Submitted by Marcos Anselmo (marcos.anselmo@unipampa.edu.br) on 2018-09-28T19:17:34Z No. of bitstreams: 1 André Tiago Rossito Goes.pdf: 1301552 bytes, checksum: 403860d83984ea13e8f76afe4c562b26 (MD5) / Approved for entry into archive by Marcos Anselmo (marcos.anselmo@unipampa.edu.br) on 2018-09-28T19:18:09Z (GMT) No. of bitstreams: 1 André Tiago Rossito Goes.pdf: 1301552 bytes, checksum: 403860d83984ea13e8f76afe4c562b26 (MD5) / Made available in DSpace on 2018-09-28T19:18:09Z (GMT). No. of bitstreams: 1 André Tiago Rossito Goes.pdf: 1301552 bytes, checksum: 403860d83984ea13e8f76afe4c562b26 (MD5) Previous issue date: 2018 / A doença de Parkinson (DP) é caracterizada por uma degeneração progressiva dos neurônios dopaminérgicos do sistema nigroestriatal e depleção de dopamina (DA) no corpo estriado. A crisina tem demonstrado ser uma abordagem não farmacológica promissora para reduzir o risco de doenças neurodegenerativas. Este estudo investigou o potencial efeito neuroprotetor da crisina em um modelo animal de DP induzida por 6-hidroxidopamina (6-OHDA) em camundongos. O presente estudo demonstrou que uma dose de crisina (10mg/kg/dia p.o.) durate 28 dias foi eficaz em modular as seguintes alterações resultantes da exposição à 6-OHDA: atenuar à alteração no comportamento tipo-depressivo (teste de suspensão de cauda) e disfunções locomotoras (teste de rota-rod e teste do cilindro), proteger contra o estresse oxidativo (GPx, GSH, GST, GH), reduzir os níveis de citocinas pró-inflamatórias (TNF-α, IFN-γ, IL-1β, IL-2 e IL-6), bem como atenuou a redução dos níveis de DA, DOPAC e HVA. Além disso, preveniu a redução de neurônios TH+ causados pela exposição a 6-OHDA, além de elevar os níveis BDNF, GDNF e NGF no estriado de camundongos. Estes resultados reforçam que um dos efeitos neuroproterores induzidos pela crisina na DP, são decorrentes dos efeitos antioxidante, anti-inflamatório e modulador de neurotrofinas. Portanto, o presente estudosugere que a crisina atenua os declínios cognitivos e motores, depressão, estresse oxidativo e neuroinflamação induzidas pela 6-OHDA suportando a hipótese de que a crisina pode ser usado como um tratamento coadjuvante ao tratamente farmacológico atual para reduzir os sinais da DP. / Parkinson's disease (PD) is characterized by a progressive degeneration of dopaminergic neurons of the nigrostriatal system and dopamine depletion (DA) in the striatum. Chrysin has been shown to be a promising non-pharmacological approach to reducing the risk of neurodegenerative diseases. This study investigated the potential neuroprotective effect of chrysin in an animal model of PD induced by 6-hydroxydopamine (6-OHDA) in mice. The present study demonstrated that a dose of chrysin (10 mg / kg / day po) for 28 days was effective in modulating the following changes resulting from exposure to 6-OHDA: attenuating the change in type-depressive behavior (tail suspension test) (GPx, GSH, GST, GH), reduce levels of proinflammatory cytokines (TNF-α, IFN-γ, IL-1β) , IL-2 and IL-6), as well as attenuated the reduction of AD, DOPAC and HVA levels. In addition, it prevented the reduction of TH + neurons caused by exposure to 6-OHDA, in addition to raising the BDNF, GDNF and NGF levels in the striatum of mice. These results reinforce that one of the neuroproteror effects induced by chrysin in PD is due to the antioxidant, anti-inflammatory and modulating effects of neurotrophins. Therefore, the present study suggests that chrysin attenuates the 6-OHDA-induced cognitive and motor declines, depression, oxidative stress and neuroinflammation by supporting the hypothesis that chrysin may be used as a adjuvant treatment to the current pharmacological treatment to reduce the signs of PD

