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Neuroinflammation and J2 prostaglandins: linking impairment of the ubiquitin-proteasome pathway and mitochondria to neurodegeneration.

Figueiredo-Pereira ME, Rockwell P, Schmidt-Glenewinkel T, Serrano P - Front Mol Neurosci (2015)

Bottom Line: J2 prostaglandins are endogenous toxic products of cyclooxygenases, and because their levels are significantly increased upon brain injury, they are actively involved in neuronal dysfunction induced by pro-inflammatory stimuli.We conclude by discussing the therapeutic potential of targeting the J2 prostaglandin pathway to prevent/delay neurodegeneration associated with neuroinflammation.In this context, we suggest a shift from the traditional view that cyclooxygenases are the most appropriate targets to treat neuroinflammation, to the notion that J2 prostaglandin pathways and other neurotoxic prostaglandins downstream from cyclooxygenases, would offer significant benefits as more effective therapeutic targets to treat chronic neurodegenerative diseases, while minimizing adverse side effects.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, Hunter College, The Graduate School and University Center, City University of New York New York, NY, USA.

ABSTRACT
The immune response of the CNS is a defense mechanism activated upon injury to initiate repair mechanisms while chronic over-activation of the CNS immune system (termed neuroinflammation) may exacerbate injury. The latter is implicated in a variety of neurological and neurodegenerative disorders such as Alzheimer and Parkinson diseases, amyotrophic lateral sclerosis, multiple sclerosis, traumatic brain injury, HIV dementia, and prion diseases. Cyclooxygenases (COX-1 and COX-2), which are key enzymes in the conversion of arachidonic acid into bioactive prostanoids, play a central role in the inflammatory cascade. J2 prostaglandins are endogenous toxic products of cyclooxygenases, and because their levels are significantly increased upon brain injury, they are actively involved in neuronal dysfunction induced by pro-inflammatory stimuli. In this review, we highlight the mechanisms by which J2 prostaglandins (1) exert their actions, (2) potentially contribute to the transition from acute to chronic inflammation and to the spreading of neuropathology, (3) disturb the ubiquitin-proteasome pathway and mitochondrial function, and (4) contribute to neurodegenerative disorders such as Alzheimer and Parkinson diseases, and amyotrophic lateral sclerosis, as well as stroke, traumatic brain injury (TBI), and demyelination in Krabbe disease. We conclude by discussing the therapeutic potential of targeting the J2 prostaglandin pathway to prevent/delay neurodegeneration associated with neuroinflammation. In this context, we suggest a shift from the traditional view that cyclooxygenases are the most appropriate targets to treat neuroinflammation, to the notion that J2 prostaglandin pathways and other neurotoxic prostaglandins downstream from cyclooxygenases, would offer significant benefits as more effective therapeutic targets to treat chronic neurodegenerative diseases, while minimizing adverse side effects.

No MeSH data available.


Related in: MedlinePlus

J2 prostaglandins target the ubiquitin proteasome pathway (UPP) and mitochondria. J2 prostaglandins affect the UPP by: (1) impairing the 26S proteasome by inducing oxidation of proteasome subunits, or promoting its disassembly, (2) inhibiting de-ubiquitinating enzymes (DUBs), and (3) covalently modifying specific active site cysteines on UPP components such as E1 activating enzymes, E2 conjugating enzymes, and some E3 ligases. J2 prostaglandins can also inhibit mitochondrial function by: (1) inhibiting NADH-ubiquinone reductase in complex I, (2) reducing membrane potential, (3) blocking fission, and (4) inducing the generation of reactive oxygen species (ROS) and apoptosis.
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Figure 7: J2 prostaglandins target the ubiquitin proteasome pathway (UPP) and mitochondria. J2 prostaglandins affect the UPP by: (1) impairing the 26S proteasome by inducing oxidation of proteasome subunits, or promoting its disassembly, (2) inhibiting de-ubiquitinating enzymes (DUBs), and (3) covalently modifying specific active site cysteines on UPP components such as E1 activating enzymes, E2 conjugating enzymes, and some E3 ligases. J2 prostaglandins can also inhibit mitochondrial function by: (1) inhibiting NADH-ubiquinone reductase in complex I, (2) reducing membrane potential, (3) blocking fission, and (4) inducing the generation of reactive oxygen species (ROS) and apoptosis.

Mentions: COX-2 neurotoxicity seems to be mediated by PGD2 but not by PGE2 (Liang et al., 2005). PGD2 is the most abundant prostaglandin in the brain (Abdel-Halim et al., 1977; Narumiya et al., 1982; Hertting and Seregi, 1989). For example, in young rats (16–18 post-natal) subjected to a 12-min asphyxial cardiac arrest, the brain levels of PGE2 assessed by UPLC–MS/MS were ~35.5 pmol/g of tissue, while those of PGD2 were at least 26 fold higher, reaching ~937 pmol/g of tissue (Shaik et al., 2014). PGD2 elicits its cytotoxicity via its bioactive metabolites J2 prostaglandins (Liu et al., 2013b). In contrast to other reviews (Musiek et al., 2005; Uchida and Shibata, 2008; Scher and Pillinger, 2009; Surh et al., 2011; Oeste and Perez-Sala, 2014), our review addresses in detail the effects of J2 prostaglandins on two targets that play key roles in the neurodegenerative process, namely, the ubiquitin-proteasome pathway and mitochondrial function (Figure 7).


