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Neurogenesis, exercise, and cognitive late effects of pediatric radiotherapy.

Rodgers SP, Trevino M, Zawaski JA, Gaber MW, Leasure JL - Neural Plast. (2013)

Bottom Line: However, RT damages the brain and disrupts ongoing developmental processes, resulting in debilitating cognitive "late" effects that may take years to fully manifest.These late effects likely derive from a long-term decrement in cell proliferation, combined with a neural environment that is hostile to plasticity, both of which are induced by RT.Potential treatments for cognitive late effects should address both of these conditions.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychology, University of Houston, Houston, TX 77204, USA.

ABSTRACT
Brain cancer is a common type of childhood malignancy, and radiotherapy (RT) is a mainstay of treatment. RT is effective for tumor eradication, and survival rates are high. However, RT damages the brain and disrupts ongoing developmental processes, resulting in debilitating cognitive "late" effects that may take years to fully manifest. These late effects likely derive from a long-term decrement in cell proliferation, combined with a neural environment that is hostile to plasticity, both of which are induced by RT. Long-term suppression of cell proliferation deprives the brain of the raw materials needed for optimum cognitive performance (such as new neurons in the hippocampus and new glia in frontal cortex), while chronic inflammation and dearth of trophic substances (such as growth hormone) limit neuroplastic potential in existing circuitry. Potential treatments for cognitive late effects should address both of these conditions. Exercise represents one such potential treatment, since it has the capacity to enhance cell proliferation, as well as to promote a neural milieu permissive for plasticity. Here, we review the evidence that cognitive late effects can be traced to RT-induced suppression of cell proliferation and hostile environmental conditions, as well as emerging evidence that exercise may be effective as an independent or adjuvant therapy.

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Histological markers of radiation injury in the mouse brain at 90, 120, 180, and 300 days after RT. (a, b) Luxol fast blue staining showing loss of myelin. (c, d) Sections of brain nerve fibers showing structural changes, microglial (outlined in green) inflammation, and myelin sheath thickening indicative of cell death (images at 50x). (e, f) Yellow and blue arrow heads point at myelin sheath surrounding the neurons and at mitochondria, respectively (scale bar = 1 μm). (g) Necrosis detected at 120 days. (h) Yellow arrows point at pericyte pulling away from endothelial cell, a sign of inflammation, with white edematous area causing vascular constriction.
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fig5: Histological markers of radiation injury in the mouse brain at 90, 120, 180, and 300 days after RT. (a, b) Luxol fast blue staining showing loss of myelin. (c, d) Sections of brain nerve fibers showing structural changes, microglial (outlined in green) inflammation, and myelin sheath thickening indicative of cell death (images at 50x). (e, f) Yellow and blue arrow heads point at myelin sheath surrounding the neurons and at mitochondria, respectively (scale bar = 1 μm). (g) Necrosis detected at 120 days. (h) Yellow arrows point at pericyte pulling away from endothelial cell, a sign of inflammation, with white edematous area causing vascular constriction.

Mentions: Such damage to the microvasculature and breach of the BBB can disturb the delicate brain microenvironment and expose the brain parenchyma and neural cells to noxious substances [70, 78, 85]. This microenvironment imbalance can set into motion a chain of events (such as cytokines release), magnifying the original signal and finally causing measurable late-term tissue damage in the irradiated brain that may play a role in cognitive impairment [86]. We and others have shown that RT induces an inflammatory response as indicated by an increase in TNF-α and intercellular adhesion molecule-1 (ICAM-1) signaling in the brain [87–90]. We have reported activated astrocytes after treatment with single and fractionated RT [78, 91]. Prolonged gliosis can create glial scar sites, which have been theorized to inhibit axonal regeneration or remyelination [92, 93]. We have demonstrated that this inflammation response is related to an increase in BBB permeability following RT and that it is abrogated when treated with antibodies to TNF-α or ICAM-1 [77, 90]. In a histological study on mouse brains we observed significant changes 120 days following fractionated RT: fewer neurons, a significant decrease in myelin suggesting complete destruction of the parts of the white matter at 120 days following RT, and at 90 days following RT, we observed swelling of nerve fibers and increased thickening of the myelin sheaths (see Figure 5(b)) indicative of dying axons.


