title: Acute administration of the small-molecule p75(NTR) ligand does not prevent hippocampal neuron loss or development of spontaneous seizures after pilocarpine-induced status epilepticus.
abstract: Neurotrophins, such as brain-derived neurotrophic factor (BDNF), are initially expressed in a precursor form (e.g., pro-BDNF) and cleaved to form mature BDNF (mBDNF). After pilocarpine-induced status epilepticus (SE), increases in neurotrophins regulate a wide variety of cell-signaling pathways, including prosurvival and cell-death machinery in a receptor-specific manner. Pro-BDNF preferentially binds to the p75 neurotrophin receptor (p75(NTR) ), whereas mBDNF is the major ligand of the tropomyosin-related kinase receptor. To elucidate a potential role for p75(NTR) in acute stages of epileptogenesis, rats were injected prior to and at onset of SE with LM11A-31, a small-molecule ligand that binds to p75(NTR) to promote survival signaling and inhibit neuronal cell death. Modulation of early p75(NTR) signaling and its effects on electrographic SE, SE-induced neurodegeneration, and subsequent spontaneous seizures were examined after LM11A-31 administration. Despite an established neuroprotective effect of LM11A-31 in several animal models of neurodegenerative disorders (e.g., Alzheimer's disease, traumatic brain injury, and spinal cord injury), high-dose LM11A-31 administration prior to and at onset of SE did not reduce the intensity of electrographic SE, prevent SE-induced neuronal cell injury, or inhibit the progression of epileptogenesis. Further studies are required to understand the role of p75(NTR) activation during epileptogenesis and in seizure-induced cell injury in the hippocampus, among other potential cellular pathologies contributing to the onset of spontaneous seizures. Additional studies utilizing more prolonged treatment with LM11A-31 are required to reach a definite conclusion on its potential neuroprotective role in epilepsy.
authors.affiliation: Department of Pediatrics, Division of Neurology, and Translational Epilepsy Research Program, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: H L
authors.initials: HL
authors.lastname: Grabenstatter
authors.forename: J
authors.initials: J
authors.lastname: Carlsen
authors.forename: Y H
authors.initials: YH
authors.lastname: Raol
authors.forename: T
authors.initials: T
authors.lastname: Yang
authors.forename: D
authors.initials: D
authors.lastname: Hund
authors.forename: Y
authors.initials: Y
authors.lastname: Cruz Del Angel
authors.forename: A M
authors.initials: AM
authors.lastname: White
authors.forename: M I
authors.initials: MI
authors.lastname: Gonzalez
authors.forename: F M
authors.initials: FM
authors.lastname: Longo
authors.forename: S J
authors.initials: SJ
authors.lastname: Russek
authors.forename: A R
authors.initials: AR
authors.lastname: Brooks-Kayal
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000927:Anticonvulsants / Q000097:blood / Q000627:therapeutic use*; D058256:Brain Waves / Q000187:drug effects; D004195:Disease Models, Animal; D004569:Electroencephalography; D005452:Fluoresceins; D007532:Isoleucine / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use; D009025:Morpholines / Q000097:blood / Q000627:therapeutic use*; D018721:Muscarinic Agonists / Q000633:toxicity; D009419:Nerve Tissue Proteins; D010862:Pilocarpine / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D017978:Receptors, Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000737:chemistry / Q000378:metabolism*; D013057:Spectrum Analysis; D013226:Status Epilepticus / Q000139:chemically induced / Q000188:drug therapy*; D013997:Time Factors
chemical_list: D000927:Anticonvulsants; D005452:Fluoresceins; C575077:LM11A-31; D009025:Morpholines; D018721:Muscarinic Agonists; D009419:Nerve Tissue Proteins; D017978:Receptors, Growth Factor; D017475:Receptors, Nerve Growth Factor; C435731:fluoro jade; D010862:Pilocarpine; D007532:Isoleucine; C068313:Ngfr protein, rat
keywords: LM11A-31 p75NTR; neurotrophin; pilocarpine; seizure; status epilepticus