RT Journal Article SR Electronic T1 A Novel Neuroprotective Mechanism for Lithium That Prevents Association of the p75NTR-Sortilin Receptor Complex and Attenuates proNGF-Induced Neuronal Death In Vitro and In Vivo JF eneuro JO eNeuro FD Society for Neuroscience SP ENEURO.0257-17.2017 DO 10.1523/ENEURO.0257-17.2017 VO 5 IS 1 A1 Shayri G. Greenwood A1 Laura Montroull A1 Marta Volosin A1 Helen E. Scharfman A1 Kenneth K. Teng A1 Matthew Light A1 Risa Torkin A1 Fredrick Maxfield A1 Barbara L. Hempstead A1 Wilma J. Friedman YR 2018 UL http://www.eneuro.org/content/5/1/ENEURO.0257-17.2017.abstract AB Neurotrophins play critical roles in the survival, maintenance and death of neurons. In particular, proneurotrophins have been shown to mediate cell death following brain injury induced by status epilepticus (SE) in rats. Previous studies have shown that pilocarpine-induced seizures lead to increased levels of proNGF, which binds to the p75NTR-sortilin receptor complex to elicit apoptosis. A screen to identify compounds that block proNGF binding and uptake into cells expressing p75 and sortilin identified lithium citrate as a potential inhibitor of proNGF and p75NTR-mediated cell death. In this study, we demonstrate that low, submicromolar doses of lithium citrate effectively inhibited proNGF-induced cell death in cultured neurons and protected hippocampal neurons following pilocarpine-induced SE in vivo. We analyzed specific mechanisms by which lithium citrate afforded neuroprotection and determined that lithium citrate prevented the association and internalization of the p75NTR-sortilin receptor complex. Our results demonstrate a novel mechanism by which low-dose treatments of lithium citrate are effective in attenuating p75NTR-mediated cell death in vitro and in vivo.