Тип публикации: статья из журнала

Год издания: 2026

Идентификатор DOI: 10.1038/s41420-026-03120-z

Ключевые слова: Cell death in the nervous system, movement disorders

Аннотация: <jats:title>Abstract</jats:title> <jats:p>Spinocerebellar ataxia type 1 (SCA1) is caused by a CAG expansion in the gene that encodes the protein Ataxin1. Accumulation of the mutant protein in cells leads to degeneration of the cerebellum and brainstem, resulting in ataxia and culminates in failure of the circuits controlling swalloПоказать полностьюwing and breathing. The nonselective NMDA receptor blocker memantine has been proposed as a potential treatment for SCA1, as it reduces excitotoxicity and neurodegeneration in other murine models of neurodegeneration. However, side effects of memantine limit its therapeutic potential, highlighting the need for more selective treatments. We have developed an SCA1 model where a lentiviral vector (LVV) selectively expresses mutant Ataxin1 in cerebellar astrocytes, triggering neuronal death through glial dysfunction and NMDA receptor-mediated excitotoxicity. Using this model, we investigate the effects of long-term administration of Ro25-6981, a selective blocker of the GluN2B subunit of glutamate receptors, typically found on extrasynaptic NMDA receptors. Chronic administration of Ro25-6981 (0.5 mg/kg day intraperitoneally) for 4 weeks prevented deterioration of motor activity in SCA1 model mice, an effect, associated with reduced neurodegeneration and decreased reactivity of Bergmann glia in the cerebellar cortex. Moreover, short-term endocannabinoid-mediated plasticity was partially preserved. Long-term blockade of NMDA receptors with Ro25-6981 caused a compensatory upregulation of expression of GluN2B and NR2A subunits. These findings suggest that specific targeting of extrasynaptic NMDA receptors with Ro25-6981 or similar drugs might offer a viable therapeutic strategy for treatment of SCA1.</jats:p>

Журнал: Cell Death Discovery

ISSN журнала: 20587716

• Belozor Olga S. (Krasnoyarsk State Medical University named after Prof. V.F. Voino-Yasenetsky)
• Mileiko Alexandra G. (Scientific Research Institute of Medical Problems of North - a separate division of Federal Research Center "Krasnoyarsk Science Center")
• Mosina Lyudmila D. (Siberian Federal University)
• Mikhailov Ilya G. (Institute of Biophysics of Siberian Branch of Russian Academy of Sciences, Federal Research Center “Krasnoyarsk Science Center SB RAS")
• Mikhailova Milana S. (Krasnoyarsk State Medical University named after Prof. V.F. Voino-Yasenetsky)
• Khilazeva Elena D. (Krasnoyarsk State Medical University named after Prof. V.F. Voino-Yasenetsky)
• Ox Darius A. (Siberian Federal University)
• Grinev Egor S. (Sirius University of Science and Technology)
• Boitsova Elizaveta B. (Krasnoyarsk Regional Clinical Hospital)
• Shuvaev Andrey N. (Siberian Federal University)
• Teschemacher Anja G. (School of Psychology and Neuroscience, University of Bristol)
• Kasparov Sergey (School of Psychology and Neuroscience, University of Bristol)
• Shuvaev Anton N. (Krasnoyarsk State Medical University named after Prof. V.F. Voino-Yasenetsky)

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