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18 http://neurology.thelancet.com Vol 4 January 2005

Thyroid hormone, when given at theright time, seems to accelerate re-myelination in a rat model of multiplesclerosis (MS; Proc Natl Acad Sci USA2004; 101: 16363–68), offering hopethat the hormone may have similareffects in patients.

“The remyelination of demyelinatedneurons does not occur in MS, possiblyas a result of oligodendrocyte precursorcells [OPCs] failing to mature andleaving them unable to producemyelin”, explains author Laura Calzà(University of Bologna, Italy). “Thyroidhormone is known to be involved inOPC maturation and differentiation, sowe investigated whether hormonetherapy could potentiate this develop-ment and initiate the remyelinationprocess.”

Experimental allergic encephalitis(EAE), a commonly-used rat model ofMS, was induced in rats by inoculationwith guinea-pig spinal-cord tissue.These animals were then given 0·2 mg

thyroid hormone 11, 13, or 15 dayslater (when they showed severeneurological defects), or in the relapseperiod at 21, 23, and 25 days, or atboth times.

“As expected, myelin was first lost”,explains Calzà, “but when the hormonetreatment was given during the acutephase of the disease, the number ofOPCs increased, as shown by the higheramounts of platelet-derived growthfactor � receptor mRNA. The myelinstaining reaction was also muchstronger—the sheaths seemed to havethickened, their morphology was morenormal, and there were more markersof mature oligendendrocytes.”

The team then examined how muchmyelin basic protein (MBP) and itsmRNA was produced. At 55 days,amounts of both were low in the EAErats, but in the hormone-treatedanimals they were near normal.

There were, however, no signs ofremyelination when the hormone was

given during the relapse phase. “It isonly during acute disease that theOPCs start to proliferate. This mustmake them become thyroid hormone-sensitive, which might help themmature into myelin-producing oligo-dendrocytes; certainly, in healthy rats,hyperthyroidism has no effect on thesecells”, explains coauthor MercedesFernández. “The hormone probablyincreases the production of nervegrowth factors, helping OPCs tosurvive and finish differentiation.”

“MS is a complex disease andremyelination likely requires factorsfrom many different cell types”,comments Peter Dowling (New JerseyMedical School, USA). “It is probablytoo hopeful to think that simply givingthyroid hormone to patients will leadto significant remyelination and axonalprotection, but it might form part of amultiapproach therapy.”

Adrian Burton

Thyroid hormone musters remyelination in MS model

The pathogenesis of West Nile virus(WNV) is one step closer to beingunderstood, as researchers have eluci-dated the mechanism by which thepathogen enters the brain (Nat Med2004; published online Nov 21, DOI:10.1038/nm1140). According to ErolFikrig (Yale University, New Haven, CT,

USA) and colleagues, the virus causesinflammation, and thus weakens theblood–brain barrier (BBB).

Toll-like receptor (Tlr) 3 recognisesviral double-stranded (ds) RNA—anintermediate of RNA-virus replication—so the researchers investigated its rolein the control of viral infection. Wild-type and Tlr3-deficient mice wereinjected with WNV and monitored dailyfor survival: Tlr-deficient mice weremore resistant (40% survival vs 0% incontrols) to lethal WNV infection.

Viral load was measured in blood andspleen, and deficient mice had “raisedviral burden”, generally confined toperipheral blood. However, after peakviraemia in the blood (around day 3)when WNV crosses the BBB and infectsthe CNS, WNV-infected cells wereabsent or rare in the brains of micelacking Tlr3. Wild-type mice had foci ofWNV infection in nearly all brain

regions. Production of inflammatorycytokines was also low in deficientmice.

A second experiment to assess therole of Tlr in BBB permeability againshowed reduced peripheral produc-tion of cytokines, despite increasedviraemia, hence Tlr may promote BBBpermeability.

These data are the first to suggestthat a Tlr-mediated inflammatory resp-onse to WNV infection, associated withthe overproduction of proinflammatorycytokines, is crucial for the modulationof the BBB, the route by which the virusgains entry to the brain. According toPhilippe Desprès (Institut Pasteur, Paris,France), “whether the TLR3 as well asTNF� signalling inhibitors can provideprotection against WNV encephalitis isa critical issue”.

Rachael Paterson

How West Nile virus crosses the blood–brain barrier

West-Nile virus uses Tlr to cross the blood–brain barrier

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