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NADPH Oxidase as a Therapeutic Target for Neuroprotection against Ischaemic Stroke: Future Perspectives.

McCann SK, Roulston CL - Brain Sci (2013)

Bottom Line: Unfortunately these improvements have not been successfully translated to the clinical setting.Targeting the source of oxidative stress may provide a superior therapeutic approach.The caution required when interpreting reports of positive outcomes after NADPH oxidase inhibition is also discussed, as effects on long term recovery are yet to be investigated and are likely to affect successful clinical translation.

View Article: PubMed Central - PubMed

Affiliation: Stroke Injury and Repair Team, O'Brien Institute, St Vincent's Hospital, 42 Fitzroy St, Fitzroy, Melbourne 3065, Australia. sarah.mccann@florey.edu.au.

ABSTRACT
Oxidative stress caused by an excess of reactive oxygen species (ROS) is known to contribute to stroke injury, particularly during reperfusion, and antioxidants targeting this process have resulted in improved outcomes experimentally. Unfortunately these improvements have not been successfully translated to the clinical setting. Targeting the source of oxidative stress may provide a superior therapeutic approach. The NADPH oxidases are a family of enzymes dedicated solely to ROS production and pre-clinical animal studies targeting NADPH oxidases have shown promising results. However there are multiple factors that need to be considered for future drug development: There are several homologues of the catalytic subunit of NADPH oxidase. All have differing physiological roles and may contribute differentially to oxidative damage after stroke. Additionally, the role of ROS in brain repair is largely unexplored, which should be taken into consideration when developing drugs that inhibit specific NADPH oxidases after injury. This article focuses on the current knowledge regarding NADPH oxidase after stroke including in vivo genetic and inhibitor studies. The caution required when interpreting reports of positive outcomes after NADPH oxidase inhibition is also discussed, as effects on long term recovery are yet to be investigated and are likely to affect successful clinical translation.

No MeSH data available.


Related in: MedlinePlus

Nox2 immunohistochemistry in the stroke affected cortex is associated with vascular sprouting, in addition to inflammatory cells, 7 days after stroke. Immunofluorescent images of von Willebrand factor labelled blood vessels (red; A,D) and Nox2 labelled cells (green; B,E) in the stroke affected cortex 7 days (A–C) and 28 days (B–E) after endothelin-1 induced stroke. Merged images (C,E) reveal angiogenic vessels at 7 days (C) are double labelled with Nox2, suggesting a role for Nox2 in vascular sprouting, an effect that is no longer present 28 days after stroke (E), once vessels have matured. Scale = 100 µm.
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brainsci-03-00561-f003: Nox2 immunohistochemistry in the stroke affected cortex is associated with vascular sprouting, in addition to inflammatory cells, 7 days after stroke. Immunofluorescent images of von Willebrand factor labelled blood vessels (red; A,D) and Nox2 labelled cells (green; B,E) in the stroke affected cortex 7 days (A–C) and 28 days (B–E) after endothelin-1 induced stroke. Merged images (C,E) reveal angiogenic vessels at 7 days (C) are double labelled with Nox2, suggesting a role for Nox2 in vascular sprouting, an effect that is no longer present 28 days after stroke (E), once vessels have matured. Scale = 100 µm.

Mentions: VEGF is a key angiogenic growth factor and stimulates the proliferation and migration of endothelial cells, primarily through VEGF receptor type2 (VEGFR2) [192]. Ischaemia/hypoxia stimulates VEGF and HIF-1 up-regulation through ROS signaling, and binding of VEGF to VEGFR2 stimulates ROS production via activation of NADPH oxidase. In this highly interdependent pathway, the resulting ROS can negatively regulate VEGFR2 [191]. While high concentrations of NADPH oxidase-derived ROS in the acute phase of stroke contribute to oxidative stress and may cause cell death, low levels of ROS, localised intracellularly, function as signaling molecules to mediate angiogenic endothelial cell proliferation and migration in the sub-acute phase of stroke. In the human brain, angiogenesis develops in the penumbra three to four days after stroke [188], and survival time post stroke correlates with the degree of angiogenesis in the damaged tissue [193]. Angiogenesis also occurs in the rodent brain after experimental cerebral ischaemia, initiated in the ischaemic boundary [194]. Using 0.5 h of MCAo in a mouse model of stroke, Hayashi et al. [195] reported that proliferating endothelial cells increased as early as one day after stroke and by three days the number of vessels had significantly increased, indicating that angiogenesis begins almost immediately after injury. There is evidence suggesting that Nox1, Nox2, Nox4 and Nox5-derived ROS act as major effectors of pro-angiogenic stimuli (e.g., growth factors, hypoxia) [29]. Nox2-derived ROS have been shown to have an important role in angiogenesis in response to hindlimb ischaemia in the mouse; Nox2 gene deletion results in clear impairment of angiogenesis [196,197]. While angiogenesis is shown to be compromised in Nox2-deficient mice, it is not eliminated. Vallet et al. [18] were the first to demonstrate that Nox4, co-localised with new capillaries, was maximally elevated between 7 and 15 days post-stroke in mice, and Nox4 has been shown to positively regulate angiogenic activities in vitro [198]. We have reported that Nox4 is also up-regulated in the damaged rat brain in the weeks after stroke, in addition to up-regulation of Nox2 and the most important pro-angiogenic factor, VEGF [199]. Importantly, we have recently shown that Nox2 is co-localised to proliferating blood vessels during angiogenesis 7 days after stroke, an effect no longer detected once new blood vessels have formed (Figure 3, [200]).


