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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

P2 receptors modulate neuroinflammation. A simplified model based on the literature mentioned in this review summarizes the interactions between neurons and glial cells. Pro-inflammatory signals modulate P2X7-mediated release of IL-1β and surface expression of P2X4 receptors in the presence of ATP released by degenerating neurons and reactive astrocytes. On the surface of neurons, P2X7 receptors mediate apoptosis with caspase 3-dependent expression of P2X4 receptors as “flags” for microglial engulfment. Microglial migration to sites of insult is mediated by P2Y12 and adenosine A3 receptors and its neurophagic activity through P2Y6 receptors. While A1 adenosine receptors inhibit general inflammatory pathways, A2a receptors activate COX-2 as well as retract microglial processes. In healthy neurons, truncated P2X7 and P2Y2 receptors enhance α-secretase activity, preventing the formation of amyloid deposits. Amyloid formation is also immediately cleared through microglial phagocytosis, mediated by P2Y2 receptors; pinocytosis, through P2Y4 receptors; and activity of MMP-9, inhibited by the tonic activity of P2Y14 receptors.
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Figure 2: P2 receptors modulate neuroinflammation. A simplified model based on the literature mentioned in this review summarizes the interactions between neurons and glial cells. Pro-inflammatory signals modulate P2X7-mediated release of IL-1β and surface expression of P2X4 receptors in the presence of ATP released by degenerating neurons and reactive astrocytes. On the surface of neurons, P2X7 receptors mediate apoptosis with caspase 3-dependent expression of P2X4 receptors as “flags” for microglial engulfment. Microglial migration to sites of insult is mediated by P2Y12 and adenosine A3 receptors and its neurophagic activity through P2Y6 receptors. While A1 adenosine receptors inhibit general inflammatory pathways, A2a receptors activate COX-2 as well as retract microglial processes. In healthy neurons, truncated P2X7 and P2Y2 receptors enhance α-secretase activity, preventing the formation of amyloid deposits. Amyloid formation is also immediately cleared through microglial phagocytosis, mediated by P2Y2 receptors; pinocytosis, through P2Y4 receptors; and activity of MMP-9, inhibited by the tonic activity of P2Y14 receptors.

Mentions: Conventionally COX-2 has been a target in various inflammatory disorders. However, the failure of NSAIDs and selective enzyme inhibitors reveal the importance of COX-2 not only in various physiological activities but also in tissue repair following neuronal injury. The COX enzymes maintain a delicate balance of tissue scavenging and tissue repair during neuroinflammation. An imbalance could lead to excessive PGE2 activity leading to increased tissue damage or chronic inflammation. All cells within the vertebrate system upon damage (hit one) release large amounts of ATP (hit two) into the extracellular space. The effect of released ATP depends on the nature of two downstream factors—(1) the type of receptors present on cells within the vicinity of the injury; and (2) the distribution and activity of hydrolyzing ectonucleotidases. In large quantities, ATP potentiates the inflammatory reaction while other nucleotides have various modulatory roles in shaping the outcome of inflammation (summarized in Figure 2). PBAIDs aim to reduce the effect of second hit by targeting P2 receptors responsible for inflammation-enhancement rather than the COX enzymes mediating PGE2 synthesis. By not interfering with the COX system PBAIDs, unlike NSAIDs, retain the housekeeping functions of PGE2, but vastly reduce the pathology through P2 receptor inhibition. Identifying the target P2 receptor, and designing a selective PBAID, remains a challenge for future therapeutic successes in neuroinflammation. Surface expression of P2 receptors under certain pathological conditions may depend on epigenetic stimuli. Silenced P2 receptors which were once active during neural development could be reprogrammed in the event of tissue injury. A global study of P2 receptor density and mutations that affect their binding to specific nucleotides, may identify newer insights into the susceptibility of neurodegenerative disorders to specific populations. Furthermore, it is essential to understand the activity of various ectonucleotidases since the steady-state levels of various nucleotides have contrasting outcome in neuroinflammation. Therapeutically increasing the activity of specific ectonucleotidases following excessive ATP release is another approach to counter neuroinflammation. Finally, the two-hit hypothesis can also be extended to various other inflammatory disorders such as arthritis, toxin exposures including nerve gas poisoning, in the inflammatory model of cancer, and in psychological stress and depression. More studies in these areas will provide new roles for PBAIDs as effective anti-inflammatory drugs.


