Orientador: Thales Rocha de Mattos Filho / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba / Made available in DSpace on 2018-07-18T11:24:49Z (GMT). No. of bitstreams: 1 Jordao_EloaJannuzziHernandes_M.pdf: 1529911 bytes, checksum: 59fcdb1116b3f5d567638adba2f7ef66 (MD5) Previous issue date: 1992 / Resumo: O propósito do trabalho foi o de avaliar a influência da droga declofenaco potássio (Cataflam 'MARCA REGISTRADA') e piroxicam (Feldene 'MARCA REGISTRADA'), sobre o fígado de ratos em regeneração. A técnica de hepatectomia parcial realizada foi a descrita por HIGGINS & ANDERSSONS (1931). PAra tanto, foram utilziados 30 ratos (Rattus norvegicus albinos, Wistar), machos, com 60 dias de idade, divididos em 3 grupos: 1º grupo (D) tratado com diclofenaco na dose de 1,5 mg/kg/dia (I.P.); 2º grupo (P) tratado com piroxicam na dose de 0,5 mg/kg/dia (I.P.); 3º grupo (C) controle que receberam NaCl 0,9% (I.P.). Foram medidas as quantidades de transaminase glutâmica oxalacética (TGO) e transaminase glutâmica pirúvica (TGP) no soro sanguíeo, em intervalos de tempo 0, 24, 48 horas, 7 e 14 dias. Os resultados mostraram que o diclofenaco potássico aumentou o nível plasmático da TGO no tempo zero quando comparado aos grupos piroxicam e controle; TGO e TGP no tempo 48 horas quando comparado ao grupo piroxicam; TGP no tempo 14 dias quando comparado ao grupo controle / Abstract: The purpose of this work was to evaluate the influence os potassium diclofenac (Cataflam "MARCA REGISTRADA') and piroxicam (Feldene 'MARCA REGISTRADA') in rat liver regeneration. The methods for a 70 % hepatectomy were the same as those described by HIGGINS and ANDERSON (1931). Thirty male rats (Rattus novergicus albinus, Wistar) sixthy days old were distributed as follows: 1th Group (D) - treated with 1,5 mg/kg/day diclofenac (I.P.); 2th Group (P) - treated with 0,5 mg/kg/day piroxicam (I.P.); 3 ths Group (C) - control group with animal received NaCl 0,9 % (I.P.). The serum concentration of aspartate aminotransferase (TGO) and alanine aminotranferase (TGP) were measured in time intervals of zero, 24, 48 hours, 7 and 14 days. The results showed that potassium diclofenac increased the plasma level of TGO in time zero in relation to piroxicam and control (p<0.05); TGO and TGP in time 48 hours in relation to control (p>0.05); TGP in time 48 hours in relation to piroxicam (p<0.05); TGP in time 14 days in relations to control (p<0.05) / Mestrado / Farmacologia / Mestre em Ciências

<p>Camellia sinensis (tea) and Aspalathus linearis (rooibos) may improve reproductive function owing to their antioxidant properties. To test this<br /> hypothesis, male and female rats were given 2% and 5% green tea (Gt), black tea (Bt), unfermented rooibos (Ur) or fermented rooibos (Fr) as sole source of drinking for 52 and 21 days respectively. Control rats received tap water. In addition, TM3 Leydig cells were exposed to 0.025, 0.05, 0.1 and 0.5 % aqueous extracts of green tea, black tea, unfermented and fermented rooibos for 24h. In vitro analysis of tea and the herbal infusion revealed the phenolic property and antioxidant capacity (FRAP) in the order Gt &gt / Bt &gt / Ur &gt / Fr. Camellia sinensis and Aspalathus linearis revealed no significant effect on serum antioxidant capacity (p &gt / 0.05) and lipid peroxidation (MDA) in the kidney or liver in both male and female rats and in the testes of the male rats (p &gt / 0.05). In addition, the antioxidant levels were maintained in the testes, liver and kidneys in both the male and female rats. In the male rats, no significant alterations were observed in body weight gain, liver and reproductive organs weight, and serum testosterone (p &gt / 0.05). Only, 5% green tea significantly increased testosterone level (p &lt / 0.05). Seminiferous tubules displayed complete spermatogenesis with abundant sperm in the lumen in all treated groups. However, a significant decrease in diameter and germinal epithelial height of these tubules were observed (p &lt / 0.05). In the epididymides, epithelial height of caput region showed a significant increase (p &lt / 0.01), while the cauda region was increased by Camellia sinensis but decreased by Aspalathus