The effect of STAT3 inhibition on status epilepticus and subsequent spontaneous seizures in the pilocarpine model of acquired epilepsy.

Pilocarpine-induced status epilepticus (SE), which results in temporal lobe epilepsy (TLE) in rodents, activates the JAK/STAT pathway. In the current study, we evaluate whether brief exposure to a selective inhibitor of the JAK/STAT pathway (WP1066) early after the onset of SE affects the severity of SE or reduces later spontaneous seizure frequency via inhibition of STAT3-regulated gene transcription. Rats that received systemic WP1066 or vehicle at the onset of SE were continuously video-EEG monitored during SE and for one month to assess seizure frequency over time. Protein and/or mRNA levels for pSTAT3, and STAT3-regulated genes including: ICER, Gabra1, c-myc, mcl-1, cyclin D1, and bcl-xl were evaluated in WP1066 and vehicle-treated rats during stages of epileptogenesis to determine the acute effects of WP1066 administration on SE and chronic epilepsy. WP1066 (two 50mg/kg doses) administered within the first hour after onset of SE results in transient inhibition of pSTAT3 and long-term reduction in spontaneous seizure frequency. WP1066 alters the severity of chronic epilepsy without affecting SE or cell death. Early WP1066 administration reduces known downstream targets of STAT3 transcription 24h after SE including cyclin D1 and mcl-1 levels, known for their roles in cell-cycle progression and cell survival, respectively. These findings uncover a potential effect of the JAK/STAT pathway after brain injury that is physiologically important and may provide a new therapeutic target that can be harnessed for the prevention of epilepsy development and/or progression.

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.

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.