Neuroinflammation and J2 prostaglandins: linking impairment of the ubiquitin-proteasome pathway and mitochondria to neurodegeneration.

Figueiredo-Pereira ME, Rockwell P, Schmidt-Glenewinkel T, Serrano P - Front Mol Neurosci (2015)

J2 prostaglandins target the ubiquitin proteasome pathway (UPP) and mitochondria. J2 prostaglandins affect the UPP by: (1) impairing the 26S proteasome by inducing oxidation of proteasome subunits, or promoting its disassembly, (2) inhibiting de-ubiquitinating enzymes (DUBs), and (3) covalently modifying specific active site cysteines on UPP components such as E1 activating enzymes, E2 conjugating enzymes, and some E3 ligases. J2 prostaglandins can also inhibit mitochondrial function by: (1) inhibiting NADH-ubiquinone reductase in complex I, (2) reducing membrane potential, (3) blocking fission, and (4) inducing the generation of reactive oxygen species (ROS) and apoptosis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4292445&req=5

Figure 7: J2 prostaglandins target the ubiquitin proteasome pathway (UPP) and mitochondria. J2 prostaglandins affect the UPP by: (1) impairing the 26S proteasome by inducing oxidation of proteasome subunits, or promoting its disassembly, (2) inhibiting de-ubiquitinating enzymes (DUBs), and (3) covalently modifying specific active site cysteines on UPP components such as E1 activating enzymes, E2 conjugating enzymes, and some E3 ligases. J2 prostaglandins can also inhibit mitochondrial function by: (1) inhibiting NADH-ubiquinone reductase in complex I, (2) reducing membrane potential, (3) blocking fission, and (4) inducing the generation of reactive oxygen species (ROS) and apoptosis.
Mentions: COX-2 neurotoxicity seems to be mediated by PGD2 but not by PGE2 (Liang et al., 2005). PGD2 is the most abundant prostaglandin in the brain (Abdel-Halim et al., 1977; Narumiya et al., 1982; Hertting and Seregi, 1989). For example, in young rats (16–18 post-natal) subjected to a 12-min asphyxial cardiac arrest, the brain levels of PGE2 assessed by UPLC–MS/MS were ~35.5 pmol/g of tissue, while those of PGD2 were at least 26 fold higher, reaching ~937 pmol/g of tissue (Shaik et al., 2014). PGD2 elicits its cytotoxicity via its bioactive metabolites J2 prostaglandins (Liu et al., 2013b). In contrast to other reviews (Musiek et al., 2005; Uchida and Shibata, 2008; Scher and Pillinger, 2009; Surh et al., 2011; Oeste and Perez-Sala, 2014), our review addresses in detail the effects of J2 prostaglandins on two targets that play key roles in the neurodegenerative process, namely, the ubiquitin-proteasome pathway and mitochondrial function (Figure 7).

Bottom Line: J2 prostaglandins are endogenous toxic products of cyclooxygenases, and because their levels are significantly increased upon brain injury, they are actively involved in neuronal dysfunction induced by pro-inflammatory stimuli.We conclude by discussing the therapeutic potential of targeting the J2 prostaglandin pathway to prevent/delay neurodegeneration associated with neuroinflammation.In this context, we suggest a shift from the traditional view that cyclooxygenases are the most appropriate targets to treat neuroinflammation, to the notion that J2 prostaglandin pathways and other neurotoxic prostaglandins downstream from cyclooxygenases, would offer significant benefits as more effective therapeutic targets to treat chronic neurodegenerative diseases, while minimizing adverse side effects.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, Hunter College, The Graduate School and University Center, City University of New York New York, NY, USA.

ABSTRACT
The immune response of the CNS is a defense mechanism activated upon injury to initiate repair mechanisms while chronic over-activation of the CNS immune system (termed neuroinflammation) may exacerbate injury. The latter is implicated in a variety of neurological and neurodegenerative disorders such as Alzheimer and Parkinson diseases, amyotrophic lateral sclerosis, multiple sclerosis, traumatic brain injury, HIV dementia, and prion diseases. Cyclooxygenases (COX-1 and COX-2), which are key enzymes in the conversion of arachidonic acid into bioactive prostanoids, play a central role in the inflammatory cascade. J2 prostaglandins are endogenous toxic products of cyclooxygenases, and because their levels are significantly increased upon brain injury, they are actively involved in neuronal dysfunction induced by pro-inflammatory stimuli. In this review, we highlight the mechanisms by which J2 prostaglandins (1) exert their actions, (2) potentially contribute to the transition from acute to chronic inflammation and to the spreading of neuropathology, (3) disturb the ubiquitin-proteasome pathway and mitochondrial function, and (4) contribute to neurodegenerative disorders such as Alzheimer and Parkinson diseases, and amyotrophic lateral sclerosis, as well as stroke, traumatic brain injury (TBI), and demyelination in Krabbe disease. We conclude by discussing the therapeutic potential of targeting the J2 prostaglandin pathway to prevent/delay neurodegeneration associated with neuroinflammation. In this context, we suggest a shift from the traditional view that cyclooxygenases are the most appropriate targets to treat neuroinflammation, to the notion that J2 prostaglandin pathways and other neurotoxic prostaglandins downstream from cyclooxygenases, would offer significant benefits as more effective therapeutic targets to treat chronic neurodegenerative diseases, while minimizing adverse side effects.

No MeSH data available.


Related in: MedlinePlus