Laquinimod Treatment Improves Myelination Deficits at the Transcriptional and Ultrastructural Levels in the YAC128 Mouse Model of Huntington Disease

Autor: Marta Garcia-Miralles, Michael R. Hayden, Mahmoud A. Pouladi, Liang Juin Tan, Jing Ying Tan, Carola I. Radulescu, Neta Zach, Haim Belinson, Harwin Sidik, Nur Amirah Binte Mohammad Yusof
Rok vydání: 2018
Předmět:
Male
0301 basic medicine
Neurology
Transcription
Genetic
Cell Count
Striatum
Quinolones
Corpus callosum
Corpus Callosum
chemistry.chemical_compound
0302 clinical medicine
Myelin Sheath
Behavior
Animal
Depression
Oligodendroglia
Huntington Disease
Phenotype
medicine.anatomical_structure
Antidepressant
Female
Microglia
medicine.medical_specialty
Neuroscience (miscellaneous)
Mice
Transgenic
Motor Activity
White matter
03 medical and health sciences
Cellular and Molecular Neuroscience
Atrophy
Immune system
Internal medicine
Cytochrome P-450 CYP1A1
medicine
Animals
Humans
Learning
Inflammation
business.industry
medicine.disease
Corpus Striatum
Disease Models
Animal
030104 developmental biology
Endocrinology
Gene Expression Regulation
Receptors
Aryl Hydrocarbon
chemistry
Astrocytes
business
Laquinimod
030217 neurology & neurosurgery
Zdroj: Molecular Neurobiology. 56:4464-4478
ISSN: 1559-1182
0893-7648
DOI: 10.1007/s12035-018-1393-1
Popis: Laquinimod, an immunomodulatory agent under clinical development for Huntington disease (HD), has recently been shown to confer behavioural improvements that are coupled with prevention of atrophy of the white matter (WM)-rich corpus callosum (CC) in the YAC128 HD mice. However, the nature of the WM improvements is not known yet. Here we investigated the effects of laquinimod on HD-related myelination deficits at the cellular, molecular and ultrastructural levels. We showed that laquinimod treatment improves motor learning and motor function deficits in YAC128 HD mice, and confirmed its antidepressant effect even at the lowest dose used. In addition, we demonstrated for the first time the beneficial effects of laquinimod on myelination in the posterior region of the CC where it reversed changes in myelin sheath thickness and rescued Mbp mRNA and protein deficits. Furthermore, the effect of laquinimod on myelin-related gene expression was not region-specific since the levels of the Mbp and Plp1 transcripts were also increased in the striatum. Also, we did not detect changes in immune cell densities or levels of inflammatory genes in 3-month-old YAC128 HD mice, and these were not altered with laquinimod treatment. Thus, the beneficial effects of laquinimod on HD-related myelination abnormalities in YAC128 HD mice do not appear to be dependent on its immunomodulatory activity. Altogether, our findings describe the beneficial effects of laquinimod treatment on HD-related myelination abnormalities and highlight its therapeutic potential for the treatment of WM pathology in HD patients.
Databáze: OpenAIRE
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