Treatment with CCR2 antagonist is neuroprotective but does not alter epileptogenesis in the pilocarpine rat model of epilepsy

Author(s)

Foresti, Maira Licia ^[1] ; Arisi, Gabriel Maisonnave ^[1] ; Campbell, James J. ^[2] ; Mello, Luiz E. ^{[1, 3]}

Affiliation

^[1] Univ Fed Sao Paulo, Physiol Dept, Rua Pedro Toledo 669, L3A, BR-04039032 Sao Paulo, SP - Brazil

^[2] ChemoCentryx Inc, Biol, 850 Maude Ave, Mountain View, CA 94043 - USA

^[3] Inst DOr Pesquisa & Ensino, Rua Diniz Cordeiro 30, BR-22281100 Botafogo, RJ - Brazil

• Document type: Journal article
• Source: Epilepsy & Behavior; v. 102, JAN 2020.
• Web of Science Citations: 0

Abstract

Neuroinflammation role on epileptogenesis has been the subject of increasing interest. Many studies showed elevation in cytokines and chemokines expression following seizures, such as, CCL2 protein (C-C motif ligand 2 chemokine) and its specific receptor, CCR2. In addition, recent studies manipulating the CCL2/CCR2 complex verified improved seizure outcome in different seizure models. In the present study, the effects of CCR2 antagonist was investigated using the pilocarpine rat model of epilepsy. Status epilepticus (SE) was induced by pilocarpine i. p. injection in adult rats. Daily oral treatment with CCR2 antagonist or vehicle was initiated 5 h following SE and lasted 5 or 10 days. Rats were euthanized 5 days after SE to evaluate neuronal damage and glial density or 30 days after SE to investigate spontaneous seizures development and seizure susceptibility to a second hit pentylenetetrazol (PTZ) test. Rats that received CCR2 antagonist presented less degenerating cells at hippocampal CA1 region. There was also a significant decrease in CA1 volume after SE that was not observed in treated rats. On the other hand, microglia cell density increased after SE regardless of CCR2 antagonist use. Treatment with CCR2 antagonist did not alter spontaneous seizure occurrence or later seizure susceptibility to PTZ in chronic rats. Additional rats were pretreated with CCR2 antagonist prior to SE induction, but this did not change SE progression. The data show that oral treatment with CCR2 antagonist is neuroprotective, but does not alter other epileptogenic factors, such as, neuroinflammation, or seizure development, after pilocarpine-induced SE in rats. (C) 2019 Elsevier Inc. All rights reserved. (AU)

• FAPESP's process: 16/08969-9 - Pharmacological manipulation of CCL2/CCR2 interaction on temporal lobe epilepsy genesis and development
• Grantee: Luiz Eugenio Araujo de Moraes Mello
• Support type: Regular Research Grants
• FAPESP's process: 15/11119-4 - Pharmacological manipulation of CCL2/CCR2 interaction on temporal lobe epilepsy genesis and development
• Grantee: Maira Licia Foresti
• Support type: Scholarships in Brazil - Post-Doctorate