Defining the therapeutic time window for suppressing the inflammatory prostaglandin E2 signaling after status epilepticus

ABSTRACT

Neuroinflammation is a common feature in nearly all neurological and some psychiatric disorders. Resembling its extraneural counterpart, neuroinflammation can be both beneficial and detrimental depending on the responding molecules. The overall effect of inflammation on disease progression is highly dependent on the extent of inflammatory mediator production and the duration of inflammatory induction. The time-dependent aspect of inflammatory responses suggests that the therapeutic time window for quelling neuroinflammation might vary with molecular targets and injury types. Therefore, it is important to define the therapeutic time window for anti-inflammatory therapeutics, as contradicting or negative results might arise when different treatment regimens are utilized even in similar animal models. Herein, we discuss a few critical factors that can help define the therapeutic time window and optimize treatment paradigm for suppressing the cyclooxygenase-2/prostaglandin-mediated inflammation after status epilepticus. These determinants should also be relevant to other anti-inflammatory therapeutic strategies for the CNS diseases.

KEYWORDS:

• Status epilepticus
• neuroinflammation
• neuronal injury
• epilepsy
• seizure
• cyclooxygenase
• prostaglandin
• cytokine
• interleukin
• therapeutic time window
• anti-inflammatory therapeutics

Financial & Competing Interests Disclosure

J. Jiang is supported by the National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS) grant R00NS082379 and NARSAD Young Investigator Grant 20,940 from the Brain & Behavior Research Foundation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key Issues

• Inflammation in the brain now is widely recognized as an important contributor to the pathophysiology of many neurological conditions, including status epilepticus.

• Many inflammation-associated genes are rapidly and persistently induced by status epilepticus with COX-2 and IL-1β induction temporally leading others, suggesting their dominant roles in seizure-promoted neuroinflammation.

• As the major prostaglandin product of COX-2 in the brain, PGE₂ plays a pivotal role in COX-2 cascade-mediated pathogenesis via its EP2 receptor subtype.

• Blockade of EP2 receptor by recently developed small-molecule antagonists provides a novel anti-inflammatory therapeutic strategy to treat status epilepticus.

• Inflammatory responses can also provide some beneficial effects in the brain, indicating that the therapeutic time windows for anti-inflammatory therapies need be defined to achieve adequate efficacy and avoid potential undesired effects.

• The therapeutic time windows are primarily determined by the target molecules and the pharmacokinetics and pharmacodynamics of the therapeutic agents; however, animal species and disease models are other potential contributory factors.

• Optimization of the treatment paradigm, i.e. dosage, time of first dose, dose number and duration, and dose interval, might yield improved therapeutic outcomes of anti-inflammatory therapeutics as well as increase the reproducibility of preclinical studies.

orcid

Jianxiong Jiang http://orcid.org/0000-0003-3955-8928