linearis. Sperm concentration improved significantly by green tea and unfermented rooibos (p &lt / 0.05), while black tea and fermented rooibos produced a non significant effect (p &gt / 0.05). Sperm viability was enhanced in all treatment groups (p &lt / 0.05). Furthermore, green tea, black tea and unfermented rooibos significantly improved the motility of rat sperm (p &lt / 0.05) / fermented rooibos tended to improve it (p &gt / 0.05). In addition, green tea, black tea and fermented rooibos enhanced acrosome reaction (p &lt / 0.05). Creatinine activity was significantly higher in rats treated with black tea, unfermented rooibos or fermented rooibos (p &lt / 0.05), green tea tended to increase it (p &gt / 0.05) reflecting the significant increased kidney weight in the treatment groups at high concentrations. Liver markers, ALT and AST, decreased significantly in all treated groups (p &lt / 0.05), except in 5% fermented rooibos where a significant increase in AST level was observed (p &lt / 0.01). In the female rats, the body weight gain, and reproductive organs weight was no affected (p &gt / 0.05). However, 5% fermented rooibos reduced the ovarian weight (p &lt / 0.05), while 5% unfermented rooibos significantly increased the uterine weight (p &lt / 0.05). Liver weight increased significantly by black tea and unfermented rooibos (p &lt / 0.05) while the kidney weight increased significantly by 5% black tea (p &lt / 0.05). No significant effect was observed in the level of FSH produced, on the other hand, Camellia sinensis significantly lowered the level of LH (p &lt / 0.05), while Aspalathus linearis had no effect (p &gt / 0.05). Creatinine activity was enhanced significantly only by 5% fermented rooibos (p &lt / 0.05). Liver markers, ALT and AST were reduced in most treated groups except in fermented rooibos where an increase was observed. In addition, histological sections revealed no obvious alteration in the ovaries, uteri, kidneys and liver of all treated female rats. Camellia sinensis and Aspalathus linearis significantly reduced the level of testosterone produced in TM3 Leydig cells under stimulated conditions in vitro (p&lt / 0.05). Furthermore, both plants maintained the viability and morphology of the cells. However, at 0.5% of either plant extracts, a significant decrease in the viability (p &lt / 0.05) and altered morphology of the TM3 Leydig cells was observed. In conclusion, Camellia sinensis and Aspalathus linearis significantly improved certain sperm function which might be attributed to their high level of antioxidant activity. However, the prolonged exposure of both plant extracts might result in subtle structural changes in the male reproductive system and impair kidney function. In addition, fermented rooibos at high concentration may also impair the functions of the liver. In vitro, both plants were shown to possess anti-androgenic property on TM3 Leydig cells. Furthermore, both Camellia sinensis and Aspalathus linearis may be classified as weak phytoestrogens due to the changes in the weight of the uterus and ovaries observed.</p>

<p>Camellia sinensis (tea) and Aspalathus linearis (rooibos) may improve reproductive function owing to their antioxidant properties. To test this<br /> hypothesis, male and female rats were given 2% and 5% green tea (Gt), black tea (Bt), unfermented rooibos (Ur) or fermented rooibos (Fr) as sole source of drinking for 52 and 21 days respectively. Control rats received tap water. In addition, TM3 Leydig cells were exposed to 0.025, 0.05, 0.1 and 0.5 % aqueous extracts of green tea, black tea, unfermented and fermented rooibos for 24h. In vitro analysis of tea and the herbal infusion revealed the phenolic property and antioxidant capacity (FRAP) in the order Gt &gt / Bt &gt / Ur &gt / Fr. Camellia sinensis and Aspalathus linearis revealed no significant effect on serum antioxidant capacity (p &gt / 0.05) and lipid peroxidation (MDA) in the kidney or liver in both male and female rats and in the testes of the male rats (p &gt / 0.05). In addition, the antioxidant levels were maintained in the testes, liver and kidneys in both the male and female rats. In the male rats, no significant