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The 1027th target candidate in stroke: Will NADPH oxidase hold up?

Radermacher KA, Wingler K, Kleikers P, Altenhöfer S, Jr Hermans J, Kleinschnitz C, Hhw Schmidt H - Exp Transl Stroke Med (2012)

Bottom Line: Oxidative stress is defined as an excess of reactive oxygen species (ROS) derived from different possible enzymatic sources.Among these, NADPH oxidases (NOX1-5) stand out as they represent the only known enzyme family that has no other function than to produce ROS.Based on data from different NOX knockout mouse models in ischemic stroke, the most relevant isoform appears to be NOX4.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmacology & Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands. h.schmidt@maastrichtuniversity.nl.

ABSTRACT
As recently reviewed, 1026 neuroprotective drug candidates in stroke research have all failed on their road towards validation and clinical translation, reasons being quality issues in preclinical research and publication bias. Quality control guidelines for preclinical stroke studies have now been established. However, sufficient understanding of the underlying mechanisms of neuronal death after stroke that could be possibly translated into new therapies is lacking. One exception is the hypothesis that cellular death is mediated by oxidative stress. Oxidative stress is defined as an excess of reactive oxygen species (ROS) derived from different possible enzymatic sources. Among these, NADPH oxidases (NOX1-5) stand out as they represent the only known enzyme family that has no other function than to produce ROS. Based on data from different NOX knockout mouse models in ischemic stroke, the most relevant isoform appears to be NOX4. Here we discuss the state-of-the-art of this target with respect to stroke and open questions that need to be addressed on the path towards clinical translation.

No MeSH data available.


Related in: MedlinePlus

Schematic overview of NADPH oxidases implicated in stroke. The blood–brain barrier (BBB) is formed by endothelial cells at the level of the cerebral capillaries. The figure shows a brain capillary in cross section, showing endothelial tight junctions and end-feet of astrocytes covering these capillaries. The figure also shows pericytes, neurons and microglial cells. Cerebral NOX activation and subsequent ROS generation contributes to BBB disruption, inflammation and postischemic neuronal injury.
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Figure 2: Schematic overview of NADPH oxidases implicated in stroke. The blood–brain barrier (BBB) is formed by endothelial cells at the level of the cerebral capillaries. The figure shows a brain capillary in cross section, showing endothelial tight junctions and end-feet of astrocytes covering these capillaries. The figure also shows pericytes, neurons and microglial cells. Cerebral NOX activation and subsequent ROS generation contributes to BBB disruption, inflammation and postischemic neuronal injury.

Mentions: The most studied isoform in stroke experiments is NOX2. After transient focal cerebral ischemia NOX2 protein levels were elevated, p47phox translocated to the membrane and ROS production increased [107]. These results show a potential role of NOX2 in stroke pathology (Figure 2). The spatiotemporal profile of NOX2 expression was studied in endothelin-1-induced stroke in conscious rats [108]. NOX2 mRNA was upregulated from 6 hours until 7 days post-stroke in the cortex and striatum. At 6 h post-stroke ROS production was found in neurons, and after 7 days in macrophages and microglia.


The 1027th target candidate in stroke: Will NADPH oxidase hold up?

Radermacher KA, Wingler K, Kleikers P, Altenhöfer S, Jr Hermans J, Kleinschnitz C, Hhw Schmidt H - Exp Transl Stroke Med (2012)

Schematic overview of NADPH oxidases implicated in stroke. The blood–brain barrier (BBB) is formed by endothelial cells at the level of the cerebral capillaries. The figure shows a brain capillary in cross section, showing endothelial tight junctions and end-feet of astrocytes covering these capillaries. The figure also shows pericytes, neurons and microglial cells. Cerebral NOX activation and subsequent ROS generation contributes to BBB disruption, inflammation and postischemic neuronal injury.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3403875&req=5

Figure 2: Schematic overview of NADPH oxidases implicated in stroke. The blood–brain barrier (BBB) is formed by endothelial cells at the level of the cerebral capillaries. The figure shows a brain capillary in cross section, showing endothelial tight junctions and end-feet of astrocytes covering these capillaries. The figure also shows pericytes, neurons and microglial cells. Cerebral NOX activation and subsequent ROS generation contributes to BBB disruption, inflammation and postischemic neuronal injury.
Mentions: The most studied isoform in stroke experiments is NOX2. After transient focal cerebral ischemia NOX2 protein levels were elevated, p47phox translocated to the membrane and ROS production increased [107]. These results show a potential role of NOX2 in stroke pathology (Figure 2). The spatiotemporal profile of NOX2 expression was studied in endothelin-1-induced stroke in conscious rats [108]. NOX2 mRNA was upregulated from 6 hours until 7 days post-stroke in the cortex and striatum. At 6 h post-stroke ROS production was found in neurons, and after 7 days in macrophages and microglia.

Bottom Line: Oxidative stress is defined as an excess of reactive oxygen species (ROS) derived from different possible enzymatic sources.Among these, NADPH oxidases (NOX1-5) stand out as they represent the only known enzyme family that has no other function than to produce ROS.Based on data from different NOX knockout mouse models in ischemic stroke, the most relevant isoform appears to be NOX4.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmacology & Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands. h.schmidt@maastrichtuniversity.nl.

ABSTRACT
As recently reviewed, 1026 neuroprotective drug candidates in stroke research have all failed on their road towards validation and clinical translation, reasons being quality issues in preclinical research and publication bias. Quality control guidelines for preclinical stroke studies have now been established. However, sufficient understanding of the underlying mechanisms of neuronal death after stroke that could be possibly translated into new therapies is lacking. One exception is the hypothesis that cellular death is mediated by oxidative stress. Oxidative stress is defined as an excess of reactive oxygen species (ROS) derived from different possible enzymatic sources. Among these, NADPH oxidases (NOX1-5) stand out as they represent the only known enzyme family that has no other function than to produce ROS. Based on data from different NOX knockout mouse models in ischemic stroke, the most relevant isoform appears to be NOX4. Here we discuss the state-of-the-art of this target with respect to stroke and open questions that need to be addressed on the path towards clinical translation.

No MeSH data available.


Related in: MedlinePlus