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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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Related in: MedlinePlus

This diagram depicts a cross section of brain parenchyma showing the structure of the BBB and the damage induced by RT. (a) Normal BBB showing intact tight junctions (TJ), lack of vesicles, astrocytes and pericytes abutting the EC providing additional barrier support, and a neuron with thick, healthy myelin. (b) Damaged BBB in which astrocytes and pericytes have pulled away from the EC, a leukocyte has adhered to the EC, and there is formation of vesicles and loss of TJ integrity.
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fig4: This diagram depicts a cross section of brain parenchyma showing the structure of the BBB and the damage induced by RT. (a) Normal BBB showing intact tight junctions (TJ), lack of vesicles, astrocytes and pericytes abutting the EC providing additional barrier support, and a neuron with thick, healthy myelin. (b) Damaged BBB in which astrocytes and pericytes have pulled away from the EC, a leukocyte has adhered to the EC, and there is formation of vesicles and loss of TJ integrity.

Mentions: The microenvironment of the brain is regulated and protected by specific barriers, which include the vascular endothelial barrier (also called the blood-brain barrier, or BBB) at the capillary-parenchyma interface and the epithelial barrier (blood-cerebrospinal fluid barrier) at the choroid plexus [56]. The BBB is more than a physical barrier: it plays a fundamental role in regulating the movement of substances between the blood and the CNS (see Figure 4(a)). The microvascular network is also the site of the BBB, and the endothelial cells (ECs) that make up the microvascular network barrier contain few pinocytotic vesicles and adhere to each other via tight junctions [57]. Tight junctions limit paracellular transport of hydrophilic compounds into the CNS as compared to non-CNS vessels [58, 59]. Also, astrocytes in close proximity to the ECs add another impediment to paracellular transport by biochemically conditioning the ECs and strengthening the tight junctions between them [60]. ECs coat, in a single layer, the interior of all blood vessels. Because of this intertwined fate with the circulatory system, ECs play a unique role in maintaining physiological homeostasis, controlling the movement of substances across from the blood compartment into the different tissues and organs with varying demands and function [61]. The ECs also play an important immune function through leukocyte surveillance and extravasation by regulating adhesion integrins and cytokine production [62]. In particular, they have been shown to directly secrete tumor necrosis factor (TNF) [63]. Thus, damage to the ECs compromises the integrity of the BBB.


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

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

This diagram depicts a cross section of brain parenchyma showing the structure of the BBB and the damage induced by RT. (a) Normal BBB showing intact tight junctions (TJ), lack of vesicles, astrocytes and pericytes abutting the EC providing additional barrier support, and a neuron with thick, healthy myelin. (b) Damaged BBB in which astrocytes and pericytes have pulled away from the EC, a leukocyte has adhered to the EC, and there is formation of vesicles and loss of TJ integrity.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig4: This diagram depicts a cross section of brain parenchyma showing the structure of the BBB and the damage induced by RT. (a) Normal BBB showing intact tight junctions (TJ), lack of vesicles, astrocytes and pericytes abutting the EC providing additional barrier support, and a neuron with thick, healthy myelin. (b) Damaged BBB in which astrocytes and pericytes have pulled away from the EC, a leukocyte has adhered to the EC, and there is formation of vesicles and loss of TJ integrity.
Mentions: The microenvironment of the brain is regulated and protected by specific barriers, which include the vascular endothelial barrier (also called the blood-brain barrier, or BBB) at the capillary-parenchyma interface and the epithelial barrier (blood-cerebrospinal fluid barrier) at the choroid plexus [56]. The BBB is more than a physical barrier: it plays a fundamental role in regulating the movement of substances between the blood and the CNS (see Figure 4(a)). The microvascular network is also the site of the BBB, and the endothelial cells (ECs) that make up the microvascular network barrier contain few pinocytotic vesicles and adhere to each other via tight junctions [57]. Tight junctions limit paracellular transport of hydrophilic compounds into the CNS as compared to non-CNS vessels [58, 59]. Also, astrocytes in close proximity to the ECs add another impediment to paracellular transport by biochemically conditioning the ECs and strengthening the tight junctions between them [60]. ECs coat, in a single layer, the interior of all blood vessels. Because of this intertwined fate with the circulatory system, ECs play a unique role in maintaining physiological homeostasis, controlling the movement of substances across from the blood compartment into the different tissues and organs with varying demands and function [61]. The ECs also play an important immune function through leukocyte surveillance and extravasation by regulating adhesion integrins and cytokine production [62]. In particular, they have been shown to directly secrete tumor necrosis factor (TNF) [63]. Thus, damage to the ECs compromises the integrity of the BBB.

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