Submitted by Marcos Anselmo (marcos.anselmo@unipampa.edu.br) on 2018-12-03T17:13:22Z No. of bitstreams: 1 MICHELLE ANTUNES.pdf: 2333470 bytes, checksum: 8ad88d537e1a1c446e2d18440cf12514 (MD5) / Approved for entry into archive by Marcos Anselmo (marcos.anselmo@unipampa.edu.br) on 2018-12-03T17:13:34Z (GMT) No. of bitstreams: 1 MICHELLE ANTUNES.pdf: 2333470 bytes, checksum: 8ad88d537e1a1c446e2d18440cf12514 (MD5) / Made available in DSpace on 2018-12-03T17:13:34Z (GMT). No. of bitstreams: 1 MICHELLE ANTUNES.pdf: 2333470 bytes, checksum: 8ad88d537e1a1c446e2d18440cf12514 (MD5) Previous issue date: 2017 / A doença de Parkinson (DP) é a segunda doença neurodegenerativa mais prevalente na população idosa, tendo como principal característica neuropatológica a depleção de dopamina (DA) estriatal, condição esta, que conduz ao aparecimento dos sintomas motores da doença. Além de sintomas motores, os pacientes acometidos com essa doença apresentam ainda sintomas não motores e neuropsiquiátricos onde destaca-se a depressão. Atualmente, nenhuma das drogas utilizadas é totalmente eficaz para a DP, nesse contexto, terapias promissoras ainda precisam ser exploradas. Alguns estudos demonstraram que o consumo de flavonoides podem diminuir a incidência e os sintomas de doenças neurodegenerativas e de transtornos depressivos. Nosso estudo anterior já constatou que o flavonoide hesperidina (4'-methoxy-7-O-rutinosyl-3',5-dihydroxyflavanone), intervém na DP e no comportamento tipo depressivo via estresse oxidativo, em um modelo induzido por 6-hidroxidopamina (6-OHDA) em camundongos. Baseando-se nas evidências, se torna interessante investigar o efeito da hesperidina em outros parâmetros da DP no modelo da 6-OHDA, além de seu efeito antidepressivo no modelo da bulbectomia olfatória (BO). Para avaliar a DP, a hesperidina ou o veículo (50 mg/kg) foram administrados via oral (gavagem) durante 28 dias. Após este período, os camundongos foram submetidos a testes comportamentais. Para avaliar a depressão no modelo OB, a hesperidina ou o veículo (50 mg/kg) foram administrados via oral (gavagem) durante 13 dias. Após este período, os camundongos foram submetidos aos testes comportamentais e neuroquímicos. No modelo induzido pela 6-OHDA, o tratamento com a hesperidina protegeu contra a inibição das enzimas mitocondriais dos complexos I, II, IV e V, da enzima Na+/K+ ATPase, diminuição do potencial de membrana mitocondrial, e aumento das atividades das caspases 3 e 9 e níveis de marcadores de inflamação. Além disso, a administração do flavonoide culminou na restauração dos níveis de fatores neurotroficos, assim como dos neurônios positivos para tirosina hidroxilase (TH), e níveis de DA e seus metabolitos no estriado. O tratamento com hesperidina também atenuou as alterações comportamentais de rotação, ansiedade, anedonia, memória e nos danos olfatórios induzidos pela 6-OHDA. No modelo de depressão induzido pela OB, o tratamento oral com hesperidina foi efetivo em reverter o declínio dos fatores neurotróficos, o aumento das citocinas pro-inflamatórias e da atividade da enzima acetilcolinesterase (AchE) no hipocampo, bem como o aumento da atividade locomotora, os prejuízos na memória, o comportamento tipo depressivo e a anedonia decorrentes da remoção dos bulbos. No modelo de DP induzido pela 6-OHDA pode-se propor que a hesperidina atua na restauração dos neurônios dopaminérgicos através do restabelecimento dos fatores neurotróficos, controle das citocinas, e modulação da atividade mitocondrial e apoptótica no estriado, o que reflete na recuperação dos prejuízos comportamentais. No modelo da depressão, indica-se que a reparação hipocampal sobre os fatores neurotróficos e marcadores inflamatórios são responsáveis pelo reestabelecimento comportamental no tratamento com hesperidina. Estes resultados certificam o efeito potencial da