Theophylline Induces Remyelination and Functional Recovery in a Mouse Model of Peripheral Neuropathy

Abstract

Charcot-Marie-Tooth disease (CMT) is a large group of inherited peripheral neuropathies that are primarily due to demyelination and/or axonal degeneration. CMT type 1A (CMT1A), which is caused by the duplication of the peripheral myelin protein 22 (PMP22) gene, is a demyelinating and the most frequent CMT subtype. Hypermyelination, demyelination, and secondary loss of large-caliber axons are hallmarks of CMT1A, and there is currently no cure and no efficient treatment to alleviate the symptoms of the disease. We previously showed that histone deacetylases 1 and 2 (HDAC1/2) are critical for Schwann cell developmental myelination and remyelination after a sciatic nerve crush lesion. We also demonstrated that a short-term treatment with Theophylline, which is a potent activator of HDAC2, enhances remyelination and functional recovery after a sciatic nerve crush lesion in mice. In the present study, we tested whether Theophylline treatment could also lead to (re)myelination in a PMP22-overexpressing mouse line (C22) modeling CMT1A. Indeed, we show here that a short-term treatment with Theophylline in C22 mice increases the percentage of myelinated large-caliber axons and the expression of the major peripheral myelin protein P0 and induces functional recovery. This pilot study suggests that Theophylline treatment could be beneficial to promote myelination and thereby prevent axonal degeneration and enhance functional recovery in CMT1A patients.

Acer truncatum Bunge seed oil ameliorated oxaliplatin-induced demyelination by improving mitochondrial dysfunction via the Pink1/Parkin mitophagy pathway

“…For example, Duman et al demonstrated that theophylline had beneficial effects on demyelination in a mouse model of peripheral neuropathy. 35 More specifically, they showed that theophylline restored demyelination by regulating the expression of sox10 and krox20. Liu et al reported that a ketogenic diet could improve remyelination by promoting Schwann cell maturation (MBP, pmp22, and sox10).…”

Preclinical Efficacy of Peripheral Nerve Regeneration by Schwann Cell-like Cells Differentiated from Human Tonsil-Derived Mesenchymal Stem Cells in C22 Mice

“…In patients with the CMT1A type, the more severe the disease, the more difficult it is to bend the instep, limiting bending and deforming the foot. These characteristics also appear in C22 mice, and the severity can be evaluated using the SFI by gait analysis [33].…”

Mechanisms of Demyelination and Remyelination Strategies for Multiple Sclerosis

“…HDAC2 prevents the targeting of Sox10 to the proteasome via deacetylating its negative regulator eukaryotic elongation factor 1A1 (eEF1A1) [ 75 ] and thereby promotes Sox10-mediated activation of promyelinating and myelin genes, such as Myrf and Myelin basic protein ( Mbp ) in OLs [ 94 ]. Theophylline, a potent HDAC2 activator when used at a low dose, increases Sox10 and myelin protein expression and remyelination in the mouse spinal cord after a demyelinating lesion by lysolecithin in young and old adults [ 75 ], in the mouse sciatic nerve after nerve crush injury [ 75 ] and in a mouse model of peripheral neuropathy [ 95 ]. On the other hand, co-immunoprecipitation analyses revealed that the association of HDAC1/2 with the transcription factor Yin Yang 1 (YY1) was weak in OPCs but enhanced in OLs [ 93 ].…”