Thrombin Levels Linked to Multiple Sclerosis Progression

Results obtained from experiments that tested a novel molecular probe directed at thrombin suggested that measurement of thrombin activity might be exploited for developing sensitive probes for preclinical detection and monitoring of inflammation and progression of multiple sclerosis (MS).

MS, which affects more than 200 million people worldwide, is an inflammatory disease in which the myelin sheaths around the axons of the brain and spinal cord are damaged by autoimmune attack, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms.

Thrombin is the central protease of the blood-clotting cascade, and beyond its key role in the dynamic process of thrombus formation, thrombin has a pronounced proinflammatory character. Investigators at the Gladstone Institutes of the University of California, San Francisco (USA) had shown previously that blood seeping into the brain due to MS-induced weakening of the blood brain barrier caused a buildup of fibrin in the brain. Fibrin is produced from fibrinogen due to the action of thrombin.

In the current study, the investigators used a mouse MS model (experimental autoimmune encephalomyelitis) to characterize the activity pattern of thrombin over the course of the disease. To determine the level of thrombin, the investigators developed a thrombin-specific "Activatable Cell-Penetrating Peptide" (ACPP), a novel type of molecular probe that delivered a fluorescent agent to regions of the mouse nervous system where thrombin was active.

Results published in the November 29, 2013, online edition of the journal Annals of Neurology revealed that thrombin activity preceded onset of neurological signs, increased at disease peak, correlated with fibrin deposition, microglial activation, demyelination, axonal damage, and clinical severity. Mice with a genetic deficit in prothrombin (the precursor of thrombin) confirmed the specificity of the thrombin probe.

"We already knew that the buildup of fibrin appears early in the development of MS - both in animal models and in human patients, so we wondered whether thrombin activity could in turn serve as an early marker of disease," said senior author Dr. Katerina Akassoglou, professor of neurology at the University of California, San Francisco. "In fact, we were able to detect thrombin activity even in our animal models, before they exhibited any of the disease's neurological signs."

"In the future," said Dr. Akassoglou, "this thrombin-specific ACPP could be developed to one day allow for early patient diagnosis and therapeutic intervention - including a way to effectively monitor how patients are responding to the latest treatments."

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