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)

P2 receptors modulate neuroinflammation. A simplified model based on the literature mentioned in this review summarizes the interactions between neurons and glial cells. Pro-inflammatory signals modulate P2X7-mediated release of IL-1β and surface expression of P2X4 receptors in the presence of ATP released by degenerating neurons and reactive astrocytes. On the surface of neurons, P2X7 receptors mediate apoptosis with caspase 3-dependent expression of P2X4 receptors as “flags” for microglial engulfment. Microglial migration to sites of insult is mediated by P2Y12 and adenosine A3 receptors and its neurophagic activity through P2Y6 receptors. While A1 adenosine receptors inhibit general inflammatory pathways, A2a receptors activate COX-2 as well as retract microglial processes. In healthy neurons, truncated P2X7 and P2Y2 receptors enhance α-secretase activity, preventing the formation of amyloid deposits. Amyloid formation is also immediately cleared through microglial phagocytosis, mediated by P2Y2 receptors; pinocytosis, through P2Y4 receptors; and activity of MMP-9, inhibited by the tonic activity of P2Y14 receptors.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: P2 receptors modulate neuroinflammation. A simplified model based on the literature mentioned in this review summarizes the interactions between neurons and glial cells. Pro-inflammatory signals modulate P2X7-mediated release of IL-1β and surface expression of P2X4 receptors in the presence of ATP released by degenerating neurons and reactive astrocytes. On the surface of neurons, P2X7 receptors mediate apoptosis with caspase 3-dependent expression of P2X4 receptors as “flags” for microglial engulfment. Microglial migration to sites of insult is mediated by P2Y12 and adenosine A3 receptors and its neurophagic activity through P2Y6 receptors. While A1 adenosine receptors inhibit general inflammatory pathways, A2a receptors activate COX-2 as well as retract microglial processes. In healthy neurons, truncated P2X7 and P2Y2 receptors enhance α-secretase activity, preventing the formation of amyloid deposits. Amyloid formation is also immediately cleared through microglial phagocytosis, mediated by P2Y2 receptors; pinocytosis, through P2Y4 receptors; and activity of MMP-9, inhibited by the tonic activity of P2Y14 receptors.
Mentions: Conventionally COX-2 has been a target in various inflammatory disorders. However, the failure of NSAIDs and selective enzyme inhibitors reveal the importance of COX-2 not only in various physiological activities but also in tissue repair following neuronal injury. The COX enzymes maintain a delicate balance of tissue scavenging and tissue repair during neuroinflammation. An imbalance could lead to excessive PGE2 activity leading to increased tissue damage or chronic inflammation. All cells within the vertebrate system upon damage (hit one) release large amounts of ATP (hit two) into the extracellular space. The effect of released ATP depends on the nature of two downstream factors—(1) the type of receptors present on cells within the vicinity of the injury; and (2) the distribution and activity of hydrolyzing ectonucleotidases. In large quantities, ATP potentiates the inflammatory reaction while other nucleotides have various modulatory roles in shaping the outcome of inflammation (summarized in Figure 2). PBAIDs aim to reduce the effect of second hit by targeting P2 receptors responsible for inflammation-enhancement rather than the COX enzymes mediating PGE2 synthesis. By not interfering with the COX system PBAIDs, unlike NSAIDs, retain the housekeeping functions of PGE2, but vastly reduce the pathology through P2 receptor inhibition. Identifying the target P2 receptor, and designing a selective PBAID, remains a challenge for future therapeutic successes in neuroinflammation. Surface expression of P2 receptors under certain pathological conditions may depend on epigenetic stimuli. Silenced P2 receptors which were once active during neural development could be reprogrammed in the event of tissue injury. A global study of P2 receptor density and mutations that affect their binding to specific nucleotides, may identify newer insights into the susceptibility of neurodegenerative disorders to specific populations. Furthermore, it is essential to understand the activity of various ectonucleotidases since the steady-state levels of various nucleotides have contrasting outcome in neuroinflammation. Therapeutically increasing the activity of specific ectonucleotidases following excessive ATP release is another approach to counter neuroinflammation. Finally, the two-hit hypothesis can also be extended to various other inflammatory disorders such as arthritis, toxin exposures including nerve gas poisoning, in the inflammatory model of cancer, and in psychological stress and depression. More studies in these areas will provide new roles for PBAIDs as effective anti-inflammatory drugs.

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