hesperidina no tratamento da DP e dos distúrbios depressivos, indicando que esse flavonoide pode atuar como terapia multialvo, associando DP e os transtornos mentais. Isso se deve à 4 regulação de fatores neurotróficos, inflamatórios e apoptóticos, atividades enzimáticas (AchE e Na+/K+ ATPase), disfunção mitocondrial e recuperação neuronal dopaminérgica. / Parkinson's disease (PD) is the second most prevalent neurodegenerative disease in the elderly population. Its main neuropathological characteristic is the striatal dopamine (DA) depletion, which leads to the appearance of the motor symptoms of the disease. In addition to motor symptoms, the patients with this disease also present non-motor and neuropsychiatric symptoms where depression stands out. Currently, none of the drugs used is fully effective for PD, in this context, promising therapies still need to be explored. Some studies have shown that consumption of flavonoids may decrease the incidence and symptoms of neurodegenerative diseases and depressive disorders. Our previous study has found that the flavonoid hesperidin (4'-methoxy-7-O-rutinosyl-3 ', 5-dihydroxyflavanone) plays a role in PD and in the depressive behavior via oxidative stress in mice induced by 6-hydroxydopamine (6 -OHDA). Based on the evidence, is interesting to investigate the effect of hesperidin in other parameters of PD in the 6-OHDA model, besides the its antidepressant effect in olfactory bulbulometric (BO) model. To evaluate the PD, hesperidin or vehicle (50 mg / kg) were administered orally (gavage) for 28 days. After this period, the mice were submitted to behavioral tests. To assess depression in the OB model, hesperidin or vehicle (50 mg / kg) were administered orally (gavage) for 13 days. After this period, the mice were submitted to behavioral and neurochemical tests. In the 6-OHDA-induced model, treatment with hesperidin protected against inhibition of mitochondrial enzymes of complexes I, II, IV and V, Na + / K + ATPase enzyme, against the decrease in mitochondrial membrane potential, and against the increase of caspases 3 and 9 activities and inflammatory markers levels. In addition, flavonoid administration culminated in restoration of neurotrophic factors levels, as well as tyrosine hydroxylase (TH) positive neurons, DA and its metabolites levels in the striatum. The treatment with hesperidin also attenuated the behavioral changes of rotation, anxiety, anhedonia, memory and olfactory damage induced by 6-OHDA. In addition, in depression model OB-induced, oral hesperidin treatment was effective in reversing the decline of neurotrophic factors, increase of proinflammatory cytokines levels and acetylcholinesterase (AchE) activity in the hippocampus, as well as increase of locomotor activity, memory impairment, depressive behavior and anhedonia due to removal of bulbs. In DP model induced by 6-OHDA it can be proposed that hesperidin acts in the restoration of dopaminergic neurons through the reestablishment of neurotrophic factors, cytokine control, and modulation of mitochondrial and apoptotic activity in striatum, which reflects in the recovery of damages behavioral. In depression model, it is indicated that hippocampal repair on neurotrophic factors and inflammatory markers are responsible for behavioral reestablishment by hesperidin treatment. These results confirm the potential effect of hesperidin in the treatment of PD and depressive disorders, indicating that this flavonoid can act as a multi-target therapy, associating PD and mental disorders. This is due to the regulation of neurotrophic, inflammatory and apoptotic factors, enzymatic activities (AchE and Na+/K+ ATPase), mitochondrial dysfunction and dopaminergic neuronal recovery.

No description available.

No description available.