Neurogenesis, exercise, and cognitive late effects of pediatric radiotherapy.

Rodgers SP, Trevino M, Zawaski JA, Gaber MW, Leasure JL - Neural Plast. (2013)

Histological markers of radiation injury in the mouse brain at 90, 120, 180, and 300 days after RT. (a, b) Luxol fast blue staining showing loss of myelin. (c, d) Sections of brain nerve fibers showing structural changes, microglial (outlined in green) inflammation, and myelin sheath thickening indicative of cell death (images at 50x). (e, f) Yellow and blue arrow heads point at myelin sheath surrounding the neurons and at mitochondria, respectively (scale bar = 1 μm). (g) Necrosis detected at 120 days. (h) Yellow arrows point at pericyte pulling away from endothelial cell, a sign of inflammation, with white edematous area causing vascular constriction.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3649702&req=5

fig5: Histological markers of radiation injury in the mouse brain at 90, 120, 180, and 300 days after RT. (a, b) Luxol fast blue staining showing loss of myelin. (c, d) Sections of brain nerve fibers showing structural changes, microglial (outlined in green) inflammation, and myelin sheath thickening indicative of cell death (images at 50x). (e, f) Yellow and blue arrow heads point at myelin sheath surrounding the neurons and at mitochondria, respectively (scale bar = 1 μm). (g) Necrosis detected at 120 days. (h) Yellow arrows point at pericyte pulling away from endothelial cell, a sign of inflammation, with white edematous area causing vascular constriction.
Mentions: Such damage to the microvasculature and breach of the BBB can disturb the delicate brain microenvironment and expose the brain parenchyma and neural cells to noxious substances [70, 78, 85]. This microenvironment imbalance can set into motion a chain of events (such as cytokines release), magnifying the original signal and finally causing measurable late-term tissue damage in the irradiated brain that may play a role in cognitive impairment [86]. We and others have shown that RT induces an inflammatory response as indicated by an increase in TNF-α and intercellular adhesion molecule-1 (ICAM-1) signaling in the brain [87–90]. We have reported activated astrocytes after treatment with single and fractionated RT [78, 91]. Prolonged gliosis can create glial scar sites, which have been theorized to inhibit axonal regeneration or remyelination [92, 93]. We have demonstrated that this inflammation response is related to an increase in BBB permeability following RT and that it is abrogated when treated with antibodies to TNF-α or ICAM-1 [77, 90]. In a histological study on mouse brains we observed significant changes 120 days following fractionated RT: fewer neurons, a significant decrease in myelin suggesting complete destruction of the parts of the white matter at 120 days following RT, and at 90 days following RT, we observed swelling of nerve fibers and increased thickening of the myelin sheaths (see Figure 5(b)) indicative of dying axons.

Bottom Line: However, RT damages the brain and disrupts ongoing developmental processes, resulting in debilitating cognitive "late" effects that may take years to fully manifest.These late effects likely derive from a long-term decrement in cell proliferation, combined with a neural environment that is hostile to plasticity, both of which are induced by RT.Potential treatments for cognitive late effects should address both of these conditions.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychology, University of Houston, Houston, TX 77204, USA.

ABSTRACT
Brain cancer is a common type of childhood malignancy, and radiotherapy (RT) is a mainstay of treatment. RT is effective for tumor eradication, and survival rates are high. However, RT damages the brain and disrupts ongoing developmental processes, resulting in debilitating cognitive "late" effects that may take years to fully manifest. These late effects likely derive from a long-term decrement in cell proliferation, combined with a neural environment that is hostile to plasticity, both of which are induced by RT. Long-term suppression of cell proliferation deprives the brain of the raw materials needed for optimum cognitive performance (such as new neurons in the hippocampus and new glia in frontal cortex), while chronic inflammation and dearth of trophic substances (such as growth hormone) limit neuroplastic potential in existing circuitry. Potential treatments for cognitive late effects should address both of these conditions. Exercise represents one such potential treatment, since it has the capacity to enhance cell proliferation, as well as to promote a neural milieu permissive for plasticity. Here, we review the evidence that cognitive late effects can be traced to RT-induced suppression of cell proliferation and hostile environmental conditions, as well as emerging evidence that exercise may be effective as an independent or adjuvant therapy.

Show MeSH
Related in: MedlinePlus