in a 58% decrease in PON activity. Apolipoprotein J (apoJ) levels, rather than being decreased, were significantly (P = 0.01) higher (36%) in Lcat (-/-) than in Lcat (+/+) mice, and the apo J/PON ratio was 3-fold greater in Lcat (-/-) than in Lcat (+/+) animals. Even though apolipoprotein A-I (apoA-I) concentration and PON activity were drastically reduced, there was no reduction in apoA-I and PON liver mRNA levels suggesting that post-transcriptional events are responsible for the reduction of plasma PON and apoA-I levels. Fast protein liquid chromatography (FPLC) revealed that in Lcat (+/+) mice both PON and PAF-AH activity is associated with large, apoA-I-containing HDL particles (9.7 nm by non-denaturing gradient gel electrophoresis) while in Lcat (-/-) mice both enzymes are associated with small 8.2 nm particles. We conclude that the concomitant reduction in HDL and apoA-I concentrations and PON and PAF-AH activities is best explained by rapid clearance of the small HDL particles found in LCAT deficiency.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed1999

Paraoxonase (PON1) polymorphism & its relation with lipids in north west Indian Punjabis.

We investigated 190 healthy, unrelated and randomly selected, north-west Indian Punjabis (M:102; F:88) for paraoxonase (PON1) polymorphism by dual substrate method and also determined lipid variables i.e., total cholesterol (TC), high density lipoprotein cholesterol (HDL), low density lipoprotein cholesterol (LDL) and triglycerides (TG) in them to determine any relationship between PON1 activity, PON1 phenotypes and lipids. The basal plasma paraoxonase (PON) activity, and PON activity in presence of 1 Mol NaCl (salt activated paraoxonase i.e., SAP) were estimated by using paraoxon as substrate whereas the, phenyl acetate esterase (A) activity was estimated by using phenylacetate as substrate. Based on the ratio of SAP/A activity, three distinct phenotypes of PON1 could be determined with gene frequencies of PON*A (low activity) and PON*B (high activity) allele being 0.847 and 0.153 respectively. In the whole population on partial correlation after normalising the variables and after adjusting the lipids for age and body mass index (BMI), a significant negative correlation was observed between SAP/A ratio and TC (r = -0.290; P < 0.01) and LDL (r = -0.154; P < 0.05). However, on analysis of covariance (ANCOVA) after normalizing the lipid variables and adjusting these for age and body mass index (BMI), no significant difference could be observed in lipid profile of these three phenotypes. The lack of a significant relationship between lipids and PON1 phenotypes, suggests that PON phenotype does not significantly influence the lipid profile in north-west Indian Punjabis. However, a significant negative correlation between the PON activity and TC and LDL suggests that low PON activity could be a risk factor for atherosclerosis in these subjects.

Adult↗
PubMed2002

[The effects of paraoxonase-1 and oxidized low density lipoprotein on nephropathy in type-2 diabetes mellitus].

OBJECTIVE: To explore the effect of paraoxonase-1 (PON-1) and oxidized low density lipoprotein (ox-LDL) in diabetic nephropathy (DN). METHODS: Serum PON-1 activity was measured by using phenyl acetate as a substrate and the concentration of plasma ox-LDL was determined by ELISA in 91 cases of type 2 diabetes mellitus (DM). Simultaneously, serum NO, VWF and GMP 140 were also determined. The patients of DM were divided into three groups according to urine albumine excretion rate (UAER) (DM I: UAER < 30 mg/24 h; DM II: UAER 30 approximately 300 mg/24 h; DM III: UAER > 300 mg/24 h) and matched with normal controls (NC). RESULTS: In the three groups of DM, PON-1 were markedly decreased and ox-LDL were obviously increased (P < 0.01). Both of their levels were different in the three groups of DM (P < 0.05). PON-1 were negatively correlated with ox-LDL (r = -0.467, P < 0.01). There were negative correlation between PON-1 and urine albumin (r = -0.697, P < 0.01), but ox-LDL was positively correlated with urine albumin (r = 0.747, P < 0.01). Serum nitrites (NO) level in DM I was significantly higher than that in NC, but the NO level in DM II and DM III was lower than that in DM I and NC. GMP 140 and VWF levels in all the 3 DM groups were higher than that in NC. PON-1 was positively correlated with NO (r(s) = 0.326, P < 0.01), and negatively correlated with VWF (r(s) = -0.365, P < 0.01). ox-LDL was negatively correlated with NO (r(s) = -0.196, P < 0.05), but positively correlated with VWF and GMP 140 (r(s) = 0.294, P < 0.05; r(s) = 0.669, P < 0.01 respectively). Logistic regression showed that ox-LDL was a dangerous factor for DN. CONCLUSION: PON-1, ox-LDL, NO, endothelial and platelet function are connected with DN; they affect one another and influence the occurrence and development of DN together.

