TY - JOUR T1 - A novel neuroprotective mechanism for lithium that prevents association of the p75<sup>NTR</sup>-sortilin receptor complex and attenuates proNGF-induced neuronal death <em>in vitro</em> and <em>in vivo</em> JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0257-17.2017 SP - ENEURO.0257-17.2017 AU - Shayri G. Greenwood AU - Laura Montroull AU - Marta Volosin AU - Helen E. Scharfman AU - Kenneth K. Teng AU - Matthew Light AU - Risa Torkin AU - Fredrick Maxfield AU - Barbara L. Hempstead AU - Wilma J. Friedman Y1 - 2018/01/11 UR - http://www.eneuro.org/content/early/2018/01/11/ENEURO.0257-17.2017.abstract N2 - 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 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, sub-micromolar doses of lithium citrate effectively inhibited proNGF-induced cell death in cultured neurons, and protected hippocampal neurons following pilocarpine-induced status epilepticus 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.Significance Statement Neuronal death occurs after prolonged severe seizures and is partially due to the induction of proNGF and its p75 neurotrophin receptor. The p75NTR utilizes a co-receptor, sortilin, to bind proNGF and promote apoptotic signaling. We show here that sub-micromolar concentrations of lithium citrate prevented p75NTR-mediated neuronal death by impairing the formation and internalization of the co-receptor complex. Although lithium has many neuroprotective functions that occur at millimolar concentrations, we demonstrate a novel mechanism for lithium citrate to afford neuroprotection from seizure-induced death at submicromolar doses. ER -