Clemastine Induces an Impairment in Developmental Myelination

Abstract

Abnormalities in myelination are associated to behavioral and cognitive dysfunction in neurodevelopmental psychiatric disorders. Thus, therapies to promote or accelerate myelination could potentially ameliorate symptoms in autism. Clemastine, a histamine H1 antagonist with anticholinergic properties against muscarinic M1 receptor, is the most promising drug with promyelinating properties. Clemastine penetrates the blood brain barrier efficiently and promotes remyelination in different animal models of neurodegeneration including multiple sclerosis, ischemia and Alzheimer’s disease. However, its role in myelination during development is unknown. We showed that clemastine treatment during development increased oligodendrocyte differentiation in both white and gray matter. However, despite the increase in the number of oligodendrocytes, conduction velocity of myelinated fibers of corpus callosum decreased in clemastine treated mice. Confocal and electron microscopy showed a reduction in the number of myelinated axons and nodes of Ranvier and a reduction of myelin thickness in corpus callosum. To understand the mechanisms leading to myelin formation impairment in the presence of an excess of myelinating oligodendrocytes, we focused on microglial cells that also express muscarinic M1 receptors. Importantly, the population of CD11c+ microglia cells, necessary for myelination, as well as the levels of insulin growth factor-1 decrease in clemastine-treated mice. Altogether, these data suggest that clemastine impact on myelin development is more complex than previously thought and could be dependent on microglia-oligodendrocyte crosstalk. Further studies are needed to clarify the role of microglia cells on developmental myelination.

Neuronal deletion of Gtf2i results in developmental microglial alterations in a mouse model related to Williams syndrome

“…Clemastine improved myelination in Gtf2i cKO mice (Barak et al, 2019), and since clemastine was previously shown to directly bind microglia and reduce their activation (Su et al, 2018; Xie et al, 2020), we systemically injected clemastine from the early postnatal stage until P30 and examined its effects on microglia. In accordance with our findings, Iba1 + cell numbers in the corpus callosum were unchanged after clemastine injection at the postnatal stage (Palma et al, 2022). Interestingly, Iba1 levels increased after clemastine injection in a mouse model for ALS (Apolloni et al, 2016), although such injection was performed in older mice than in our study (Apolloni et al, 2016).…”

“…Post hoc analysis indicated a decrease in CD68 in the M2 cortex of Gtf2i cKO mice. This result is compatible with data showing that binding of clemastine to microglia induced an anti‐inflammatory effect (Liu et al, 2016; Palma et al, 2022). Moreover, we found that Iba1 transcript in the whole cortex after clemastine injection showed two significant main effects and a significant interaction effect.…”

“…We used clemastine to manipulate microglia at this critical stage. Clemastine improved myelination in Gtf2i cKO mice (Barak et al, 2019), and since clemastine was previously shown to directly bind microglia and reduce their activation (Palma et al, 2022). Interestingly, Iba1 levels increased after clemastine injection in a mouse model for ALS (Apolloni et al, 2016), although such injection was performed in older mice than in our study (Apolloni et al, 2016).…”

Clemastine and metformin extend the window of NMDA receptor surface expression in ageing oligodendrocyte precursor cells

“…Both metformin and clemastine have been shown to act on other CNS cells such as microglia 41 – 43 , and it is therefore possible that metformin and clemastine modulate OPC membrane properties indirectly. For instance, cytokine signalling from glial cells can modulate glutamate receptors in neurons 44 , and inflammatory cytokines are known to be increased in the ageing brain 45 , 46 , while both clemastine and metformin have been shown to reduce pro-inflammatory cytokine release as well as microglia and astrocytic reactivity 41 , 47 .…”

Utilizing hiPSC-derived oligodendrocytes to study myelin pathophysiology in neuropsychiatric and neurodegenerative disorders.

“…Most recently a variation on the Douvaras and Fossati (2015) protocol showed that supplementation of media with the promyelinating compound clemastine fumarate reduced the differentiation time of OPCs to OLs down to 28 days ( Assetta et al, 2020 ; Mattingly and Chetty, 2023 ). Clemastine was previously identified as a promyelinating compound independent from its use as an antihistamine ( Li et al, 2015 ; Liu et al, 2016 ; Green et al, 2017 ; Bohlen et al, 2023 ) and its ability to promote OPC differentiation appears to be through blockade of the M1 muscarinic acetylcholine receptor, which is a most common subtype of muscarinic acetylcholine receptor which regulates OPC proliferation and differentiations ( Xiang et al, 2012 ; Chen et al, 2021 ; Palma et al, 2022 ).…”