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bioRxiv · 10.1101/2020.05.12.090654

Annexin-A1 tripeptide attenuates surgery-induced neuroinflammation and memory deficits through regulation of the NLRP3 inflammasome

Zhang, Z.·Ma, Q.·Velagapudi, R.·Barclay, W. E.·Rodriguiz, R. M.·Wetsel, W. C.·Shinohara, M. L.·Terrando, N.
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Abstract

Neuroinflammation is a growing hallmark of perioperative neurocognitive disorders (PNDs), including delirium and longer-lasting cognitive deficits. We have developed a clinically-relevant orthopedic mouse model to study the impact of a common surgical procedure on the vulnerable brain. The mechanism underlying PNDs remain unknown. Here we evaluated the impact of surgical trauma on the NLRP3 inflammasome signaling, including the expression of apoptosis-associated speck-like protein containing a CARD (ASC), caspase-1, and IL-1{beta} in the hippocampus of C57BL6/J male mice, adult (3-months) and aged (>18-months). Surgery triggered ASC specks formation in CA1 hippocampal microglia, but without inducing significant morphological changes in NLRP3 and ASC knockout mice. Since no therapies are currently available to treat PNDs, we assessed the neuroprotective effects of a biomimetic peptide derived from the endogenous inflammation-ending molecule, Annexin-A1 (ANXA1). We tested the hypothesis that this peptide (ANXA1sp) inhibits NLRP3 inflammasome activation, thus preventing microglial activation and hippocampal-dependent memory deficits. Together these results uncover a previously underrecognized role of the NLRP3 inflammasome in triggering postoperative neuroinflammation and offer a new target for advancing treatment of PNDs through resolution of inflammation.

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Zhang, Z., Ma, Q., Velagapudi, R., Barclay, W. E., Rodriguiz, R. M., Wetsel, W. C., Shinohara, M. L., Terrando, N.. 2020-05-14. Annexin-A1 tripeptide attenuates surgery-induced neuroinflammation and memory deficits through regulation of the NLRP3 inflammasome. https://doi.org/10.1101/2020.05.12.090654

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