The novel synthetic microneurotrophin BNN27 protects mature oligodendrocytes against cuprizone‐induced death, through the NGF receptor TrkA

Abstract

BNN27, a member of a chemical library of C17-spiroepoxy derivatives of the neurosteroid DHEA, has been shown to regulate neuronal survival through its selective interaction with NGF receptors (TrkA and p75 ), but its role on glial populations has not been studied. Here, we present evidence that BNN27 provides trophic action (rescue from apoptosis), in a TrkA-dependent manner, to mature oligodendrocytes when they are challenged with the cuprizone toxin in culture. BNN27 treatment also increases oligodendrocyte maturation and diminishes microglia activation in vitro. The effect of BNN27 in the cuprizone mouse model of demyelination in vivo has also been investigated. In this model, that does not directly involve the adaptive immune system, BNN27 can protect from demyelination without affecting the remyelinating process. BNN27 preserves mature oligodendrocyte during demyelination, while reducing microgliosis and astrogliosis. Our findings suggest that BNN27 may serve as a lead molecule to develop neurotrophin-like blood-brain barrier (BBB)-permeable protective agents of oligodendrocyte populations and myelin, with potential applications in the treatment of demyelinating disorders.

Spatio-temporal expression profile of NGF and the two-receptor system, TrkA and p75NTR, in experimental autoimmune encephalomyelitis

“…Regarding the expression on glial cells, our analysis showed that only a small portion of the oligodendrocyte population expresses TrkA and p75NTR located strictly within the inflammatory loci in both phases of the EAE model while there is no expression in NAWM and in the white matter of the control group. Our observation is partly supported by previous studies according to which no p75NTR expression is described in vivo under physiological conditions, whereas in the cuprizone demyelinating model, several, but not all, oligodendrocytes of the corpus callosum express TrkA and p75NTR [51,52]. NGF exhibits sparsely scattered immunoreactivity with oligodendrocytes (data not shown).…”

CD8 T-cell Recruitment Into the Central Nervous System of Cuprizone-Fed Mice: Relevance to Modeling the Etiology of Multiple Sclerosis

“…Indeed, the process of infiltration may have been facilitated by the activation of innate immune cells (microglia and astrocytes), their presentation of myelin antigens and the release of tumor necrosis factor-γ and reactive oxygen species (Bonetto et al, 2017), that are known to increase the permeability of the BBB and attract CD8 + T-cell (Suidan et al, 2006). Notably, the predominance of CD8 + T-cell in the CNS of mice (Study 2) resembles that seen at MS lesion sites where the key steps include recruitment and clonal expansion (Hauser et al, 1986;Friese and Fugger, 2005), with CD8 + outnumbering CD4 + T-cells by 3-10 fold (Booss et al, 1983;Babbe et al, 2000).…”

Therapeutic effect of oligomeric proanthocyanidin in cuprizone‐induced demyelination

“…In addition, oligodendrocyte death is the main cause of demyelination in the CPZ-induced model, and damage to oligodendrocytes in vivo is mainly exacerbated by CNS inflammation induced by local activation of microglia (Bonetto, Charalampopoulos, Gravanis, & Karagogeos, 2017;Taraboletti et al, 2017). Abnormally activated microglia play an important role in neurodegenerative diseases via activation of various pro-inflammatory signalling pathways (Davis, Foster, & Thomas, 1994;Kreutzberg, 1996).…”