AUTHOR=Shavit-Stein Efrat , Berkowitz Shani , Davidy Tal , Fennig Uri , Gofrit Shani Guly , Dori Amir , Maggio Nicola 

TITLE=Modulation of the Thrombin Pathway Restores LTP in a Pilocarpine Mice Model of Status Epilepticus

JOURNAL=Frontiers in Cellular Neuroscience

VOLUME=Volume 16 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2022.900925

DOI=10.3389/fncel.2022.900925

ISSN=1662-5102

ABSTRACT=Background: Status epilepticus (SE) leads to memory impairment following a seizure, attributed to long-term potentiation (LTP) reduction. Thrombin, a coagulation factor that activates protease-activated receptor 1 (PAR1) is involved in cognitive impairment following traumatic brain injury by reducing hippocampal LTP and in seizures as seen in a SE pilocarpine-induced mice model. Thrombin pathway inhibition prevents this cognitive impairment. We evaluated the effect of thrombin pathway inhibition in the pilocarpine-induced SE mice model, on LTP, hippocampal, and serum markers for inflammation, the PAR1 pathway and neuronal cell damage. 

Methods: SE was induced by injecting C57BL/6J mice with pilocarpine. Before pilocarpine injection, mice were injected with either the specific thrombin inhibitor α-NAPAP (Nα-(2- naphthalene-sulfonyl glycyl)-4-amidino- D L – phenylalaninepiperidide), the PAR1 antagonist SCH79797, or vehicle-only solution. Recordings of excitatory postsynaptic potentials (EPSP) were conducted from hippocampal slices 24 hours following pilocarpine injection. Hippocampal real-time PCR for the quantification of the PAR1, prothrombin, and tumor necrosis factor α (TNF-α) mRNA expression levels were conducted. Serum levels of neurofilament light chain (NfL) and TNF-α were measured by a single molecule array assay. 

Results: The EPSP was reduced in the pilocarpine-induced SE mice (p<0.001). This reduction was prevented by both NAPAP and SCH79797 treatments (p<0.001 for both treatments). Hippocampal expression of TNF-α was elevated in the pilocarpine-induced SE group compared to control (p=0.01), however, serum levels of TNF-α were not changed. NfL levels were elevated in the pilocarpine-induced SE group (p=0.04) but not in the treated groups. 

Conclusions: Pilocarpine-induced SE reduces LTP, in a thrombin PAR1 related mechanism. Elevation of serum NfL supports neuronal damage accompanying this functional abnormality which may be prevented by PAR1 pathway modulation.