Allopregnanolone and neuroinflammation: a focus on multiple sclerosis

The progesterone derivative allopregnanolone (ALLO) is one of the most widely studied compounds among neurosteroids. Through interactions with GABA-A receptors expressed by neurons and glial cells, ALLO has been shown to affect diverse aspects of neural cell physiology, including cell proliferation and survival, migration, and gene expression. Recent data point to important roles for ALLO in different neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and multiple sclerosis (MS). Dysregulation in ALLO biosynthesis pathways has been reported in brain tissue from MS patients as well as in the central nervous system (CNS) tissue derived from MS animal models. Administration of ALLO has been shown to ameliorate neurobehavioral deficits together with neuropathology and inflammation in the CNS of animals with autoimmune demyelination. These findings are in line with previous reports indicating growth- and differentiation-promoting actions of ALLO on neurons and glial cells as well as its neuroprotective effects in the context of other CNS diseases. Nonetheless, these findings have also raised the possibility that ALLO might influence leukocyte biology and associated neuroinflammatory mechanisms independent of its neuroregenerative properties. Herein, we review the current knowledge regarding the role of ALLO in the pathogenesis of MS, and discuss the potential cellular and molecular pathways that might be influenced by ALLO in the context of disease.