phytosterols and Amyotrophic-Lateral-Sclerosis

Statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, are commonly used in the therapy of cardiovascular diseases. Recent studies suggest that statins may induce amyotrophic lateral sclerosis (ALS) in some patients, but no pathogenic mechanism has been proposed for this association. Herein the hypothesis is proposed that statins may induce or aggravate ALS by impairing liver X receptor (LXR) signaling. The hypothesis is supported by the following observations: 1) statins inhibit the synthesis of endogenous LXR agonists, oxysterols, and decrease the expression of LXR target genes in many cells, 2) mice lacking LXRbeta exhibit sn ALS-like phenotype, 3) statins increase the concentration of plant sterols in plasma and tissues, partially by impairing LXR-dependent signaling, which results in augmented intestinal absorption and impaired biliary excretion of plant sterols, and 4) some plant sterols are toxic to motor neurons of the spinal cord, which are primarily affected in ALS patients. If this hypothesis is confirmed, LXR agonists could be used together with statins in patients predisposed to develop ALS or in those known to have the disorder to prevent motor neuron degeneration.

Topics: Amyotrophic Lateral Sclerosis; Animals; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Liver X Receptors; Mice; Models, Biological; Orphan Nuclear Receptors; Phytosterols; Signal Transduction

The factors responsible for ALS-parkinsonism dementia complex (ALS-PDC), the unique neurological disorder of Guam, remain unresolved, but identification of causal factors could lead to clues for related neurodegenerative disorders elsewhere. Earlier studies focused on the consumption and toxicity of the seed of Cycas circinalis, a traditional staple of the indigenous diet, but found no convincing evidence for toxin-linked neurodegeneration. We have reassessed the issue in a series of in vitro bioassays designed to isolate non-water soluble compounds from washed cycad flour and have identified three sterol beta-d-glucosides as potential neurotoxins. These compounds give depolarizing field potentials in cortical slices, induce alterations in the activity of specific protein kinases, and cause release of glutamate. They are also highly toxic, leading to release of lactate dehydrogenase (LDH). Theaglycone form, however, is non-toxic. NMDA receptor antagonists block the actions of the sterol glucosides, but do not compete for binding to the NMDA receptor. The most probable mechanism leading to cell death may involve glutamate neuro/excitotoxicity. Mice fed cycad seed flour containing the isolated sterol glucosides show behavioral and neuropathological outcomes, including increased TdT-mediated biotin-dUTP nick-end labelling (TUNEL) positivity in various CNS regions. Astrocytes in culture showed increased caspase-3 labeling after exposure to sterol glucosides. The present results support the hypothesis that cycad consumption may be an important factor in the etiology of ALS-PDC and further suggest that some sterol glucosides may be involved in other neurodegenerative disorders.

Topics: Amyotrophic Lateral Sclerosis; Animals; Astrocytes; Biological Assay; Cells, Cultured; Cerebral Cortex; Cholesterol; Cycas; Dementia; Glucose; Glucosides; Guam; Humans; In Vitro Techniques; Male; Mice; Neurons; Neurotoxins; Parkinsonian Disorders; Patch-Clamp Techniques; Phytosterols; Plant Extracts; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Seeds; Sitosterols; Stigmasterol