alterations were observed in body weight gain, liver and reproductive organs weight, and serum testosterone (p &gt / 0.05). Only, 5% green tea significantly increased testosterone level (p &lt / 0.05). Seminiferous tubules displayed complete spermatogenesis with abundant sperm in the lumen in all treated groups. However, a significant decrease in diameter and germinal epithelial height of these tubules were observed (p &lt / 0.05). In the epididymides, epithelial height of caput region showed a significant increase (p &lt / 0.01), while the cauda region was increased by Camellia sinensis but decreased by Aspalathus linearis. Sperm concentration improved significantly by green tea and unfermented rooibos (p &lt / 0.05), while black tea and fermented rooibos produced a non significant effect (p &gt / 0.05). Sperm viability was enhanced in all treatment groups (p &lt / 0.05). Furthermore, green tea, black tea and unfermented rooibos significantly improved the motility of rat sperm (p &lt / 0.05) / fermented rooibos tended to improve it (p &gt / 0.05). In addition, green tea, black tea and fermented rooibos enhanced acrosome reaction (p &lt / 0.05). Creatinine activity was significantly higher in rats treated with black tea, unfermented rooibos or fermented rooibos (p &lt / 0.05), green tea tended to increase it (p &gt / 0.05) reflecting the significant increased kidney weight in the treatment groups at high concentrations. Liver markers, ALT and AST, decreased significantly in all treated groups (p &lt / 0.05), except in 5% fermented rooibos where a significant increase in AST level was observed (p &lt / 0.01). In the female rats, the body weight gain, and reproductive organs weight was no affected (p &gt / 0.05). However, 5% fermented rooibos reduced the ovarian weight (p &lt / 0.05), while 5% unfermented rooibos significantly increased the uterine weight (p &lt / 0.05). Liver weight increased significantly by black tea and unfermented rooibos (p &lt / 0.05) while the kidney weight increased significantly by 5% black tea (p &lt / 0.05). No significant effect was observed in the level of FSH produced, on the other hand, Camellia sinensis significantly lowered the level of LH (p &lt / 0.05), while Aspalathus linearis had no effect (p &gt / 0.05). Creatinine activity was enhanced significantly only by 5% fermented rooibos (p &lt / 0.05). Liver markers, ALT and AST were reduced in most treated groups except in fermented rooibos where an increase was observed. In addition, histological sections revealed no obvious alteration in the ovaries, uteri, kidneys and liver of all treated female rats. Camellia sinensis and Aspalathus linearis significantly reduced the level of testosterone produced in TM3 Leydig cells under stimulated conditions in vitro (p&lt / 0.05). Furthermore, both plants maintained the viability and morphology of the cells. However, at 0.5% of either plant extracts, a significant decrease in the viability (p &lt / 0.05) and altered morphology of the TM3 Leydig cells was observed. In conclusion, Camellia sinensis and Aspalathus linearis significantly improved certain sperm function which might be attributed to their high level of antioxidant activity. However, the prolonged exposure of both plant extracts might result in subtle structural changes in the male reproductive system and impair kidney function. In addition, fermented rooibos at high concentration may also impair the functions of the liver. In vitro, both plants were shown to possess anti-androgenic property on TM3 Leydig cells. Furthermore, both Camellia sinensis and Aspalathus linearis may be classified as weak phytoestrogens due to the changes in the weight of the uterus and ovaries observed.</p>