Tardive dyskinesia (TD), first appearing in humans after introduction of the phenothiazine class of antipsychotics in the 1950s, is now recognized as an abnormality resulting predominately by long-term block of dopamine (DA) D2 receptors (R). TD is thus reproduced in primates and rodents by chronic administration of D2-R antagonists. Through a series of studies predominately since the 1980s, it has been shown in rodent modeling of TD that when haloperidol or other D2-R antagonist is added to drinking water, rats develop spontaneous oral dyskinesias, vacuous chewing movements (VCMs), after ~3 months, and this TD is associated with an increase in the number of striatal D2-R. This TD persists for the duration of haloperidol administration and another ~2 months after haloperidol withdrawal. By neonatally lesioning dopaminergic nerves in brain in neonatal rats with 6-hydroxydopamine (6-OHDA), it has been found that TD develops sooner, at ~2 months, and also is accompanied by a much higher number of VCMs in these haloperidol-treated lesioned rats, and the TD persists lifelong after haloperidol withdrawal, but is not associated with an increased D2-R number in the haloperidol-withdrawn phase. TD apparently is related in part to supersensitization of both D1-R and serotoninergic 5-HT2-R, which is also a typical outcome of neonatal 6-OHDA (n6-OHDA) lesioning. Testing during the haloperidol-withdrawn phase in n6-OHDA rats displaying TD reveals that receptor agonists and antagonists of a host of neuronal phenotypic classes have virtually no effect on spontaneous VCM number, except for 5-HT2-R antagonists which acutely abate the incidence of VCMs in part. Extrapolating to human TD, it appears that (1)5-HT2-R supersensitization is the crucial alteration accounting for persistence of TD, (2) dopaminergic-perhaps age-related partial denervation-is a risk factor for the development of TD, and (3) 5-HT2-R antagonists have the therapeutic potential to alleviate TD, particularly if/when an antipsychotic D2-R blocker is withdrawn.

Dopamine receptor supersensitivity (DARSS) often is invoked as a mechanism possibly underlying disordered thought processes and agitation states in psychiatric disorders. This review is focused on identified means for producing DARSS and associating the role of other monoaminergic systems in modulating DARSS. Dopamine (DA) receptors, experimentally, are prone to become supersensitive and to thus elicit abnormal behaviors when coupled with DA or a receptor agonist. In intact (control) rats repeated DA D1 agonist treatments fail to sensitize D1 receptors, while repeated D 2 agonist treatments sensitize D2 receptors. D2 RSS is attenuated by a lesion with DSP-4 (N-(2-chlorethyl)-N-ethyl-2- bromobenzylamine) in early postnatal ontogeny, indicating that noradrenergic nerves have a permissive effect on D2 DARSS. However, if DSP-4 is co-administered with 5,7-dihydroxytryptamine to destroy serotonin (5-HT) nerves, then D2 RSS is restored. In rats treated early in postnatal ontogeny with the neurotoxin 6-hydroxydopamine to largely destroy DA innervation of striatum, both repeated D1 and D2 agonists sensitize D1 receptors. 5-HT nerves appear to have a permissive effect on D1 DARSS, as a 5-HT lesion reduces the otherwise enhanced effect of a D1 agonist. The series of findings demonstrate that DARSS is able to be produced by repeated agonist treatments, albeit under different circumstances. The involvement of other neuronal phenotypes as modulators of DARSS provides the potential for targeting a variety of sites in the aim to prevent or attenuate DARSS. This therapeutic potential broadens the realm of approaches toward treating psychiatric disorders.

A selective neurotoxin takes many forms: as an antibody to a neurotrophin, as an alkylator, as an excitotoxin, as a blocker of requisite neuronal excitation during ontogenetic development, as a generator of oxidative stress, as an inhibitor of vital intraneuronal processes, and as an agent adversely affecting a host of multiple sites in neurons. Neurotoxins have been invaluable for elucidating cellular mechanisms attending or preventing neuronal necrosis and apoptosis, and for modeling and thereby discerning mechanisms invoked in neurological and psychiatric disorders. Neuroprotectants, endogenous and exogenous, are being explored as potentially useful agents to ward off diseases. Finally, hypothesized as posing a risk to humans as environmental constituents, neurotoxins are now being remodeled as adjuncts for therapeutic intervention in a variety of human medical disorders.

