Abstract
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.
| Original language | English (US) |
|---|---|
| Article number | e0257-17.2017 |
| Journal | eNeuro |
| Volume | 5 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 1 2018 |
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All Science Journal Classification (ASJC) codes
- Neuroscience(all)
Keywords
- Apoptosis
- Neuroprotection
- Neurotrophins
- P75
- ProNGF
- Seizures
Cite this
}
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. / Greenwood, Shayri G.; Montroull, Laura; Volosin, Marta; Scharfman, Helen E.; Teng, Kenneth K.; Light, Matthew; Torkin, Risa; Maxfield, Fredrick; Hempstead, Barbara L.; Friedman, Wilma.
In: eNeuro, Vol. 5, No. 1, e0257-17.2017, 01.01.2018.Research output: Contribution to journal › Article
TY - JOUR
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
AU - Greenwood, Shayri G.
AU - Montroull, Laura
AU - Volosin, Marta
AU - Scharfman, Helen E.
AU - Teng, Kenneth K.
AU - Light, Matthew
AU - Torkin, Risa
AU - Maxfield, Fredrick
AU - Hempstead, Barbara L.
AU - Friedman, Wilma
PY - 2018/1/1
Y1 - 2018/1/1
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 (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.
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.
KW - Apoptosis
KW - Neuroprotection
KW - Neurotrophins
KW - P75
KW - ProNGF
KW - Seizures
UR - http://www.scopus.com/inward/record.url?scp=85040962853&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85040962853&partnerID=8YFLogxK
U2 - 10.1523/ENEURO.0257-17.2017
DO - 10.1523/ENEURO.0257-17.2017
M3 - Article
C2 - 29349290
AN - SCOPUS:85040962853
VL - 5
JO - eNeuro
JF - eNeuro
SN - 2373-2822
IS - 1
M1 - e0257-17.2017
ER -