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

Fiebich BL, Akter S, Akundi RS - Front Cell Neurosci (2014)

Bottom Line: Previous attempts to reduce neuronal inflammation through COX inhibition, by use of nonsteroidal anti-inflammatory drugs (NSAIDs), have met with limited success.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Psychotherapy, Neurochemistry Research Laboratory, University of Freiburg Medical School Freiburg, Germany.

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.

No MeSH data available.


Related in: MedlinePlus

The two-hit model of neuroinflammation. The ATP-mediated enhancement of neuroinflammation can be explained through the two-hit model. A variety of insults, such as bacterial LPS, various cytokines, or amyloid peptides, can act as the first hit, resulting in microglial activation, COX-2 induction and PGE2 release. The second hit, following neuronal injury, death or persistent glial cell activation, results in the release of ATP, which acts on both neuronal and glial P2 receptors, leading to enhanced microglial PGE2 release. NSAIDs target COX enzymes affecting the housekeeping roles of PGE2. ATP potentiates the effects of first hit multi-fold, and thus, would be the most relevant target for therapeutic intervention. By acting on P2 receptors, PBAIDs are believed to reduce PGE2 to pre-inflammatory levels without affecting the activity of COX enzymes.
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Figure 1: The two-hit model of neuroinflammation. The ATP-mediated enhancement of neuroinflammation can be explained through the two-hit model. A variety of insults, such as bacterial LPS, various cytokines, or amyloid peptides, can act as the first hit, resulting in microglial activation, COX-2 induction and PGE2 release. The second hit, following neuronal injury, death or persistent glial cell activation, results in the release of ATP, which acts on both neuronal and glial P2 receptors, leading to enhanced microglial PGE2 release. NSAIDs target COX enzymes affecting the housekeeping roles of PGE2. ATP potentiates the effects of first hit multi-fold, and thus, would be the most relevant target for therapeutic intervention. By acting on P2 receptors, PBAIDs are believed to reduce PGE2 to pre-inflammatory levels without affecting the activity of COX enzymes.

Mentions: An interesting observation in the past decade and half showed that the inflammatory response of microglia—the release of mature IL-1β from lipopolysaccharide (LPS)-primed cells—could be significantly modulated with the addition of exogenous adenosine triphosphate (ATP; Ferrari et al., 1997). More diversified studies showed that ATP is able to mediate the release of PGE2 in IL-1β-treated astrocytes (Xu et al., 2003) or in LPS-activated macrophages (Barberà-Cremades et al., 2012). We found a similar synergistic effect of ATP on LPS-mediated PGE2 release in primary rat microglial cells (unpublished observation). These studies conclusively showed that exogenous ATP significantly modulates inflammation. In this review, we are proposing the two-hit model for neuroinflammation. The first hit is the injury itself—nerve injury, bacterial infections, hypoxia-ischemia, autoimmune reactions or proteopathies associated with neurodegeneration—leading to the activation of glial cells (Figure 1). The second hit is the release of large pools of cytosolic ATP from damaged neurons into the extracellular milieu, in response to direct injury or following glial cell activation. This excess ATP, despite mechanisms regulating their concentration outside the cell, activates a wide variety of purinergic receptors present on cells in the vicinity, thus modulating glial activity and neuronal response to inflammation. Such a model was earlier proposed for the release of mature IL-1β following bacterial infections (Ferrari et al., 2006). Identifying the pro-inflammatory receptors of ATP, and targeting them pharmacologically, will significantly diminish the dramatic release of prostanoids and cytokines to clinically manageable levels; thus, balancing their functional roles in active defence and tissue repair.


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

Fiebich BL, Akter S, Akundi RS - Front Cell Neurosci (2014)

The two-hit model of neuroinflammation. The ATP-mediated enhancement of neuroinflammation can be explained through the two-hit model. A variety of insults, such as bacterial LPS, various cytokines, or amyloid peptides, can act as the first hit, resulting in microglial activation, COX-2 induction and PGE2 release. The second hit, following neuronal injury, death or persistent glial cell activation, results in the release of ATP, which acts on both neuronal and glial P2 receptors, leading to enhanced microglial PGE2 release. NSAIDs target COX enzymes affecting the housekeeping roles of PGE2. ATP potentiates the effects of first hit multi-fold, and thus, would be the most relevant target for therapeutic intervention. By acting on P2 receptors, PBAIDs are believed to reduce PGE2 to pre-inflammatory levels without affecting the activity of COX enzymes.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4150257&req=5

Figure 1: The two-hit model of neuroinflammation. The ATP-mediated enhancement of neuroinflammation can be explained through the two-hit model. A variety of insults, such as bacterial LPS, various cytokines, or amyloid peptides, can act as the first hit, resulting in microglial activation, COX-2 induction and PGE2 release. The second hit, following neuronal injury, death or persistent glial cell activation, results in the release of ATP, which acts on both neuronal and glial P2 receptors, leading to enhanced microglial PGE2 release. NSAIDs target COX enzymes affecting the housekeeping roles of PGE2. ATP potentiates the effects of first hit multi-fold, and thus, would be the most relevant target for therapeutic intervention. By acting on P2 receptors, PBAIDs are believed to reduce PGE2 to pre-inflammatory levels without affecting the activity of COX enzymes.
Mentions: An interesting observation in the past decade and half showed that the inflammatory response of microglia—the release of mature IL-1β from lipopolysaccharide (LPS)-primed cells—could be significantly modulated with the addition of exogenous adenosine triphosphate (ATP; Ferrari et al., 1997). More diversified studies showed that ATP is able to mediate the release of PGE2 in IL-1β-treated astrocytes (Xu et al., 2003) or in LPS-activated macrophages (Barberà-Cremades et al., 2012). We found a similar synergistic effect of ATP on LPS-mediated PGE2 release in primary rat microglial cells (unpublished observation). These studies conclusively showed that exogenous ATP significantly modulates inflammation. In this review, we are proposing the two-hit model for neuroinflammation. The first hit is the injury itself—nerve injury, bacterial infections, hypoxia-ischemia, autoimmune reactions or proteopathies associated with neurodegeneration—leading to the activation of glial cells (Figure 1). The second hit is the release of large pools of cytosolic ATP from damaged neurons into the extracellular milieu, in response to direct injury or following glial cell activation. This excess ATP, despite mechanisms regulating their concentration outside the cell, activates a wide variety of purinergic receptors present on cells in the vicinity, thus modulating glial activity and neuronal response to inflammation. Such a model was earlier proposed for the release of mature IL-1β following bacterial infections (Ferrari et al., 2006). Identifying the pro-inflammatory receptors of ATP, and targeting them pharmacologically, will significantly diminish the dramatic release of prostanoids and cytokines to clinically manageable levels; thus, balancing their functional roles in active defence and tissue repair.

Bottom Line: Previous attempts to reduce neuronal inflammation through COX inhibition, by use of nonsteroidal anti-inflammatory drugs (NSAIDs), have met with limited success.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Psychotherapy, Neurochemistry Research Laboratory, University of Freiburg Medical School Freiburg, Germany.

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.

No MeSH data available.


Related in: MedlinePlus