Researchers report that myelin breakdown results in an accumulation of very long-chain fatty acids (VLCFA) and their intermediates, which triggers an autoimmune response that damages brain cells. Reducing the levels of VLCFA using approved drugs bezafibrate and fingolimod had a synergistic beneficial effect on multiple sclerosis (MS) in an animal model, suggesting a potential and  more effective treatment for MS patients.

The team published its results “Very-long-chain fatty acids induce glial-derived sphingosine-1-phosptate synthesis, secretion, and neuroinflammation” in Cell Metabolism.

”VLCFAs (very-long-chain fatty acids) are the most abundant fatty acids in myelin. Hence, during demyelination or aging, glia are exposed to higher levels of VLCFA than normal. We report that glia convert these VLCFA into sphingosine-1-phosphate (S1P) via a glial-specific S1P pathway. Excess S1P causes neuroinflammation, NF-kB activation, and macrophage infiltration into the CNS,” write the investigators.

“Suppressing the function of S1P in fly glia or neurons, or administration of Fingolimod, an S1P receptor antagonist, strongly attenuates the phenotypes caused by excess VLCFAs. In contrast, elevating the VLCFA levels in glia and immune cells exacerbates these phenotypes. Elevated VLCFA and S1P are also toxic in vertebrates based on a mouse model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE).

“Indeed, reducing VLCFA with bezafibrate ameliorates the phenotypes. Moreover, simultaneous use of bezafibrate and fingolimod synergizes to improve EAE, suggesting that lowering VLCFA and S1P is a treatment avenue for MS.”

Fruit fly studies

Hyunglok Chung, PhD, Baylor College of Medicine, first and co-corresponding author of this study, had previously reported that excess VLCFA is harmful to nerve cells in fruit flies. In the first part of this study, Chung and his colleagues show, also in fruit flies, that accumulation of S1P, a key product of VLCFA degradation, causes inflammation in nerve cells and potentially damages them.

The team then collaborated with co-corresponding author Hyun-Kyoung Lee, PhD, associate professor of pediatrics–neurology at Baylor and investigator at the Jan and Dan Duncan Neurological Research Institute (Duncan NRI), to explore the role of S1P in MS progression in a mouse model.

Co-first author Qi Ye, PhD, a postdoctoral associate in the Lee lab, found that pre-symptomatic treatment of these mice with bezafibrate, a lipid-lowering drug that inhibits the synthesis of VLCFA, slowed the progression of this debilitating disorder by reducing myelin loss, neuronal damage, and infiltration of immune cells into the brain. Qi next tested the potential therapeutic effect of lowering VLCFA and S1P on MS.

“When we administered bezafibrate along with fingolimod at the onset of symptoms, we saw a synergistic improvement in paralysis and motor performance, and in myelin and neuronal loss. The combined effects of these drugs were significantly better than the effect of either drug alone in every parameter we tested, suggesting that a combined therapy could be more effective and offer better outcomes for MS patients,” noted Chung.

“We are excited by the potential clinical implications of this study not just in the treatment of MS but also for other neurodegenerative conditions that are associated with myelin loss, disruptions in lipid metabolism, and neuroinflammation [e.g., Alzheimer’s or Huntington’s disease],” said Hugo J. Bellen, DVM, PhD, Distinguished Service Professor in molecular and human genetics at Baylor and the Duncan NRI. He also is a co-corresponding author of this study.

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