Philosophiae Doctor - PhD / Camellia sinensis (tea) and Aspalathus linearis (rooibos) may improve reproductive function owing to their antioxidant properties. To test this hypothesis, male and female rats were given 2% and 5% green tea (Gt), black tea (Bt), unfermented rooibos (Ur) or fermented rooibos (Fr) as sole source of drinking for 52 and 21 days respectively. Control rats received tap water. In addition, TM3 Leydig cells were exposed to 0.025, 0.05, 0.1 and 0.5 % aqueous extracts of green tea, black tea, unfermented and fermented rooibos for 24h. In vitro analysis of tea and the herbal infusion revealed the phenolic property and antioxidant capacity (FRAP) in the order Gt > Bt > Ur > Fr. Camellia sinensis and Aspalathus linearis revealed no significant effect on serum antioxidant capacity (p > 0.05) and lipid peroxidation (MDA) in the kidney or liver in both male and female rats and in the testes of the male rats (p > 0.05). In addition, the antioxidant levels were maintained in the testes, liver and kidneys in both the male and female rats. In the male rats, no significant alterations were observed in body weight gain, liver and reproductive organs weight, and serum testosterone (p > 0.05). Only, 5% green tea significantly increased testosterone level (p < 0.05). Seminiferous tubules displayed complete spermatogenesis with abundant sperm in the lumen in all treated groups. However, a significant decrease in diameter and germinal epithelial height of these tubules were observed (p < 0.05). In the epididymides, epithelial height of caput region showed a significant increase (p < 0.01), while the cauda region was increased by Camellia sinensis but decreased by Aspalathus linearis. Sperm concentration improved significantly by green tea and unfermented rooibos (p < 0.05), while black tea and fermented rooibos produced a non significant effect (p > 0.05). Sperm viability was enhanced in all treatment groups (p < 0.05). Furthermore, green tea, black tea and unfermented rooibos significantly improved the motility of rat sperm (p < 0.05); fermented rooibos tended to improve it (p > 0.05). In addition, green tea, black tea and fermented rooibos enhanced acrosome reaction (p < 0.05). Creatinine activity was significantly higher in rats treated with black tea, unfermented rooibos or fermented rooibos (p < 0.05), green tea tended to increase it (p > 0.05) reflecting the significant increased kidney weight in the treatment groups at high concentrations. Liver markers, ALT and AST, decreased significantly in all treated groups (p < 0.05), except in 5% fermented rooibos where a significant increase in AST level was observed (p < 0.01). In the female rats, the body weight gain, and reproductive organs weight was no affected (p > 0.05). However, 5% fermented rooibos reduced the ovarian weight (p < 0.05), while 5% unfermented rooibos significantly increased the uterine weight (p < 0.05). Liver weight increased significantly by black tea and unfermented rooibos (p < 0.05) while the kidney weight increased significantly by 5% black tea (p < 0.05). No significant effect was observed in the level of FSH produced, on the other hand, Camellia sinensis significantly lowered the level of LH (p < 0.05), while Aspalathus linearis had no effect (p > 0.05). Creatinine activity was enhanced significantly only by 5% fermented rooibos (p < 0.05). Liver markers, ALT and AST were reduced in most treated groups except in fermented rooibos where an increase was observed. In addition, histological sections revealed no obvious alteration in the ovaries, uteri, kidneys and liver of all treated female rats. Camellia sinensis and Aspalathus linearis significantly reduced the level of testosterone produced in TM3 Leydig cells under stimulated conditions in vitro (p< 0.05). Furthermore, both plants maintained the viability and morphology of the cells. However, at 0.5% of either plant extracts, a significant decrease in the viability (p < 0.05) and altered morphology of the TM3 Leydig cells was observed. In conclusion, Camellia sinensis and Aspalathus linearis significantly improved certain sperm function which might be attributed to their high level of antioxidant activity. However, the prolonged exposure of both plant extracts might result in subtle structural changes in the male reproductive system and impair kidney function. In addition, fermented rooibos at high concentration may also impair the functions of the liver. In vitro, both plants were shown to possess anti-androgenic property on TM3 Leydig cells. Furthermore, both Camellia sinensis and Aspalathus linearis may be classified as weak phytoestrogens due to the changes in the weight of the uterus and ovaries observed. / South Africa

