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The GR‐ANXA1 pathway is a pathological player and a candidate target in epilepsy
Author(s) -
Zub Emma,
Canet Geoffrey,
Garbelli Rita,
Blaquiere Marine,
Rossini Laura,
Pastori Chiara,
Sheikh Madeeha,
Reutelingsperger Chris,
Klement Wendy,
Bock Frederic,
Audinat Etienne,
Givalois Laurent,
Solito Egle,
Marchi Nicola
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201901596r
Subject(s) - epileptogenesis , epilepsy , annexin a1 , hippocampal sclerosis , status epilepticus , medicine , pathophysiology , inflammation , hippocampal formation , hippocampus , endocrinology , neuroscience , psychology , pathology , temporal lobe , annexin , staining
Immune changes occur in experimental and clinical epilepsy. Here, we tested the hypothesis that during epileptogenesis and spontaneous recurrent seizures (SRS) an impairment of the endogenous anti‐inflammatory pathway glucocorticoid receptor (GR)‐annexin A1 (ANXA1) occurs. By administrating exogenous ANXA1, we studied whether pharmacological potentiation of the anti‐inflammatory response modifies seizure activity and pathophysiology. We used an in vivo model of temporal lobe epilepsy based on intrahippocampal kainic acid (KA) injection. Video‐electroencephalography, molecular biology analyses on brain and peripheral blood samples, and pharmacological investigations were performed in this model. Human epileptic cortices presenting type II focal cortical dysplasia (IIa and b), hippocampi with or without hippocampal sclerosis (HS), and available controls were used to study ANXA1 expression. A decrease of phosphorylated (phospho‐) GR and phospho‐GR/tot‐GR protein expression occurred in the hippocampus during epileptogenesis. Downstream to GR, the anti‐inflammatory protein ANXA1 remained at baseline levels while inflammation installed and endured. In peripheral blood, ANXA1 and corticosterone levels showed no significant modifications during disease progression except for an early and transient increase poststatus epilepticus. These results indicate inadequate ANXA1 engagement over time and in these experimental conditions. By analyzing human brain specimens, we found that where significant inflammation exists, the pattern of ANXA1 immunoreactivity was abnormal because the typical perivascular ANXA1 immunoreactivity was reduced. We next asked whether potentiation of the endogenous anti‐inflammatory mechanism by ANXA1 administration modifies the disease pathophysiology. Although with varying efficacy, administration of exogenous ANXA1 somewhat reduced the time spent in seizure activity as compared to saline. These results indicate that the anti‐inflammatory GR‐ANXA1 pathway is defective during experimental seizure progression. The prospect of pharmacologically restoring or potentiating this endogenous anti‐inflammatory mechanism as an add‐on therapeutic strategy for specific forms of epilepsy is proposed.—Zub, E., Canet, G., Garbelli, R., Blaquiere, M., Rossini, L., Pastori, C., Sheikh, M., Reutelingsperger, C., Klement, W., de Bock, F., Audinat, E., Givalois, L., Solito, E., Marchi, N. The GR‐ANXA1 pathway is a pathological player and a candidate target in epilepsy. FASEB J. 33, 13998‐14009 (2019). www.fasebj.org