Adult↗
PubMed2002

Serum paraoxonase activity and paraoxonase gene polymorphism in type 2 diabetic patients with or without vascular complications.

BACKGROUND: Serum paraoxonase (PON) activity and the relevance of PON gene polymorphism in vascular complications of type 2 diabetic patients were investigated in a case-control study. METHODS: The population included 105 control subjects, 96 diabetic patients without vascular complications and 71 diabetics with vascular complications. RESULTS: Serum PON activity was significantly decreased (p<0.001) in diabetic patients without vascular complications: 207 IU (25-817) compared with the controls: 259 IU (24-950). Although serum PON activity was also decreased: 232 IU (34-797) in the population with vascular complications, the difference was not statistically significant (p=0.11). The Q192 allele frequency is significantly higher (p<0.005) in diabetics without vascular complications (77%), and with vascular complications (73%) than in the controls (63%). No significant association was found between either PON(1)55 L/M and PON(2)311 C/S gene polymorphisms and vascular complications. CONCLUSIONS: The difference in allele frequency for the PON(1) Q/R 192 gene polymorphism may be the cause of the low paraoxonase activity observed in type 2 diabetes mellitus. Further studies need to be conducted to elucidate the role of the enzyme in the development of vascular complications in diabetes.

Adult↗
PubMed2004

Motor projections to the basis pontis in rhesus monkey.

Motor corticopontine studies suggest that the pons is topographically organized, but details remain unresolved. We used physiological mapping in rhesus monkey to define subregions in precentral motor cortex (M1), injected isotope tracers into M1 and the supplementary motor area (SMA), and studied projections to the basis pontis. Labeled fibers descend in the internal capsule (SMA in anterior limb and genu; M1 in posterior limb) and traverse the midsection of the cerebral peduncle, where SMA fibers are medial, and face, arm, and leg fibers are progressively lateral. Each motor region has unique terminations in the ipsilateral basis pontis and nucleus reticularis tegmenti pontis. Projections are topographically organized, preferentially in the caudal half of the pons, situated in close proximity to traversing corticofugal fibers. In nuclei that receive multiple inputs, terminations appear to interdigitate. Projections from the SMA-face region are most medial and include the median pontine nucleus. M1-face projections are also medial but are lateral to those from SMA-face. Hand projections are in medially placed curved lamellae in mid- and caudal pons. Dorsal trunk projections are in medial and ventral locations. Ventral trunk/hip projections encircle the peduncle in the caudal pons. Foot projections are heaviest caudally in laterally placed, curved lamellae. These results have relevance for anatomical clinical correlations in the human basis pontis. Furthermore, the dichotomy of motor-predominant caudal pons projections to cerebellar anterior lobe, contrasted with associative-predominant rostral pons projections to cerebellar posterior lobe, is consistent with new hypotheses regarding the cerebellar contribution to motor activity and cognitive processing.

Animals↗
PubMed2004

Involvement of adenosinergic A1 systems in the occurrence of respiratory perturbations encountered in newborns following an in utero caffeine exposure. a study on brainstem-spinal cord preparations isolated from newborn rats.

Involvement of adenosinergic A1 systems in the occurrence of respiratory perturbations encountered in newborns following an in utero caffeine exposure has been investigated on pontomedullary-spinal cord, caudal pons-medullary-spinal cord and medullary-spinal cord preparations isolated from newborn rats. According to the drinking fluid of dams (tap water or 0.02% caffeine), two groups of preparations were distinguished, no-caffeine and caffeine. In the no-caffeine group, adenosine A1 receptor activation induces a decrease in respiratory frequency (Rf) in caudal pons-medullary-spinal cord and medullary-spinal cord preparations whereas, in presence of the rostral pons, an increase is observed. A parallel Fos detection indicates that this discrepancy may be due to the excitatory action of the medial parabrachial nucleus at the rostral pontine level that surpasses inhibitory influence of the adenosine A1 receptor activation at the medullary level particularly in the ventrolateral reticular nucleus of the medulla. In caffeine group, an increase in the baseline Rf in presence of the pons and no change in medullary-spinal cord preparations have been observed. Depending on Fos detection, we assume that the medial parabrachial nucleus is the main region involved in the exaggeration of Rf. Moreover, adenosine A1 receptor activation was modified by in utero caffeine exposure with an overcharge of the Rf increase in pontomedullary-spinal cord preparations and an exaggeration of the Rf decrease in medullary-spinal cord preparations. Based on Fos detection, we link the overcharge in Rf of pontomedullary spinal cord preparations to an increase in the medial parabrachial nucleus neuronal activity. Similarly, exaggeration of Rf decrease observed without the pons is linked with a decrease in activity of the ventrolateral reticular neurons. This study brings evidence for the involvement of adenosinergic A1 systems in the occurrence of respiratory perturbations in newborns following in utero caffeine exposure and the importance of rostral pons in the adenosinergic A1 modulation of the respiratory control.