Dans le cadre du changement climatique et de l'évolution de la réglementation concernant les intrants azotés, la culture du colza risque d'être fortement pénalisée dans la mesure où c'est une culture qui nécessite d'importants apports azotés pour atteindre son potentiel de rendement. Par ailleurs, comme chez le colza un déficit hydrique induit l'accumulation de certains composés azotés, il est vraisemblable que cela conduise au détournement d'une quantité importante d'azote vers les organes végétatifs aux dépens des organes reproducteurs et donc du rendement. Chez le colza, la réponse métabolique au déficit hydrique se traduit par une très forte accumulation de proline et dans une moindre mesure une augmentation de la teneur en GABA (acide γ-aminobutyrique), deux acides aminés connus chez la plupart des plantes pour leur réponse à de nombreux stress abiotiques. L'objectif de cette thèse est de déterminer comment le métabolisme de ces deux molécules contribue à l'allocation de l'azote au cours du développement de la plante en situation normale comme en condition de stress hydrique et/ou azoté. Pour répondre à cette question nous avons fait le choix de caractériser deux voies enzymatiques majeures impliquées dans le catabolisme de la proline et du GABA : la proline déshydrogénase (ProDH) et la GABA-transaminase (GABA-T) et d'évaluer l'impact de carences hydriques et/ou azotées sur ces voies. Cette étude nécessitait d'identifier au préalable les gènes codant ces enzymes afin d'aborder une approche fonctionnelle. Les résultats montrent l'existence de multiples copies de gènes ProDH et GABA-T dans le génome du colza. L'analyse de leurs profils d'expression suggère que des processus de sub-fonctionnalisation sont en cours conduisant à l'expression spécifique, de certaines copies en réponse aux stress, et d'autres dans les processus développementaux. La comparaison des profils métaboliques avec les profils spécifiques des transcrits a permis d'élaborer des hypothèses sur le rôle de ces voies dans la gestion de l'azote. L'étude conjointe des métabolismes de la proline et du GABA suggère l'existence de régulations connexes entre les deux. Enfin, l'utilisation de plantules a permis - d'approfondir la régulation des gènes étudiés à des stades précoces de développement - et de mettre en évidence les effets délétères de l'inhibition de la GABA-T par une approche pharmacologique. En conclusion ces résultats apportent des précisions sur la régulation de ces deux enzymes et fournissent des éléments de réponse quant au rôle fonctionnel des catabolismes de la proline et du GABA dans les processus de gestion de l'eau et de l'azote chez le colza. Ces travaux constituent donc une première étape dans une démarche de validation de ces gènes comme candidats pour des programmes d'amélioration du colza visant à sélectionner des génotypes mieux adaptés aux conditions environnementales futures. / In the context of climate change and recent regulation concerning nitrogen inputs, the oilseed rape yields may be severely decreased because its crop requires significant nitrogen supply to reach high yield performance. Moreover, as water deficit induces the accumulation of some nitrogen compounds in oilseed rape, it is likely that this could lead to diversion of significant amounts of nitrogen to the vegetative organs at the expense of the reproductive ones and therefore of the yield. In oilseed rape, the metabolic response to water deficit results in a very high proline accumulation and, to a lesser extent, an increased content of GABA (γ-aminobutyric acid), both these amino acids known for their response to many environmental stresses in most species. The objective of the work presented here was to determine how the metabolism of proline and GABA contributes to the nitrogen allocation during plant development under optimal conditions and under water stress and/or nitrogen depletion. To answer this question, we have chosen to characterize two major enzymatic pathways involved in the catabolism of proline and GABA, proline dehydrogenase (ProDH) and GABA transaminase (GABA-T), and assess the impact of water and/or