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Role of PPARs in Radiation-Induced Brain Injury.

Ramanan S, Zhao W, Riddle DR, Robbins ME - PPAR Res (2009)

Bottom Line: At present, there are no proven long-term treatments or preventive strategies for this significant radiation-induced late effect.Peroxisomal proliferator-activated receptors (PPARs) are ligand-activated transcription factors that belong to the steroid/thyroid hormone nuclear receptor superfamily.PPAR agonists have been shown to cross the blood-brain barrier and confer neuroprotection in animal models of CNS disorders such as stroke, multiple sclerosis and Parkinson's disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Cancer Biology, Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.

ABSTRACT
Whole-brain irradiation (WBI) represents the primary mode of treatment for brain metastases; about 200 000 patients receive WBI each year in the USA. Up to 50% of adult and 100% of pediatric brain cancer patients who survive >6 months post-WBI will suffer from a progressive, cognitive impairment. At present, there are no proven long-term treatments or preventive strategies for this significant radiation-induced late effect. Recent studies suggest that the pathogenesis of radiation-induced brain injury involves WBI-mediated increases in oxidative stress and/or inflammatory responses in the brain. Therefore, anti-inflammatory strategies can be employed to modulate radiation-induced brain injury. Peroxisomal proliferator-activated receptors (PPARs) are ligand-activated transcription factors that belong to the steroid/thyroid hormone nuclear receptor superfamily. Although traditionally known to play a role in metabolism, increasing evidence suggests a role for PPARs in regulating the response to inflammation and oxidative injury. PPAR agonists have been shown to cross the blood-brain barrier and confer neuroprotection in animal models of CNS disorders such as stroke, multiple sclerosis and Parkinson's disease. However, the role of PPARs in radiation-induced brain injury is unclear. In this manuscript, we review the current knowledge and the emerging insights about the role of PPARs in modulating radiation-induced brain injury.

No MeSH data available.


Related in: MedlinePlus

Model for the role of PPARs in radiation-induced brain injury. Irradiation is hypothesized to modify the brain microenvironment via the generation of an inflammatory and/or oxidative stress response which is also characterized by increased cell death of the neural precursor cells residing in the neurogenic regions of the brain. This alteration in the microenvironment is proposed to play a role in the dysfunction of the various cell-types in the brain (e.g., astrocytes, endothelial cells, microglia, neurons, and oligodendrocytes) and the reduction in ongoing adult neurogenesis ultimately contributing to radiation-induced brain injury including cognitive impairment. Activation of PPARs using specific ligands is hypothesized to play a role in normalizing the brain microenvironment and preserving cellular function following irradiation in part via inhibition of proinflammatory signaling pathways and by upregulation of antioxidant enzyme activities thus ameliorating the detrimental effects of radiation on the brain.
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fig1: Model for the role of PPARs in radiation-induced brain injury. Irradiation is hypothesized to modify the brain microenvironment via the generation of an inflammatory and/or oxidative stress response which is also characterized by increased cell death of the neural precursor cells residing in the neurogenic regions of the brain. This alteration in the microenvironment is proposed to play a role in the dysfunction of the various cell-types in the brain (e.g., astrocytes, endothelial cells, microglia, neurons, and oligodendrocytes) and the reduction in ongoing adult neurogenesis ultimately contributing to radiation-induced brain injury including cognitive impairment. Activation of PPARs using specific ligands is hypothesized to play a role in normalizing the brain microenvironment and preserving cellular function following irradiation in part via inhibition of proinflammatory signaling pathways and by upregulation of antioxidant enzyme activities thus ameliorating the detrimental effects of radiation on the brain.

Mentions: Based on our findings, we propose a model for the role of PPARs in the regulation of radiation-induced brain injury. Irradiating the brain leads to increased proinflammatory response as evidenced by (1) increased activity of NF-κB and AP-1 and (2) increased levels of TNFα, IL-1β and Cox-2. Microglia probably are the primary source of these mediators, although other cells likely contribute to the proinflammatory response [107, 120]. These cytokines might diffuse into the extracellular space and act on astrocytes, endothelial cells, neurons, and neighboring microglia, initiating a cytokine signaling cascade that alters the brain microenvironment (enhanced neuroinflammation, decreased hippocampal neurogenesis) and ultimately contributes to radiation-induced cognitive impairment (Figure 1).


