Mitochondrial dysfunction plays a key role in progressive axonal loss in Multiple Sclerosis.

Multiple Sclerosis is the most common inflammatory demyelinating disease of the central nervous system and is the leading cause of non traumatic neurological disability in young adults. In recent years it has become increasingly evident that axonal degeneration is a key player in the pathogenesis of disability in MS but the mechanisms that lead to axonal damage are not fully understood. It seems likely that the causes of axonal damage vary at different stages of the disease and several theories have evolved that address the mechanisms leading to axonal loss in the acute stages of demyelination. There has been relatively little attention given to investigation of the mechanisms involved in chronic axonal loss in the progressive stages of MS. We propose a hypothesis that mitochondria play a key role in this chronic axonal loss. Following demyelination there is redistribution of sodium channels along the axon and mitochondria are recruited to the demyelinated regions to meet the increased energy requirements necessary to maintain conduction. The mitochondria present within the chronically demyelinated axons will be functioning at full capacity. The axon may well be able to function for many years due to these adaptive mechanisms but we propose that eventually, despite antioxidant defences, free radical damage will accumulate and mitochondrial function will become compromised. ATP concentration within the axon will decrease and the effect on axonal function will be profound. The actual cause of cell death could be due to a number of mechanisms related to mitochondrial dysfunction including failure of ionic homeostasis, calcium influx, mitochondrial mediated cell death or impaired axonal transport. Whatever the cause of axonal loss our hypothesis is that mitochondria are central to this process. We explore steps to test this hypothesis and discuss the possible therapeutic approaches which target the mitochondrial mechanisms that may contribute to chronic axonal loss.

Low-density lipoproteins inhibit endothelium-dependent relaxation in rabbit aorta.

The vascular endothelium, in response to pulsatile flow and vasoactive agents including acetylcholine, secretes the endothelium-derived relaxing factor (EDRF), a substance which regulates vascular tone. Recent interest in EDRF has focused on its possible dysfunction in atherosclerosis. In animal models of the disease, endothelium-dependent relaxation is markedly reduced. The continuous exposure of the endothelium in hyperlipidaemia to high concentrations of low-density lipoprotein (LDL), a known atherogenic risk factor, may explain this dysfunction. Here, we demonstrate that pathophysiological concentrations of LDL directly inhibit endothelium-dependent relaxation. Chemically modified LDL, in contrast, is inactive, implying that the inhibition is through a receptor-dependent mechanism.

Intracellular mechanisms in the activation of human platelets by low-density lipoproteins.

Low-density lipoproteins (LDL) have been shown to cause aggregation of human blood platelets at concentrations above 2 g of protein/l. The secretion of the contents of platelet dense granules was detected, but not that of the lysosomes. LDL gave rise to a mobilization of [3H]arachidonic acid from phospholipids and the appearance of products of the cyclo-oxygenase pathway after only 10 s. LDL-promoted aggregation was inhibited by both aspirin and indomethacin. There was an increase in 3H-labelled diacylglycerols and the phosphorylation of 47 kDa proteins. LDL therefore shares at least some of the mechanisms of stimulus/response coupling with those of other agonists.