Adenosine↗
PubMed2004

Functional and structural models of pontine modulation of mechanoreceptor and chemoreceptor reflexes.

The dorsolateral and ventrolateral pons (dl-pons, vl-pons) are critical brainstem structures mediating the plasticity of the Hering-Breuer mechanoreflex (HBR) and carotid chemoreflex (CCR). Review of anatomical evidence indicates that dl-pons and vl-pons are connected reciprocally with one another and with medullary nucleus tractus solitarius (NTS) and ventral respiratory group (VRG). With this structural map, functional models of HBR and CCR are proposed in which the respiratory rhythm is modulated by short-term depression (STD) or potentiation (STP) of corresponding primary NTS-VRG and auxiliary pons-VRG excitatory or inhibitory pathways. Behaviorally, STD and STP of respiratory reflexes are akin to non-associative learning such as habituation, sensitization or desensitization to afferent inputs. Computationally, the STD and STP effects amount to signal differentiation and integration in the time domain, or high-pass and low-pass filtering in the frequency domain, respectively. These functional and structural models of pontomedullary signal processing provide a novel conceptual framework that unifies a wealth of experimental observations regarding mechanoreceptor and chemoreceptor reflex control of breathing.

Animals↗
PubMed1984

Vitamin content of some normal human brain segments.

Nicotinates, pantothenates, riboflavin, vitamins B6 and B12' free (acetyl) and total (free and bound) choline, biopterin, thiamin, biotin, methylated and nonmethylated folates in frontal, temporal, precentral, postcentral, and occipital cortex, thalamus, cerebellum, pons, basal ganglia, and substantia nigra were estimated. Nicotinates are significantly more concentrated in basal ganglia and thalamus than pons. Nonmethylated folate content is not significantly varied in brain segments; the pons contains more methylated folate. Riboflavin content is higher in the basal ganglia and temporal cortex than frontal cortex. Biotin is concentrated in pons and basal ganglia. Thiamin concentration is less in the postcentral cortex than the thalamus and substantia nigra. Biopterin is significantly higher in substantia nigra and basal ganglia than the other brain segments. Total choline content is high in substantia nigra, pons, and thalamus; free (acetyl) choline is significantly elevated in basal ganglia. B12 content is less concentrated in the cortex segments. B6 is highly concentrated in the basal ganglia. Pantothenate content is elevated in pons when compared to the various cortex segments and cerebellum.

Adult↗
PubMed2001

Quantitative proton MR spectroscopic imaging of normal human cerebellum and brain stem.

Quantitative, multislice proton MR spectroscopic imaging (MRSI) was used to investigate regional metabolite levels and ratios in the normal adult human posterior fossa. Six normal volunteers (36 +/- 3 years, five male, one female) were scanned on a 1.5 T scanner using multislice MRSI at long echo time (TE 280 msec). The entire cerebellum was covered using three oblique-axial slice locations, which also included the pons, mid-brain, insular cortex, and parieto-occipital lobe. Concentrations of N-acetylaspartate (NAA), choline (Cho), and creatine (Cr) were estimated using the phantom replacement technique. Regional variations of the concentrations were assessed using ANOVA (P < 0.05). High-resolution MRSI data was obtained in all subjects and brain regions examined. Metabolite concentrations (mM) (mean +/- SD) were as follows: cerebellar vermis: 2.3 +/- 0.4, 8.8 +/- 1.7 and 7.6 +/- 1.0 for Cho, Cr, and NAA respectively; cerebellar hemisphere: 2.2 +/- 0.6, 8.9 +/- 2.1, 7.5 +/- 0.8; pons 2.2 +/- 0.5, 4.3 +/- 1.1, 8.3 +/- 0.9; insular cortex, 1.8 +/- 0.5, 7.8 +/- 2, 8.0 +/- 1.1, parieto-occipital gray matter, 1.3 +/- 0.3, 5.7 +/- 1.1, 7.2 +/- 0.9, and occipital white matter, 1.4 +/- 0.3, 5.3 +/- 1.3, 7.5 +/- 0.8. Consistent with previous reports, significantly higher levels of Cr were found in the cerebellum compared to parieto-occipital gray and occipital white matter, and pons (P < 0.0001). NAA was essentially uniformly distributed within the regions chosen for analysis, with the highest level in the pons (P < 0.04). Cho was significantly higher in the cerebellum and pons than parieto-occipital gray and occipital white matter (P < 0.002) and was also higher in the pons than in the insular cortex (P < 0.05). Quantitative multislice MRSI of the posterior fossa is feasible and significant regional differences in metabolite concentrations were found.

