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Protective role of anakinra against transthyretin-mediated axonal loss and cell death in a mouse model of familial amyloidotic polyneuropathy.

Journal of neuropathology and experimental neurology (2015-02-11)
Nádia Pereira Gonçalves, Maria Teixeira-Coelho, Maria João Saraiva
ABSTRACT

Familial amyloidotic polyneuropathy (FAP) is characterized by a length-dependent axonal loss in the peripheral nervous system that results from deposition of extracellular prefibrillar transthyretin (TTR) and amyloid fibrils. We have previously shown that an inflammatory stimulus in the peripheral nerve in a mouse model of FAP triggers local TTR expression and deposition, leading to poor regeneration. We also demonstrated that blocking interleukin-1 (IL-1) signaling by the IL-1 receptor antagonist anakinra is beneficial in preventing nerve TTR deposition and associated toxicity. Here, we investigated whether IL-1 signaling influences TTR biology after an injury stimulus in a V30M FAP mouse model. Animals were treated with anakinra 48 hours before sciatic nerve ligation; the nerves were analyzed 7 days postlesion. Anakinra decreased TTR expression by Schwann cells and TTR extracellular deposition after nerve injury, which resulted in improved regeneration. Moreover, treated mice had less apoptotic cell death. In wild-type mice, inflammation is important for regeneration but, in the FAP model mice, an altered threshold of the inflammatory response differentially regulates TTR. Taken together, our results show that anakinra administration before injury can modulate TTR-induced peripheral nervous system pathology, thereby corroborating the protective interference of this drug in a FAP preclinical model.

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