# Experimental status epilepticus, COX-2 and BDNF: Connecting the dots

Nicola Marchi

► To cite this version:

Nicola Marchi. Experimental status epilepticus, COX-2 and BDNF: Connecting the dots. Epilepsia Open, 2021, 6 (3), pp.466-467. 10.1002/epi4.12501 . hal-04724152

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# Experimental status epilepticus, COX-2 and BDNF: Connecting the dots

Nicola Marchi ID

Cerebrovascular and Glia Research, Institut de Génomique Fonctionnelle (University of Montpellier, CNRS UMR5203, INSERM U1191), Montpellier, France

**Correspondence:** Nicola Marchi, Cerebrovascular and Glia Research, Institut de Génomique Fonctionnelle (University of Montpellier, CNRS UMR5203, INSERM U1191), 141 rue de la Cardonille, 34094 Montpellier, Cedex 5, France.
Email: nicola.marchi@igf.cnrs.fr

Brain and peripheral inflammation and immune pathways play distinct roles in a variety of epilepsies. Disease modification(s) and reduction in seizure burden by targeting specific pro-inflammatory mediators have represented a demanding and controversial quest.¹⁻³ Within this realm, the inducible cyclooxygenase-2 (COX-2) and brain-derived neurotrophic factor (BDNF), and their signaling cascades, were proposed as relevant candidate entry points in central nervous system (CNS) disorders.²,⁴⁻⁶ COX-2 is upstream to, and controls, a broad inflammatory pathway leading to the production of prostaglandin E2 (PGE2). As COX-2 brain expression increases during seizures, the effectiveness of COX-2 inhibitors has been tested with varying outcomes.²

Here, Yu and Jiang have outlined previously missing links and the temporal dynamics of COX-2 and BDNF expression in the hippocampus in response to status epilepticus (SE).⁷ To avoid possible model-specific biases, they elicited experimental SE by injecting either KA or pilocarpine in rodents. With a panel of molecular biology tools, they showed that, in the hippocampus, the induction of COX-2 temporally preceded that of BDNF and that blocking COX-2 activity with a specific inhibitor (SC-58125) prevented the BDNF surge post-SE. Next, in proceeding to validate their hypothesis: i) They found that PGE2, a key COX-2 product, was sufficient to promote BDNF secretion from hippocampal cells; and ii) they targeted the PGE2 receptor EP2 by using a selective, brain-permeable antagonist (TG6-10-1) that subsequently decreased downstream BDNF and TrkB (BDNF receptor) signaling in the hippocampus post-SE. From these data, they conclude that, after experimental SE, COX-2 controls BDNF/

TrkB signaling via PGE₂/EP2. Because the EP2 antagonist TG6-10-1 reduced BDNF/TrkB signaling, the authors propose this pharmacological strategy to limit the inflammatory pathophysiology typical of post-SE in these models.

These results support the general concept that an early and targeted pharmacological intervention after an acute brain insult (here SE⁸) may curb the pathological sequel over time, here epileptogenesis leading to spontaneous seizures. Because of the post-SE rapidly evolving pathophysiological traits, identifying or targeting a specific culprit is challenging, particularly when it comes to inflammation and the varying, even contrasting, roles that specific cell types or soluble factors may have as a function of time, brain regions, and tissue lesion. Furthermore, when considering specific factors and their receptors, the extent of supra-threshold stimulation(s) should be considered. Thus, the activation of BDNF is required for a variety of physiological processes including learning and memory,⁹ while an excessive BDNF/TrkB interplay, or activation, plays a pathological role in certain brain diseases including epilepsies.⁴ These delicate and varying equilibriums need to be controlled when planning the ensuing large-scale (pre)clinical trials and in case of clinical applications, along with a methodical examination of systemic and brain unwanted side effects associated with pro- or anti-inflammatory modifications or adaptations.¹,¹⁰⁻¹²

In conclusion, this work connects COX-2 activation to BDNF/TrkB and PGE2/EP2 in the hippocampus after experimental SE. The authors propose the use of a brain-permeable antagonist as a strategy to suppress the abnormal BDNF/TrkB activity with a hypothesized preclinical application to post-insult settings.
Read the winning article—https://doi.org/10.1002/epi4.12409

## ACKNOWLEDGMENTS

None.

## CONFLICTS OF INTEREST

I have no conflicts to disclose. I confirm that I have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

## ORCID

Nicola Marchi https://orcid.org/0000-0001-9124-0226

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**How to cite this article:** Marchi N. Experimental status epilepticus, COX-2 and BDNF: Connecting the dots. *Epilepsia Open*. 2021;6:466–467. https://doi.org/10.1002/epi4.12501