A novel fatty acid-binding protein 5 and 7 inhibitor ameliorates oligodendrocyte injury in multiple sclerosis mouse models

Abstract

Background: Multiple sclerosis (MS) is an autoimmune disease characterised by the demyelination of mature oligodendrocytes in the central nervous system. Recently, several studies have indicated the vital roles of fatty acid-binding proteins (FABPs) 5 and 7 in regulating the immune response. Methods: We assessed a novel FABP5/FABP7 inhibitor, FABP ligand 6 (MF 6), as a potential therapeutic for MS therapy. In vivo, we established MOG 35-55 -administered experimental autoimmune encephalomyelitis (EAE) mice as an MS mouse model, followed by prophylactic and symptomatic treatment with MF 6. The therapeutic effect of MF 6 was determined using behavioural and biochemical analyses. In vitro, MF 6 effects on astrocytes and oligodendrocytes were examined using both astrocyte primary culture and KG-1C cell lines. Findings: Prophylactic and symptomatic MF 6 therapy reduced myelin loss and clinical EAE symptoms. Furthermore, oxidative stress levels and GFAP-positive and ionised calcium-binding adaptor protein-1-positive cells were reduced in the spinal cord of MF 6-treated mice. In addition, MF 6 attenuated lipopolysaccharidestimulated interleukin-1b and tumour necrosis factor-a accumulation in primary astrocyte culture. Moreover, MF 6 indicated a powerful protective function for the mitochondria in the oligodendrocytes of EAE mice via FABP5 inhibition. Interpretations: MF 6 is a potent inhibitor of FABP5 and FABP7; targeted inhibition of the two proteins may confer potential therapeutic effects in MS via immune inhibition and oligodendrocyte protection.

Single-cell RNA sequencing reveals dysregulation of spinal cord cell types in a severe spinal muscular atrophy mouse model

“…Apoe encodes a member of the apolipoprotein A1/A4/E family, and mutations in this gene are the strongest genetic risk factors for AD [47]. Fabp7 encodes a member of the fatty acid-binding protein family, which can bind to fatty acids, a crucial component of myelin [48; 49]. The BP analysis of DEGs revealed that downregulated DEGs were mainly related to protein synthesis, whereas upregulated DEGs were mainly concentrated in myelination-related pathways (Fig.…”

Fatty acids role in multiple sclerosis as “metabokines”

“…Fatty acid desaturase 2 (FADS2) single nucleotide polymorphisms (SNPs) rs174611 and rs174618 are both independent protective factors of MS incidence [46], and a higher level of serum fatty acid-binding protein (FABP4) associates with more severe symptoms evaluated by EDSS score [47]. A novel FABP5/7 inhibitor MF6 is proved to attenuate CNS demyelination in MS animal models by modulating inflammatory cytokines production of astrocytes and microglia, thus supporting oligodendrocytes survival by mitigating mitochondria oxidative stress [48].…”

Targeting the Sphingolipid Rheostat in Gliomas

“…An extensive metabolic investigation is warranted to examine the roles of each PA transporter in different glioma subtypes. Specific inhibitors targeting FABP5 and FAT/CD36 have been developed and successfully tested in other disease models, which can be applied to glioma research [ 40 , 41 ].…”