nitrogen deficiency on these pathways. This study has required to preliminary identify the genes encoding these enzymes in order to initiate a functional approach. The results show the presence of multiple copies of ProDH and GABA-T genes in the oilseed rape genome. Analysis of their expression profiles suggests that sub-functionalization processes are occurring, leading to the specific expression of some copies in response to stress, and some in developmental processes. Comparison of metabolic profiles with specific profiles of transcripts allows us to hypothesize about the role of these pathways in management of nitrogen. The combined study of proline and GABA metabolisms suggests the existence of relationships between them. Finally, the use of seedlings allows - further studying the regulation of genes in the early stages of development - and highlighting the deleterious effects of the inhibition of GABA-T by a pharmacological approach. In conclusion these results supply information on the regulation of these two enzymes and provide answers about the functional roles of proline and GABA catabolisms in the management processes of water and nitrogen in oilseed rape. These works constitute a first step in validation process of these genes as putative candidates for oilseed rape breeding programs to select genotypes better adapted to future environmental conditions.

In a lipase investigation, Candida antarctica lipase B (CALB) are explored for enzyme catalytic promiscuity. Enzyme catalytic promiscuity is shown by enzymes catalyzing alternative catalytic transformations proceeding via different transition state structures than normal. CALB normally performs hydrolysis reactions by activating and coordinating carboxylic acid/ester substrates in an oxyanion hole prior to nucleophilic attack from an active-site serine resulting in acyl enzyme formation. The idea of utilizing the carbonyl activation oxyanion hole in the active-site of CALB to catalyze promiscuous reactions arose by combining catalytic and structural knowledge about the enzyme with chemical imagination. We choose to explore conjugate addition and direct epoxidation activities in CALB by combining molecular modeling and kinetic experiments. By quantum-chemical calculations, the investigated promiscuous reactions were shown to proceed via ordered reaction mechanisms that differ from the native ping pong bi bi reaction mechanism. The investigated promiscuous activities were shown to take place in the enzyme active-site by various kinetic experiments, but despite this, no enantioselectivity was displayed. The reason for this is unknown, but can be a result of a too voluminous active-site or the lack of covalent coordination of the substrates during enzyme-catalysis (Paper I-IV). Combining enzyme structural knowledge with chemical imagination may provide numerous novel enzyme activities to be discovered. In an ω-transaminase investigation, two (S)-selective ω-transaminases from Arthrobacter citreus (Ac-ωTA) and Chromobacterium violaceum (Cv-ωTA) are explored aiming to improve their catalytic properties. Structural knowledge of these enzymes was provided by homology modeling. A homology structure of Ac-ωTA was successfully applied for rational design resulting in enzyme variants with improved enantioselectivity. Additionally, a single-point mutation reversed the enantiopreference of the enzyme from (S) to (R), which was further shown to be substrate dependent (Paper V). A homology structure of Cv-ωTA guided the creation of an enzyme variant showing reduced isopropyl amine inhibition. / QC20100609