Adult↗
PubMed1979

Developmental plasticity of central noradrenaline neurons after neonatal damage--changes in transmitter functions.

The effects of neonatal 6-hydroxydopamine (6-OH-DA) treatment (systemic administration) on noradrenaline (NA) metabolism, turn over, and receptor characteristics have been investigated in rat brain in the adult stage. This treatment is known to preferentially affect the locus coeruleus (LC) NA system leading to a marked NA denervation in the central cortex and hyperinnervation of NA nerve terminals in the pons and medulla oblongata without influencing the LC perikarya. The main NA metabolite, 3-methoxy-4-hydroxy-phenylglycol (MOPEG) was reduced by about 70% in the cerebral cortex after 6-OH-DA treatment at birth while the endogenous NA was almost completely depleted (-92%). The MOPEG levels were not significantly changed in the pons medulla after 6-OH-DA treatment in contrast to the 60% increase of the endogenous NA concentration. The relative reduction of NA in the cerebral cortex of 6-OH-DA treated rats increased in the cerebral cortex following administration of the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine (H44/68) compared to the control, while the H44/68 induced depletion of NA was reduced in the pons medulla after 6-OH-DA. The steady-state level of endogenous NA and the effect of H44/68 were unchanged in the LC perikarya after 6-OH-DA treatment. These results indicate that the NA turn over in remaining NA nerve terminals in the cerebral cortex is increased after 6-OH-DA, while decreased in the pons-medulla, possible related to changes in the activation of presynaptic alpha-adrenoreceptors in both regions. NA-induced formation of cAMP in vitro was found to be markedly increased in the cerebral cortex after 6-OH-DA, whereas no consistent change was observed in the pons medulla. Measurements of alpha- and beta-receptor binding in vitro using radioligand techniques showed an increase of binding sites (20%--50%) for both receptors in the neocortex aster 6-OH-DA, whereas no changes were observed in the pons medulla. The 6-OH-DA induced changes in NA turnover, cAMP generating systems, and receptor density may all represent compensatory processes following the altered development of the NA neurons induced by 6-OH-DA.

Aging↗
PubMed2004

Atorvastatin effect on high-density lipoprotein-associated paraoxonase activity and oxidative DNA damage.

OBJECTIVE: High-density lipoprotein (HDL)-associated antioxidant paraoxonase (PON) may reduce low-density lipoprotein (LDL) oxidation and prevent atherosclerosis. The aim of this present study was to investigate the effect of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor atorvastatin on hydrogen-peroxide-induced DNA damage by comet assay and the correlation between oxidative DNA damage and antioxidant PON activity. METHODS: Thirteen type-II/a hyperlipidemic patients were enrolled in the study. We examined the effect of 10 mg/day atorvastatin treatment on lipid levels and the degree of DNA damage in lymphocytes separated from hyperlipidemic patients, nitric oxide (NO), thiobarbituric acid-reactive substances (TBARS), PON levels and activity. RESULTS: After 6 months, atorvastatin treatment significantly decreased serum cholesterol and LDL-cholesterol levels. The triglyceride level did not change, and there was no significant change in the HDL cholesterol level. The visual score characteristic to the degree of DNA damage in comet assay was significantly decreased, as well as the TBARS level, while the level of NO was non-significantly increased. PON activity and the PON/HDL ratio were significantly increased after atorvastatin treatment. There was a negative correlation between DNA damage and PON activity, as well as between DNA damage and the PON/HDL ratio before and after atorvastatin treatment. CONCLUSION: These findings show that atorvastatin treatment favorably affected the lipid profile, increasing the activity of HDL-associated PON and decreasing the cytotoxic effect of oxidative stress.

Adult↗