NADPH Oxidase as a Therapeutic Target for Neuroprotection against Ischaemic Stroke: Future Perspectives.

McCann SK, Roulston CL - Brain Sci (2013)

Nox2 immunohistochemistry in the stroke affected cortex is associated with vascular sprouting, in addition to inflammatory cells, 7 days after stroke. Immunofluorescent images of von Willebrand factor labelled blood vessels (red; A,D) and Nox2 labelled cells (green; B,E) in the stroke affected cortex 7 days (A–C) and 28 days (B–E) after endothelin-1 induced stroke. Merged images (C,E) reveal angiogenic vessels at 7 days (C) are double labelled with Nox2, suggesting a role for Nox2 in vascular sprouting, an effect that is no longer present 28 days after stroke (E), once vessels have matured. Scale = 100 µm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4061864&req=5

brainsci-03-00561-f003: Nox2 immunohistochemistry in the stroke affected cortex is associated with vascular sprouting, in addition to inflammatory cells, 7 days after stroke. Immunofluorescent images of von Willebrand factor labelled blood vessels (red; A,D) and Nox2 labelled cells (green; B,E) in the stroke affected cortex 7 days (A–C) and 28 days (B–E) after endothelin-1 induced stroke. Merged images (C,E) reveal angiogenic vessels at 7 days (C) are double labelled with Nox2, suggesting a role for Nox2 in vascular sprouting, an effect that is no longer present 28 days after stroke (E), once vessels have matured. Scale = 100 µm.
Mentions: VEGF is a key angiogenic growth factor and stimulates the proliferation and migration of endothelial cells, primarily through VEGF receptor type2 (VEGFR2) [192]. Ischaemia/hypoxia stimulates VEGF and HIF-1 up-regulation through ROS signaling, and binding of VEGF to VEGFR2 stimulates ROS production via activation of NADPH oxidase. In this highly interdependent pathway, the resulting ROS can negatively regulate VEGFR2 [191]. While high concentrations of NADPH oxidase-derived ROS in the acute phase of stroke contribute to oxidative stress and may cause cell death, low levels of ROS, localised intracellularly, function as signaling molecules to mediate angiogenic endothelial cell proliferation and migration in the sub-acute phase of stroke. In the human brain, angiogenesis develops in the penumbra three to four days after stroke [188], and survival time post stroke correlates with the degree of angiogenesis in the damaged tissue [193]. Angiogenesis also occurs in the rodent brain after experimental cerebral ischaemia, initiated in the ischaemic boundary [194]. Using 0.5 h of MCAo in a mouse model of stroke, Hayashi et al. [195] reported that proliferating endothelial cells increased as early as one day after stroke and by three days the number of vessels had significantly increased, indicating that angiogenesis begins almost immediately after injury. There is evidence suggesting that Nox1, Nox2, Nox4 and Nox5-derived ROS act as major effectors of pro-angiogenic stimuli (e.g., growth factors, hypoxia) [29]. Nox2-derived ROS have been shown to have an important role in angiogenesis in response to hindlimb ischaemia in the mouse; Nox2 gene deletion results in clear impairment of angiogenesis [196,197]. While angiogenesis is shown to be compromised in Nox2-deficient mice, it is not eliminated. Vallet et al. [18] were the first to demonstrate that Nox4, co-localised with new capillaries, was maximally elevated between 7 and 15 days post-stroke in mice, and Nox4 has been shown to positively regulate angiogenic activities in vitro [198]. We have reported that Nox4 is also up-regulated in the damaged rat brain in the weeks after stroke, in addition to up-regulation of Nox2 and the most important pro-angiogenic factor, VEGF [199]. Importantly, we have recently shown that Nox2 is co-localised to proliferating blood vessels during angiogenesis 7 days after stroke, an effect no longer detected once new blood vessels have formed (Figure 3, [200]).

Bottom Line: Unfortunately these improvements have not been successfully translated to the clinical setting.Targeting the source of oxidative stress may provide a superior therapeutic approach.The caution required when interpreting reports of positive outcomes after NADPH oxidase inhibition is also discussed, as effects on long term recovery are yet to be investigated and are likely to affect successful clinical translation.

View Article: PubMed Central - PubMed

Affiliation: Stroke Injury and Repair Team, O'Brien Institute, St Vincent's Hospital, 42 Fitzroy St, Fitzroy, Melbourne 3065, Australia. sarah.mccann@florey.edu.au.

ABSTRACT
Oxidative stress caused by an excess of reactive oxygen species (ROS) is known to contribute to stroke injury, particularly during reperfusion, and antioxidants targeting this process have resulted in improved outcomes experimentally. Unfortunately these improvements have not been successfully translated to the clinical setting. Targeting the source of oxidative stress may provide a superior therapeutic approach. The NADPH oxidases are a family of enzymes dedicated solely to ROS production and pre-clinical animal studies targeting NADPH oxidases have shown promising results. However there are multiple factors that need to be considered for future drug development: There are several homologues of the catalytic subunit of NADPH oxidase. All have differing physiological roles and may contribute differentially to oxidative damage after stroke. Additionally, the role of ROS in brain repair is largely unexplored, which should be taken into consideration when developing drugs that inhibit specific NADPH oxidases after injury. This article focuses on the current knowledge regarding NADPH oxidase after stroke including in vivo genetic and inhibitor studies. The caution required when interpreting reports of positive outcomes after NADPH oxidase inhibition is also discussed, as effects on long term recovery are yet to be investigated and are likely to affect successful clinical translation.

No MeSH data available.


Related in: MedlinePlus