Arginine utilization in Pseudomonas aeruginosa with multiple catabolic pathways represents one of the best examples of metabolic versatility of this organism. To identify genes of this complex arginine network, we employed DNA microarray to analyze the transcriptional profiles of this organism in response to L-arginine. While most genes in arginine uptake, regulation and metabolism have been identified as members of the ArgR regulon in our previous study, eighteen putative transcriptional units of 38 genes including the two known genes of the arginine dehydrogenase (ADH) pathway, kauB and gbuA, were found inducible by exogenous L-arginine but independent of ArgR. The potential physiological functions of those candidate genes in L-arginine utilization were studied by growth phenotype analysis in knockout mutants. The insertion mutation of aruH encoding an L-arginine:pyruvate transaminase abolished the capability to grow on L-arginine of an aruF mutant devoid of a functional arginine succinyltransferase (AST) pathway, the major route of arginine utilization. The aruH gene was cloned and over-expressed in E. coli. Taking L-arginine and pyruvate as the substrates, the reaction products of recombinant enzyme were identified by MS and HPLC as 2-ketoarginine and L-alanine. Lineweaver-Burk plots of the data revealed a series of parallel lines characteristic of ping-pong kinetics mechanism, and the apparent Km and catalytic efficiency (Kcat/Km) were 1.6 ± 0.1 mM and 24.1 mM-1 s-1 for pyruvate and 13.9 ± 0.8 mM and 2.8 mM-1 s-1 for L-arginine. Recombinant AruH showed an optimal pH at 9.0 and substrate specificity with an order of preference being Arg > Lys > Met > Leu > Orn > Gln. These data led us to propose the arginine transaminase (ATA) pathway that removes the α-amino group of L-arginine via transamination instead of oxidative deamination by dehydrogenase or oxidase as originally proposed. In the same genetic locus, we also identified a two-component system, AruRS, for the regulation of arginine-responsive induction of the ATA pathway. Our latest DNA microarray experiments under D-arginine conditions also revealed PA3863 as the candidate gene encoding D-arginine dehydrogenase which might lead to the recognition of a wider network of arginine metabolism than we previously recognized.

No description available.

Phenelzine (PLZ) is a monoamine oxidase (MAO) inhibitor that also inhibits the activity of GABA-transaminase (GABA-T), causing significant and long-lasting increases in brain GABA levels. Inhibition of MAO prior to PLZ administration has been shown to prevent the GABAergic effects of the drug, strongly suggesting that a metabolite of PLZ formed by the action of MAO is responsible for the GABAergic effects. While PLZ has been used clinically for decades for its antidepressant and antipanic effects, it has more recently been shown to be neuroprotective in an animal model of ischemia. The aim of the experiments described in this thesis was to identify the active metabolite of PLZ, and to determine the neurochemical mechanisms by which PLZ and this metabolite exert their neuroprotective effects (with a particular focus on degenerative mechanisms observed in cerebral ischemia and Alzheimers disease (AD)). The development of an analytical assay for -phenylethylidenehydrazine (PEH) was a major breakthrough in this project and permitted the positive identification of this compound as the active metabolite of PLZ. Further experiments demonstrated that PLZ and PEH could be neuroprotective in cerebral ischemia and AD not only by reducing excitotoxicity via increased GABAergic transmission, but also by (a) increasing brain ornithine, which could potentially lead to a decrease in glutamate synthesis and/or a decrease in polyamines (whose metabolism produces toxic aldehydes); (b) inhibiting the activity of human semicarbazide-sensitive amine oxidase (SSAO), an enzyme whose activity is increased in AD producing excessive amounts of the toxic aldehyde formaldehyde (FA); (c) by sequestering FA in vitro, forming a non-reactive hydrazone product. Since PEH appears to mediate or share the neurochemical effects of PLZ, two propargylated analogs of PEH were synthesized and tested for their potential as PEH prodrugs. Surprisingly these analogs were not particularly effective prodrugs in vivo, but they possessed an interesting neurochemical properties on their own (the ability to elevate brain levels of glycine), and warrant further investigation as potential antipsychotic agents. Together, these results suggest that PLZ and its active metabolite, PEH, should be further investigated for their neuroprotective potential in cerebral ischemia and in AD. / Neurochemistry

Zugl.: Hohenheim, Univ., Diss., 2008. / Enthält u.a. vier Abstracts.