title: The two-hit hypothesis for neuroinflammation: role of exogenous ATP in modulating inflammation in the brain.
abstract: Brain inflammation is a common occurrence following responses to varied insults such as bacterial infections, stroke, traumatic brain injury and neurodegenerative disorders. A common mediator for these varied inflammatory responses is prostaglandin E2 (PGE2), produced by the enzymatic activity of cyclooxygenases (COX) 1 and 2. Previous attempts to reduce neuronal inflammation through COX inhibition, by use of nonsteroidal anti-inflammatory drugs (NSAIDs), have met with limited success. We are proposing the two-hit model for neuronal injury-an initial localized inflammation mediated by PGE2 (first hit) and the simultaneous release of adenosine triphosphate (ATP) by injured cells (second hit), which significantly enhances the inflammatory response through increased synthesis of PGE2. Several evidences on the role of exogenous ATP in inflammation have been reported, including contrary instances where extracellular ATP reduces inflammatory events. In this review, we will examine the current literature on the role of P2 receptors, to which ATP binds, in modulating inflammatory reactions during neurodegeneration. Targeting the P2 receptors, therefore, provides a therapeutic alternative to reduce inflammation in the brain. P2 receptor-based anti-inflammatory drugs (PBAIDs) will retain the activities of essential COX enzymes, yet will significantly reduce neuroinflammation by decreasing the enhanced production of PGE2 by extracellular ATP.
authors.affiliation: Department of Psychiatry and Psychotherapy, Neurochemistry Research Laboratory, University of Freiburg Medical School Freiburg, Germany.
authors.forename: Bernd L
authors.initials: BL
authors.lastname: Fiebich
authors.affiliation: Neuroinflammation Research Laboratory, Faculty of Life Sciences and Biotechnology, South Asian University New Delhi, Delhi, India.
authors.forename: Shamima
authors.initials: S
authors.lastname: Akter
authors.affiliation: Neuroinflammation Research Laboratory, Faculty of Life Sciences and Biotechnology, South Asian University New Delhi, Delhi, India.
authors.forename: Ravi Shankar
authors.initials: RS
authors.lastname: Akundi
keywords: ATP; NSAIDs; P2 receptors; PBAIDs; microglia; neuroinflammation; prostaglandin E2