LXR Agonists: New Potential Therapeutic Drug for Neurodegenerative Diseases

Abstract

Liver X receptors (LXRs) are nuclear receptors involved in the regulation of lipid metabolism and inflammatory responses in the central nervous system. Defects in cholesterol homeostasis contribute to the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and Huntington's disease. Inflammatory responses could enhance the neurodegenerative process or act independently. The natural and synthetic LXR agonists induce the transcriptional activity of LXR target genes, thus attenuate the imbalance of cholesterol metabolism and overactivation of microglia and astrocytes in inflammation and are widely used in a variety of neurodegenerative diseases animal models. By developing more specific, potent, penetrable, and functional LXR agonist may lead to a better curative effect for neurodegenerative diseases and avoidance of potentially deleterious side effects. Here, we focus on recent advances in our understanding of the role of LXRs and their agonists in cholesterol homeostasis, inflammation, and the potential therapeutic effects in neurodegenerative diseases.

Neurosteroidogenesis Today: Novel Targets for Neuroactive Steroid Synthesis and Action and Their Relevance for Translational Research

“…Moreover, as recently demonstrated in an experimental model of diabetes, activation of liver X receptor increases neuroactive steroid levels directly in the central (210) as well as the peripheral nervous system (211). In agreement, activation of liver X receptors exerts protective effects in diabetic peripheral neuropathy (211), global or focal cerebral ischemia (212), as well as in neurodegenerative diseases, such as multiple sclerosis, Alzheimer's and Parkinson's diseases (93, 213). …”

Nuclear Receptor NR1H3 in Familial Multiple Sclerosis

“…They are also instrumental for the generation of physiologically relevant cellular and animal models in which to study the disease pathways and develop and assess therapeutic options. The central role of LXRs in the regulation of cholesterol homeostasis has already triggered a growing interest in LXR synthetic agonists for the treatment of atherosclerosis, coronary heart disease, diabetes and neurodegenerative diseases amongst others (Xu et al, 2013). Although the therapeutic use of these agonists has been hampered by serious adverse effects, agonists with a more finite biological effects are under development (Temml et al, 2014).…”

Neuroactive steroids and the peripheral nervous system: An update

“…Moreover, protective effects have been also reported in experimental model of multiple sclerosis [94] or Alzheimer's disease [95]. Similarly, activation of LXR exerts protective effects in global [96] or focal cerebral ischemia [97] as well as in neurodegenerative diseases, such multiple sclerosis, Alzheimer and Parkinson diseases [98]. On this basis, similar therapeutic strategies have been also applied in the PNS.…”