No description available.

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / The present work evaluated the cytoprotective effect of chalcone-enriched fraction (CEF) and 2-methyl-inositol (MIT) in primary rat mesencephalic cell culture exposed to the neurotoxin 6-hydroxydopamine (6-OHDA). The CEF was obtained from Myracrodruon urundeuva, a Brazilian medicinal plant used as an antiinflamatory and wound healing agent.in female genital tract. In this fraction there are the dimerics chalcones urundeuvinas A, B e C The other compound was the MIT isolated from Magonia glabrata, a plant popularly known as âTingui de Bolaâ, which bark from its root is used as poison to catch the fishes from lakes and rivers. The immunohistochemical assay for tyrosine hydroxylase revealed that the percentage of dopaminergic cells in our cultures is approximately 2%. After exposition to 6-OHDA (40 and 200 microM) the cellular viability was reduced to 88,81% and 35,45% respectively. The mitochondrial activity was reduced to 88,8 and 35,4%, the nitrite levels was increased to 551,9% and 721,3% respectively and the lipid peroxidation was increased to 166,84% in the concentration of 200 microM, as observed in the MTT, nitrite and TBARS assays respectively. The results show that the exposition to CEF (100 microg/mL) before 6-OHDA (neuroprevention experiment) or after 6-OHDA (neurorescue experiment) reduced significantly the cell death caused by 6-OHDA (40 e 200 microM). The CEF prevented significantly the increase in nitrite levels induced by 6-OHDA (40 and 200 microM) (in both experiments), except in the neurorescue experiment in which the CEF failed to revert the increase in nitrite levels generated by 6-OHDA (200 microM). The CEF inhibited the lipid peroxidation induced by 6-OHDA (200 microM) in both experiments, and also showed antiapoptotic activity against 6-OHDA (40 and 200 microM) in both experiments. The MIT protected significantly TH- and TH+ cells from injury induced by 6-OHDA (40 and 200 microM) in both experiments. It showed a reduction in the nitrite levels generated by 6-OHDA in both experiments. The MIT also reverted the lipid peroxidation generated by 6-OHDA (200 microM) and showed antiapoptotic activity against 6-OHDA (40 and 200 microM) in both experiments. These results suggest that the neuroprotective action these compounds, CEF and MIT are due to antioxidant, besides a possible mitochondrial protection of these polyphenols. In related to MIT not must be discarded the idea of a second messenger action through the production of inositol triphosphate and protein kinase C activation. The findings may have a clinical importance in neurodegenerative conditions like Parkinsonâs disease / No presente trabalho, estudou-se o efeito citoprotetor da fraÃÃo enriquecida de chalconas (FEC) e do 2-O-metilinositol (MIT) em cultura primÃria de cÃlulas mesencefÃlicas de ratos expostas à neurotoxina 6-hidroxidopamina (6-OHDA). A FEC foi isolada de Myracrodruoun urundeuva, planta medicinal brasileira comumente utilizada como antiinflamatÃrio do trato genital feminino. Nesta fraÃÃo estÃo presentes as chalconas dimÃricas urundeuvinas A, B e C. Outro composto estudado foi o MIT, isolado de Magonia glabrata, uma planta popularmente conhecida como âTingui de Bolaâ, cujas cascas de suas raÃzes sÃo usadas como âvenenoâ para facilitar a pesca nos lagos e rios. O MIT à um monossacarideo com um Ãnico anel da estrutura poli-hidroxilada. Apesar de relatos da toxicidade desta planta, o composto estudado nÃo apresentou toxicidade. As cÃlulas foram cultivadas durante quatro dias e apÃs