275 research outputs found
Újabb terápiás lehetőségek a Huntington kór állatmodelljében = Novel therapeutic possibilities in an animal model of Huntington's disease.
A pathomechanizmus vizsgálata: A transzgenetikus állatok motoros aktivitása 12 hĂ©ttĹ‘l kezdĹ‘dĹ‘en romlott, mĂg az exploratĂv magatartásuk már 8 hetes korban csökkent. Az neuroaktĂv aminosavak szintje szignifikánsan alacsonyabb Huntington kĂłr ill. Parkinson kĂłr modelljĂ©ben. Ez a csökkenĂ©s 24 Ăłra elteltĂ©vel rendezĹ‘dött. A Parkinson kĂłros betegek plazmájában a kinurenin aminotranszferáz (KAT) izoenzimek aktivitása, valamint a kinurĂ©nsav (KYNA) szintje is alacsonyabb volt, mint a kontroll csoportban. Fokális dystĂłniában szenvedĹ‘ betegek plazmájában KAT izoenzimek aktivitása csökkent, mĂg aKYNA szintje nem változott. Az agyspecifikus TPPP/p25 protein expressziĂłja nem mutathatĂł ki a transzgentikus egerekben. A glĂĽkolĂzis vizsgálata során az állatokban a GAPDH aktivitása lecsökkent, mĂg az ATP szint megemelkedett. Ennek további vizsgálata folyamatban van. A terápiás vizsgálatok: (a szabadalmi eljárások miatt a vegyĂĽletek pontos nevĂ©t jelenleg nem közölhetjĂĽk): Egy antioxidáns hatásĂş vizsgálati szer (vizsg. anyag1) Ă©s egy transzporter gátlĂł szer (vizsg. anyag2) növelte az állatok tĂşlĂ©lĂ©sĂ©t, Ă©s kĂ©sleltette a betegsĂ©g kialakulását. A neuroprotektĂv hatás szövettani alátámasztása folyamatban van. Egy proteáz inhibitor (vizsg. anyag3), egy antipszichotikum (vizsg. anyag4) Ă©s antioxidáns hatásĂş szer (vizsg. anyag5) is növelte az állatok tĂşlĂ©lĂ©sĂ©t, Ă©s kĂ©sleltette a betegsĂ©g kialakulását. E szerek esetĂ©n a szövettani vizsgálatra jelenleg mĂ©g nincs elegendĹ‘ állatunk. | Studies on pathomechanism: From 12th weeks of age the motor activities of the transgenic mice deteriorated, while the explorative behavior has been decreased from 8th weeks of age. In a toxin model of Huntington's disease and Parkinson's disease, the levels of neuroactive amino acids decreased, which were recovered after 24 hours. In the plasma of parkinsonian patients the activity of kynurenine aminotransferase (KAT) and the level of kynurenic acid (KYNA) were decreased. In focal dystonia, the KAT activity is decreased in the plasma, while the KYNA level was not changed. The brain specific TPPP/p25 protein can not be detected in the transgenic mice. In transgenic mice the GAPDH activity was decreased, while the ATP level was increased. More studies needed to clarify the data. Therapeutic studies (due to the patent issues the drugs can not be identified): An antioxidant (drug1) and a transporter inhibitor (drug2) increased the survival of the mice and delayed the onset of the symptoms. The histological evaluation of this protective effect is in progress. A protease inhibitor (drug3), a antipsychotic drug (drug4) and an antioxidant expert neuroprotective effects in this model. The histological studies prolonged due to the lack of sufficient number of transgenic mice
Effect of 3-nitropropionic acid on sirtuin gene expression in Sirt3 deficient mice
Huntington's disease (HD) is an autosomal inherited progressive neurodegenerative disorder which is caused by the CAG trinucleotide repeat in the huntingtin gene. The mutation induces mitochondrial dysfunction in neurons, which leads to striatal neuronal loss. The efficacy of the available therapies is limited, thus acquisition of more data about the pathomechanism of HD and development of new strategies is urgent Sirtuins (Sirt1-7) belong to the histone deacetylase family, and interestingly they have been associated with HD, however, their role in HD is still not fully understood. To clarify the role of sirtuins in HD, we utilized a 3-nitropropionic acid (3-NP) induced HD model and assessed alterations in gene expression using RT-PCR. Moreover, we studied the extension of neurodegeneration in the striatum, and behavioural changes. Furthermore, we involved Sirt3 knockout (Sirt3KO) mice to investigate the impact of Sirt3 deficiency in the expression of the other sirtuins. Our results showed that with 3-NP treatment, the mRNA level of Sirt2,5,7 changed significantly in wild-type (WT) mice, whereas in Sirt3KO animals there was no change. Interestingly, Sirt3 deficiency did not exacerbate 3-NP-mediated striatal neuronal loss, while Sirt3KO animals showed higher mortality than WT littermates. However, the absence of Sirt3 did not affect the behaviour of animals. Finally, we demonstrated that the changes in the expression of sirtuins are age- and sex- dependent. According to our findings, there is evidence that Sirt3 has a major impact on the regulation of other sirtuin isoforms, survival and neuroprotection. However, this neuroprotective effect does not manifest in the behaviour
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