Premium
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
Author(s) -
Grabenstatter H.L.,
Carlsen J.,
Raol Y.H.,
Yang T.,
Hund D.,
Cruz Del Angel Y.,
White A.M.,
Gonzalez M.I.,
Longo F.M.,
Russek S.J.,
BrooksKayal A.R.
Publication year - 2014
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.23402
Subject(s) - epileptogenesis , status epilepticus , neuroprotection , low affinity nerve growth factor receptor , pilocarpine , neurotrophin , tropomyosin receptor kinase b , neuroscience , brain derived neurotrophic factor , hippocampal formation , neurotrophic factors , hippocampus , neurodegeneration , epilepsy , pharmacology , receptor , medicine , biology , disease
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. © 2014 Wiley Periodicals, Inc.