The two-hit hypothesis for neuroinflammation: role of exogenous ATP in modulating inflammation in the brain

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 cy...

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Bibliographic Details
Published in:Frontiers in cellular neuroscience 2014-09, Vol.8, p.260-260
Main Authors: Fiebich, Bernd L, Akter, Shamima, Akundi, Ravi Shankar
Format: Article
Language:English
Subjects:
Adenosine triphosphate
ATP
Bacterial infections
Brain research
Cytokines
Disease
Enzymatic activity
Enzymes
Gene expression
Infections
Inflammation
Ischemia
Kinases
Laboratories
Microglia
Neurodegeneration
Neurodegenerative diseases
Neuroinflammation
Neuroscience
Neurosciences
Nonsteroidal anti-inflammatory drugs
NSAIDs
P2 receptors
Prostaglandin E2
Purine P2 receptors
Traumatic brain injury
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Summary: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.
ISSN:1662-5102
1662-5102
DOI:10.3389/fncel.2014.00260