Editors' ChoiceMultiple Sclerosis

Dissecting the Mystery Around Multiple Sclerosis

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Science Translational Medicine  28 Nov 2012:
Vol. 4, Issue 162, pp. 162ec216
DOI: 10.1126/scitranslmed.3005334

In patients with multiple sclerosis (MS), disseminated demyelination of brain and spinal cord neurons progressively produces neurologic deficits. The etiology of MS remains largely unknown; although existing therapies can achieve symptomatic relief, disease-modifying strategies have been disappointing. A better understanding of the molecular mechanisms of this disease is required to rationalize drug target development. In experimental autoimmune encephalomyelitis (EAE), the animal counterpart of MS, Muramatsu and colleagues now report that prostacyclin, a lipid member of the arachidonic acid–derived eicosanoid family, is elaborated during disease-associated angiogenesis and can actually promote neuronal remodeling.

The researchers observed that, as diseased neurons tried to repair the EAE deficits, sprouting neurons formed collaterals and improved motor dysfunction resulting from the anatomical lesions in the spinal cord of EAE mice. New blood vessels appeared to be a prerequisite for this process, and co-culture of neurons with vascular endothelial cells pointed toward prostacyclin from the endothelial cells as the responsible factor. Muramatsu and colleagues tested—and supported—this hypothesis in a series of mechanistic experiments: Block of the prostacyclin receptor weakened the recovery of motor function. Conversely, iloprost, a prostacyclin receptor agonist, improved motor function by triggering formation of neuron collaterals in EAE mice. Likewise, an agonist of cyclic adenosine monophosphate, the downstream signal transducer of prostacyclin, promoted neuron elongation. Silencing prostacyclin synthase with small interfering RNA confirmed that vascular endothelial cells were the source of prostacyclin. And in fact, marked expression of prostacyclin synthase was seen in newly formed blood vessels in EAE mice and in autopsy samples from patients with MS.

The researchers concluded that, in the inflammatory environment of EAE, prostacyclin originates from newly formed vessels and promotes the formation of a collateral neuronal network that can restore motor performance in these mice. If this process could be augmented in humans, it may prove beneficial to patients with MS, although the path to a therapy might be complex. Other studies suggest that cyclooxygenase-2 inhibitors, which reduce prostacyclin formation, limit neuron demyelination in MS models.

R. Muramatsu et al., Angiogenesis induced by CNS inflammation promotes neuronal remodeling through vessel-derived prostacyclin. Nat. Med. 18, 1658–1664 (2012). [Abstract]

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