este tempo foram prÃ-incubadas com FEC ou MIT trÃs horas antes (Protocolo de neuroprevenÃÃo) ou trÃs horas apÃs (Protocolo de neuroresgate) a adiÃÃo da 6-OHDA. A imunohistoquÃmica para tirosina hidroxilase revelou um percentual de cÃlulas dopaminÃrgicas em torno de 2%. A 6-OHDA (40 e 200 microM), promoveu uma diminuiÃÃo na viabilidade celular em torno de 37,65% e 63,44% para cÃlulas nÃo dopaminÃrgicas (TH-) e (79,78% e 93,75%) para cÃlulas dopaminÃrgicas (TH+) e aumentou os nÃveis de nitrito para 551,9% e 721,3% respectivamente em relaÃÃo ao controle. AlÃm disso induziu uma grande peroxidaÃÃo lipÃdica (aumento de 166,84%) como observados pelos ensaios MTT, nitrito e TBARS, respectivamente. Na concentraÃÃo de 200microM a 6-OHDA induziu uma grande morte celular, com aumento de cÃlulas em apoptose tardia e necrose. Os resultados mostraram que a FEC (1; 10 e 100 microg/mL) reduziu significativamente e de maneira dose-dependente (p menor igual a0,05) a morte celular induzida pela 6-OHDA (40 e 200 microM). AlÃm disso preveniu o aumento de nitrito e a peroxidaÃÃo lipÃdica. A FEC demonstrou atividade antiapoptÃtica e preveniu a necrose causada pela 6-OHDA (200 microM) (nos dois Protocolos estudados). O MIT (1, 10 e 100 microg/mL) protegeu tanto as cÃlulas TH- quanto TH+ do dano induzido pela 6-OHDA (40 e 200microM) (em ambos os Protocolos), reduzindo os nÃveis de nitrito e a peroxidaÃÃo lÃpidica. TambÃm demonstrou uma potente atividade antiapoptÃtica. Estes resultados demonstram que a neuroproteÃÃo dos compostos estudados, FEC e MIT, se deva as aÃÃes antioxidante, alÃm de uma proteÃÃo a nÃvel mitocondrial destes polifenois, no caso do MIT tambÃm nÃo se podendo descartar uma aÃÃo a nÃvel de segundo mensageiro, via formaÃÃo de inositol trifosfato e ativaÃÃo de PKC. Os achados podem ter uma futura importÃncia clÃnica em doenÃas neurodegenerativas tais como na DoenÃa de Parkinson

Dopamine (DA) receptor supersensitivity refers to the phenomenon of an enhanced physiological, behavioral or biochemical response to a DA agonist. Literature related to ontogenetic aspects of this process was reviewed. Neonatal 6-hydroxydopamine (6-OHDA) destruction of rat brain DA neurons produces overt sensitization to D1 agonist-induced oral activity, overt sensitization of some D2 agonist-induced stereotyped behaviors and latent sensitization of D1 agonist-induced locomotor and some stereotyped behaviors. This last process is unmasked by repeated treatments with D1 (homologous "priming") or D2 (heterologous "priming") agonists. A serotonin (5-HT) neurotoxin (5,7-dihydroxytryptamine) and 5-HT2C receptor antagonist (mianserin) attenuate some enhanced behavioral effects of D1 agonists, indicating that 5-HT neurochemical systems influence D1 receptor sensitization. Unlike the relative absence of change in brain D1 receptor number, DA D2 receptor proliferation accompanies D2 sensitization in neonatal 6-OHDA-lesioned rats. Robust D2 receptor supersensitization can also be induced in intact rats by repeated treatments in ontogeny with the D2 agonist quinpirole. In these rats quinpirole treatments produce vertical jumping at 3-5 wk after birth and subsequent enhanced quinpirole-induced antinociception and yawning. The latter is thought to represent D3 receptor sensitization. Except for enhanced D1 agonist-induced expression of c-fos, there are no changes in the receptor or receptor-mediated processes which account for receptor sensitization. Adaptive mechanisms by multiple "in series" neurons with different neurotransmitters may account for the phenomenon known as receptor supersensitivity.