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

• Published in: Molecular neurobiology Vol. 56; no. 6; pp. 4464 - 4478
• Main Authors: Garcia-Miralles, Marta, Yusof, Nur Amirah Binte Mohammad, Tan, Jing Ying, Radulescu, Carola I., Sidik, Harwin, Tan, Liang Juin, Belinson, Haim, Zach, Neta, Hayden, Michael R., Pouladi, Mahmoud A.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.06.2019; Springer Nature B.V
• Subjects: Animals; Astrocytes - drug effects; Astrocytes - metabolism; Astrocytes - pathology; Atrophy; Behavior, Animal; Biomedical and Life Sciences; Biomedicine; Cell Biology; Cell Count; Corpus callosum; Corpus Callosum - drug effects; Corpus Callosum - pathology; Corpus Callosum - physiopathology; Corpus Striatum - drug effects; Corpus Striatum - pathology; Corpus Striatum - physiopathology; Cytochrome P-450 CYP1A1 - metabolism; Depression - complications; Depression - drug therapy; Depression - physiopathology; Disease Models, Animal; Female; Gene expression; Gene Expression Regulation - drug effects; Humans; Huntington Disease - complications; Huntington Disease - drug therapy; Huntington Disease - genetics; Huntington Disease - physiopathology; Huntington's disease; Huntingtons disease; Immunomodulation; Inflammation; Inflammation - genetics; Inflammation - pathology; Learning; Male; Mice; Mice, Transgenic; Microglia - drug effects; Microglia - metabolism; Microglia - pathology; Motor Activity - drug effects; Motor skill learning; Myelin proteolipid protein; Myelin Sheath - drug effects; Myelin Sheath - pathology; Myelin Sheath - ultrastructure; Myelination; Neostriatum; Neurobiology; Neurology; Neurosciences; Oligodendroglia - drug effects; Oligodendroglia - metabolism; Oligodendroglia - pathology; Phenotype; Quinolones - pharmacology; Quinolones - therapeutic use; Receptors, Aryl Hydrocarbon - metabolism; Substantia alba; Transcription; Transcription, Genetic - drug effects; Oligodendroglia; Laquinimod; Myelination; Behaviour; White matter; Huntington disease
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-018-1393-1

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.