Role of PPARs in Radiation-Induced Brain Injury.

Ramanan S, Zhao W, Riddle DR, Robbins ME - PPAR Res (2009)

Model for the role of PPARs in radiation-induced brain injury. Irradiation is hypothesized to modify the brain microenvironment via the generation of an inflammatory and/or oxidative stress response which is also characterized by increased cell death of the neural precursor cells residing in the neurogenic regions of the brain. This alteration in the microenvironment is proposed to play a role in the dysfunction of the various cell-types in the brain (e.g., astrocytes, endothelial cells, microglia, neurons, and oligodendrocytes) and the reduction in ongoing adult neurogenesis ultimately contributing to radiation-induced brain injury including cognitive impairment. Activation of PPARs using specific ligands is hypothesized to play a role in normalizing the brain microenvironment and preserving cellular function following irradiation in part via inhibition of proinflammatory signaling pathways and by upregulation of antioxidant enzyme activities thus ameliorating the detrimental effects of radiation on the brain.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2748193&req=5

fig1: Model for the role of PPARs in radiation-induced brain injury. Irradiation is hypothesized to modify the brain microenvironment via the generation of an inflammatory and/or oxidative stress response which is also characterized by increased cell death of the neural precursor cells residing in the neurogenic regions of the brain. This alteration in the microenvironment is proposed to play a role in the dysfunction of the various cell-types in the brain (e.g., astrocytes, endothelial cells, microglia, neurons, and oligodendrocytes) and the reduction in ongoing adult neurogenesis ultimately contributing to radiation-induced brain injury including cognitive impairment. Activation of PPARs using specific ligands is hypothesized to play a role in normalizing the brain microenvironment and preserving cellular function following irradiation in part via inhibition of proinflammatory signaling pathways and by upregulation of antioxidant enzyme activities thus ameliorating the detrimental effects of radiation on the brain.
Mentions: Based on our findings, we propose a model for the role of PPARs in the regulation of radiation-induced brain injury. Irradiating the brain leads to increased proinflammatory response as evidenced by (1) increased activity of NF-κB and AP-1 and (2) increased levels of TNFα, IL-1β and Cox-2. Microglia probably are the primary source of these mediators, although other cells likely contribute to the proinflammatory response [107, 120]. These cytokines might diffuse into the extracellular space and act on astrocytes, endothelial cells, neurons, and neighboring microglia, initiating a cytokine signaling cascade that alters the brain microenvironment (enhanced neuroinflammation, decreased hippocampal neurogenesis) and ultimately contributes to radiation-induced cognitive impairment (Figure 1).

Bottom Line: At present, there are no proven long-term treatments or preventive strategies for this significant radiation-induced late effect.Peroxisomal proliferator-activated receptors (PPARs) are ligand-activated transcription factors that belong to the steroid/thyroid hormone nuclear receptor superfamily.PPAR agonists have been shown to cross the blood-brain barrier and confer neuroprotection in animal models of CNS disorders such as stroke, multiple sclerosis and Parkinson's disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Cancer Biology, Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.

ABSTRACT
Whole-brain irradiation (WBI) represents the primary mode of treatment for brain metastases; about 200 000 patients receive WBI each year in the USA. Up to 50% of adult and 100% of pediatric brain cancer patients who survive >6 months post-WBI will suffer from a progressive, cognitive impairment. At present, there are no proven long-term treatments or preventive strategies for this significant radiation-induced late effect. Recent studies suggest that the pathogenesis of radiation-induced brain injury involves WBI-mediated increases in oxidative stress and/or inflammatory responses in the brain. Therefore, anti-inflammatory strategies can be employed to modulate radiation-induced brain injury. Peroxisomal proliferator-activated receptors (PPARs) are ligand-activated transcription factors that belong to the steroid/thyroid hormone nuclear receptor superfamily. Although traditionally known to play a role in metabolism, increasing evidence suggests a role for PPARs in regulating the response to inflammation and oxidative injury. PPAR agonists have been shown to cross the blood-brain barrier and confer neuroprotection in animal models of CNS disorders such as stroke, multiple sclerosis and Parkinson's disease. However, the role of PPARs in radiation-induced brain injury is unclear. In this manuscript, we review the current knowledge and the emerging insights about the role of PPARs in modulating radiation-induced brain injury.

No MeSH data available.


Related in: MedlinePlus