vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/vjgb-26-91vavilov-5297Research ArticleГЕНЕТИКА ЖИВОТНЫХANIMAL GENETICSЭпигенетическая регуляция транскрипционной активности генов, связанных с нейропротекторным действием цефтриаксона, в головном мозге у крыс на модели спорадической болезни Альцгеймера: участие гистоновой деацетилазы 1Epigenetic regulation of the transcriptional activity of genes mediating the neuroprotective activity of ceftriaxone in the brain in a rat model of sporadic Alzheimer disease: the involvement of histone deacetylase 1БаширзадеА. А.BashirzadeA. A.

Новосибирск

Novosibirsk

ТихоноваМ. А.TikhonovaM. A.

Новосибирск

Novosibirsk

tikhonovama@neuronm.ruБеличенкоВ. М.BelichenkoV. M.

Новосибирск

Novosibirsk

ФедосееваЛ. А.FedoseevaL. A.

Новосибирск

Novosibirsk

БеляевМ. Д.BelyaevM. D.

Новосибирск

Novosibirsk

РеннТ.-И.RennT.-Y.

Тайбэй

Taipei

ЧанЧ.-М.ChangH.-M.

Тайбэй

Taipei

КолосоваН. Г.KolosovaN. G.

Новосибирск

Novosibirsk

БеляевН. Д.BelyaevN. D.

Новосибирск

Novosibirsk

АмстиславскаяТ. Г.AmstislavskaT. G.

Новосибирск

Novosibirsk

Научно-исследовательский институт нейронаук и медициныРоссияScientific Research Institute of Neurosciences and MedicineRussian FederationНаучно-исследовательский институт нейронаук и медицины; Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии нааукРоссияScientific Research Institute of Neurosciences and Medicine; Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of SciencesRussian FederationФедеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии нааукРоссияInstitute of Cytology and Genetics of the Siberian Branch of the Russian Academy of SciencesRussian FederationТайбэйский медицинский университетТайваньTaipei Medical UniversityTaiwan, Province of China202613102026306899907Copyright © Баширзаде А.А., Тихонова М.А., Беличенко В.М., Федосеева Л.А., Беляев М.Д., Ренн Т., Чан Ч., Колосова Н.Г., Беляев Н.Д., Амстиславская Т.Г., 20262026Баширзаде А.А., Тихонова М.А., Беличенко В.М., Федосеева Л.А., Беляев М.Д., Ренн Т., Чан Ч., Колосова Н.Г., Беляев Н.Д., Амстиславская Т.Г.Bashirzade A.A., Tikhonova M.A., Belichenko V.M., Fedoseeva L.A., Belyaev M.D., Renn T., Chang H., Kolosova N.G., Belyaev N.D., Amstislavska T.G.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/5297

Гистоновые деацетилазы (HDAC) – это ферменты, обеспечивающие подавление транскрипции генов, а ингибиторы HDAC рассматриваются как потенциальные лекарственные средства для лечения болезни Альцгеймера (БА). Ранее мы обнаружили, что цефтриаксон, антибиотик с нейропротекторной активностью, повышает уровни мРНК генов Ide и Mme, кодирующих ферменты, которые участвуют в катаболизме амилоидабета, в миндалине мозга у крыс линии OXYS, модели спорадической БА. С другой стороны, нарушения нейротрофических факторов (в частности, BDNF) играют важную роль в патогенезе БА. Более того, HDAC класса I (HDAC1) участвуют в регуляции транскрипционной активности Bdnf. Целью данного исследования было оценить влияние цефтриаксона на обогащение HDAC1 в промоторах генов Mme, Ide и Bdnf в миндалине у крыс OXYS и на уровни мРНК Bdnf в миндалине крыс OXYS и Вистар. Для эпигенетического анализа и определения уровней мРНК Bdnf использовали хроматин-иммунопреципитацию и количественную ПЦР, соответственно. Не выявлено значимого обогащения HDAC1 или его изменений под действием цефтриаксона в промоторах Mme и Ide. В то же время цефтриаксон ослаблял связывание HDAC1 с промотором IV Bdnf. Это новый механизм регуляции транскрипции в головном мозге цефтриаксоном, который может быть задействован в его нейропротекторной активности. У 5-месячных крыс OXYS он, по-видимому, играет минорную роль, поскольку цефтриаксон не изменял уровни транскрипта 5 Bdnf, содержащего экзоны IV и IX. Мы также впервые продемонстрировали транскриптспецифическую регуляцию транскрипции Bdnf с помощью цефтриаксона. Цефтриаксон значительно повысил уровни транскрипта 6 Bdnf, содержащего экзоны VII, VIII и IX. Результаты исследования могут быть учтены при терапии БА.

Histone deacetylases (HDACs) are enzymes that provide transcriptional repression, while HDAC inhibitors are considered to be potential drugs in the treatment of Alzheimer disease (AD). Earlier we found that ceftriaxone (CEF), an antibiotic with neuroprotective activity, augmented mRNA levels of Ide and Mme, encoding enzymes involved in the catabolism of amyloid beta in the amygdala of OXYS rats, a model of sporadic AD. On the other hand, disturbances of neurotrophic factors (BDNF in particular) play an important role in AD pathogenesis. Moreover, HDACs of class I (HDAC1) are involved in the regulation of Bdnf transcriptional activity. The study was aimed to assess the effects of CEF on HDAC1 enrichment at Mme, Ide, and Bdnf gene promoters in the amygdala of OXYS rats and on Bdnf mRNA levels in the amygdala of OXYS and Wistar rats. Chromatin immunoprecipitation and qPCR were utilized for epigenetic analysis and assay of Bdnf mRNA levels, respectively. Neither significant HDAC1 enrichment, nor its alteration under CEF treatment at the Mme or Ide promoters were found, whereas CEF attenuated HDAC1 binding at Bdnf promoter IV. This is a novel mechanism of transcription regulation by CEF in the brain, which may be involved in its neuroprotective activity. In 5-month-old OXYS rats, it seems to play a minor role, as CEF did not change Bdnf transcript 5 (containing exons IV and IX) levels. We were first to demonstrate the transcript-specific regulation of Bdnf transcription by CEF. CEF significantly increased the levels of Bdnf transcript 6 (containing exons VII, VIII, and IX). The results of our study can be taken into account in AD treatment.

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The authors declare that there are no conflicts of interest present.