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Alzheimer’s disease (AD) is a neurodegenerative pathology that affects elderly people all over the world. Several studies have demonstrated that oxidative stress is an aggravating factor for AD development and progression. Therefore, this study aimed to evaluate the activity of two oxidative stress markers, glutathione peroxidase (GPx) and δ -aminolevulinate dehydratase ( δ -ALA-D), as well as correlate them with blood metal levels and AD progression. For this purpose, 88 elderly individuals were divided in two groups: AD group (34 patients diagnosed with AD) and control group (34 subjects paired by age with the AD group). The Mini-Mental State Examination and the Clinical Dementia Rating (CDR ) were used as tools to classify the AD progression. GPx and δ -ALA-D activities were measured in all subjects through blood tests. Both enzymes’ activities were decreased in AD patients when compared to the age-matched control group, regardless of the CDR. Moreover, GPx activity was positively correlated with selenium levels in the blood; and the δ -ALA-D activity was negatively correlated with blood cop- per levels. Taken together, our results indicated that, for the first time, blood δ -ALA-D activity was significantly inhibited in AD patients. While literature reports conflicting data regarding GPx activity in AD patients, the δ - ALA-D activity seems to be a more consistent tool to be applied as an earlier AD marker., EXCLI Journal;Vol. 18 2019

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES Nectandra grandiflora (Lauraceae) is a native species from Rio Grande do Sul, Brazil, whose essential oil (EO) is rich in sesquiterpenoids, such as, (+)-dehydrofukinone (DHF), (-)-selin-11-en-4-alpha-ol (SEL), and the compounds of unprecedented chemical structures, (+)-eremophil-11-en-10-ol (ERM) and (+)-dehydrofukinone epoxide (DFX). The GABAergic system is the major target for the terpenoids that diminish the Central Nervous System (CNS) excitability. Therefore, this work aims to evaluate the interaction of DHF, SEL, ERM and DFX with the GABAa receptors. For this purpose, it was conducted an investigation of: (1) (10-3 - 102 μM) DHF and (0,1-100 μM) DFX, ERM and SEL effect on membrane potential and calcium mobilization in synaptosomes from mice cortex; (2) DHF (3; 10; 30 or 100 mg/kg) effect against pentylenetetrazole (PTZ; 50 mg/Kg, i.p.)-induced seizures in mice; (3) the long-term exposure to (12,5-25 mg/L) SEL-, ERM- and DFX-induced sedation on silver catfish (Rhamdia quelen); (4) the anxiolytic potential (open field and elevated plus maze tests) of the EO and isolated compounds DHF SEL, ERM e DFX (10, 30 e 100 mg/ kg, v.o.) in mice; (5) the involvement of the GABAa receptors in the actions of the EO and compounds on the CNS; (6) the compounds presence in the mice cerebral cortex by gas chromatography. Experimental protocols were approved by the Animal Ethics Committee of Federal University of Santa Maria. Results showed that: DHF, DFX, ERM and SEL facilitate the membrane hyperpolarization and inhibit the downstream calcium influx in synaptosomes; DHF blunted PTZ-induced seizures in mice. EO and compounds induce anxiolytic effects in mice; SEL, ERM e DFX induce persistent sedation in fish; EO induced an increase in the GABAa/α2 subunit expression, SEL increase the GABAa/ β1, δ and γ2 subunits expression, while the compound ERM decrease the GABAa/α1 subunit expression in silver catfish; The CNS effects displayed by the N. grandiflora EO and compounds are mostly due to their interaction with GABAa receptors. However, we did not rule out the possibility of other molecular targets. These thesis results improved the pharmacological characterization of N. grandiflora, whose EO and isolated compounds may be useful as sedatives on fish farming procedures and indicating a therapeutic potential of this species for the treatment of CNS pathologies, such as epilepsy and anxiety disorders. A espécie Nectandra grandiflora (Lauraceae), nativa do Rio Grande do Sul, Brasil, é produtora de óleo essencial (OE) rico em sesquiterpenoides, entre eles (+)-deidrofuquinona (DHF), (-)-selin-11-en-4-α-ol (SEL) e os compostos de estrutura química inédita (+)-eremofil-11-en-10-ol (ERM) e (+)-epóxido de deidrofuquinona (DFX). Um dos principais mecanismos farmacológicos pelo qual compostos terpenoides exercem seus efeitos depressores do Sistema Nervoso Central (SNC) é a modulação do sistema GABAérgico. Portanto, este trabalho tem como objetivo avaliar a interação de DHF, SEL, ERM e DFX com o SNC e com os receptores GABAa usando diferentes modelos experimentais. Desta forma, foi proposta a investigação: (1) do efeito de DHF (10-3 - 102 μM), DFX, ERM e SEL (0,1-100 μM) sobre o potencial de membrana e mobilização do cálcio em sinaptossomas de camundongos; (2) do efeito de DHF (3; 10; 30 ou 100 mg/kg, i.p.) frente a crises epilépticas induzidas pelo pentilenotetrazol (PTZ; 50 mg/Kg, i.p.) em camundongos; (3) do efeito da longa exposição a SEL, ERM e DFX (12,5-25 mg/L) e a modulação de genes codificadores de subunidades do receptor GABAa por estes compostos e pelo OE em peixes da espécie Rhamdia quelen (jundiás); (4) do potencial ansiolítico (testes: campo aberto e labirinto em cruz elevado) do OE e dos compostos DHF, SEL, ERM e DFX (10, 30 e 100 mg/ kg, v.o.) em camundongos; (5) da participação dos receptores GABAa nos efeitos do OE e constituintes isolados sobre o SNC; (6) da presença dos compostos isolados no córtex total de cérebro de camundongos por cromatografia gasosa. As metodologias empregadas no presente estudo foram aprovadas pelo Comitê de Ética e Bem-Estar Animal da Universidade Federal de Santa Maria. Os resultados desta tese indicam que: DHF, SEL, ERM e DFX facilitam a hiperpolarização da membrana e inibem o influxo de cálcio em sinaptossomas; DHF atenua crises epilépticas induzidas pelo PTZ; o OE de N. grandiflora e os compostos DHF, SEL, ERM e DFX induzem efeito tipo- ansiolítico em camundongos; o OE e os compostos SEL, ERM e DFX induzem sedação persistente em peixes; o OE induz o aumento da expressão da subunidade α2/GABAa, o composto SEL aumenta a expressão da subunidade β1, δ e γ2 do receptor GABAa, enquanto o composto ERM diminui a expressão da subunidade α1 deste receptor em peixes; Os efeitos depressores do SNC relatados para o OE e os compostos DHF SEL, ERM e DFX são principalmente decorrentes da interação com os receptores GABAa. No entanto, não se descarta outros alvos moleculares. Os resultados desta tese contribuem para a caracterização farmacológica da espécie N. grandiflora e propõem: a aplicação de seu óleo essencial e compostos isolados como agentes sedativos para a prática de piscicultura; e, um potencial desta planta para o tratamento de patologias que envolvam o aumento da excitabilidade neuronal, como a epilepsia e os transtornos de ansiedade.