A TSPO ligand is protective in a mouse model of multiple sclerosis

Daniel J. Daugherty, Vimal Selvaraj, Olga V. Chechneva, Xiao Bo Liu, David E Pleasure, Wenbin Deng

Research output: Contribution to journalArticle

77 Citations (Scopus)

Abstract

Local production of neurosteroids such as progesterone and allopregnanolone confers neuroprotection in central nervous system (CNS) inflammatory diseases. The mitochondrial translocator protein (TSPO) performs a rate-limiting step in the conversion of cholesterol to pregnenolone and its steroid derivatives. Previous studies have shown that TSPO is upregulated in microglia and astroglia during neural inflammation, and radiolabelled TSPO ligands such as PK11195 have been used to image and localize injury in the CNS. Recent studies have shown that modulating TSPO activity with pharmacological ligands such as etifoxine can initiate the production of neurosteroids locally in the injured CNS. In this study, we examined the effects of etifoxine, a clinically available anxiolytic drug, in the development and progression of mouse experimental autoimmune encephalomyelitis (EAE), an experimental model for multiple sclerosis (MS). Our results showed that etifoxine attenuated EAE severity when administered before the development of clinical signs and also improved symptomatic recovery when administered at the peak of the disease. In both cases, recovery was correlated with diminished inflammatory pathology in the lumbar spinal cord. Modulation of TSPO activity by etifoxine led to less peripheral immune cell infiltration of the spinal cord, and increased oligodendroglial regeneration after inflammatory demyelination in EAE. Our results suggest that a TSPO ligand, e.g. etifoxine, could be a potential new therapeutic option for MS with benefits that could be comparable to the administration of systemic steroids but potentially avoiding the detrimental side effects of long-term direct use of steroids.

Original languageEnglish (US)
Pages (from-to)891-903
Number of pages13
JournalEMBO Molecular Medicine
Volume5
Issue number6
DOIs
StatePublished - Jun 2013

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Multiple Sclerosis
Autoimmune Experimental Encephalomyelitis
Ligands
Spinal Cord
Steroids
Proteins
Neurotransmitter Agents
Central Nervous System
Pregnanolone
Pregnenolone
Mitochondrial Proteins
Central Nervous System Diseases
Anti-Anxiety Agents
Microglia
Demyelinating Diseases
Astrocytes
Progesterone
Regeneration
Theoretical Models
Cholesterol

Keywords

  • Autoimmune demyelination
  • Etifoxine
  • Mitochondria
  • Multiple sclerosis
  • Translocator protein

ASJC Scopus subject areas

  • Molecular Medicine

Cite this

A TSPO ligand is protective in a mouse model of multiple sclerosis. / Daugherty, Daniel J.; Selvaraj, Vimal; Chechneva, Olga V.; Liu, Xiao Bo; Pleasure, David E; Deng, Wenbin.

In: EMBO Molecular Medicine, Vol. 5, No. 6, 06.2013, p. 891-903.

Research output: Contribution to journalArticle

Daugherty, Daniel J. ; Selvaraj, Vimal ; Chechneva, Olga V. ; Liu, Xiao Bo ; Pleasure, David E ; Deng, Wenbin. / A TSPO ligand is protective in a mouse model of multiple sclerosis. In: EMBO Molecular Medicine. 2013 ; Vol. 5, No. 6. pp. 891-903.
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