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Radiation-induced brain injury: A review.

Greene-Schloesser D, Robbins ME, Peiffer AM, Shaw EG, Wheeler KT, Chan MD - Front Oncol (2012)

Bottom Line: Irradiating pediatric and young adult rodent brains leads to several hippocampal changes including neuroinflammation and a marked reduction in neurogenesis.Studies using older rodents, that more closely match the adult human brain tumor population, indicate that, unlike pediatric and young adult rats, older rats fail to show a radiation-induced decrease in neurogenesis or a loss of mature neurons.Recently developed techniques in neuroscience and neuroimaging provide not only an opportunity to accomplish this, but they also offer the opportunity to identify new biomarkers and new targets for interventions to prevent or ameliorate these late effects.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiation Oncology, Wake Forest School of Medicine, Winston-Salem, NC, USA.

ABSTRACT
Approximately 100,000 primary and metastatic brain tumor patients/year in the US survive long enough (>6 months) to experience radiation-induced brain injury. Prior to 1970, the human brain was thought to be highly radioresistant; the acute CNS syndrome occurs after single doses >30 Gy; white matter necrosis occurs at fractionated doses >60 Gy. Although white matter necrosis is uncommon with modern techniques, functional deficits, including progressive impairments in memory, attention, and executive function have become important, because they have profound effects on quality of life. Preclinical studies have provided valuable insights into the pathogenesis of radiation-induced cognitive impairment. Given its central role in memory and neurogenesis, the majority of these studies have focused on the hippocampus. Irradiating pediatric and young adult rodent brains leads to several hippocampal changes including neuroinflammation and a marked reduction in neurogenesis. These data have been interpreted to suggest that shielding the hippocampus will prevent clinical radiation-induced cognitive impairment. However, this interpretation may be overly simplistic. Studies using older rodents, that more closely match the adult human brain tumor population, indicate that, unlike pediatric and young adult rats, older rats fail to show a radiation-induced decrease in neurogenesis or a loss of mature neurons. Nevertheless, older rats still exhibit cognitive impairment. This occurs in the absence of demyelination and/or white matter necrosis similar to what is observed clinically, suggesting that more subtle molecular, cellular and/or microanatomic modifications are involved in this radiation-induced brain injury. Given that radiation-induced cognitive impairment likely reflects damage to both hippocampal- and non-hippocampal-dependent domains, there is a critical need to investigate the microanatomic and functional effects of radiation in various brain regions as well as their integration at clinically relevant doses and schedules. Recently developed techniques in neuroscience and neuroimaging provide not only an opportunity to accomplish this, but they also offer the opportunity to identify new biomarkers and new targets for interventions to prevent or ameliorate these late effects.

No MeSH data available.


Related in: MedlinePlus

Both RAS inhibitors and PPAR agonists prevent radiation-induced cognitive impairment in young adult male rats that received a total 40 Gy dose of fWBI delivered in 5 Gy fractions, twice/week for 4 weeks, and then tested for cognition at 6–12 months post-irradiation using the NOR task. Rats were administered, (A) the ARB, L-158,809 before, during, and for 54 weeks post-fWBI; tested at 52 weeks, (B) the ACEI, ramipril, before, during, and for 28 weeks post-fWBI; tested at 26 weeks, (C) the PPARγ agonist, pioglitazone, before, during, and for 54 weeks post-fWBI; tested at 52 weeks, and (D) the PPARα agonist, fenofibrate, before, during, and for 29 weeks post-fWBI; tested at 26 weeks. *P <0.05, **P <0.01, ***P <0.001 compared to sham-irradiated rats.
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Figure 6: Both RAS inhibitors and PPAR agonists prevent radiation-induced cognitive impairment in young adult male rats that received a total 40 Gy dose of fWBI delivered in 5 Gy fractions, twice/week for 4 weeks, and then tested for cognition at 6–12 months post-irradiation using the NOR task. Rats were administered, (A) the ARB, L-158,809 before, during, and for 54 weeks post-fWBI; tested at 52 weeks, (B) the ACEI, ramipril, before, during, and for 28 weeks post-fWBI; tested at 26 weeks, (C) the PPARγ agonist, pioglitazone, before, during, and for 54 weeks post-fWBI; tested at 52 weeks, and (D) the PPARα agonist, fenofibrate, before, during, and for 29 weeks post-fWBI; tested at 26 weeks. *P <0.05, **P <0.01, ***P <0.001 compared to sham-irradiated rats.

Mentions: Several rodent studies designed to prevent or ameliorate radiation-induced cognitive impairment have shown promise using anti-inflammatory peroxisome proliferator-activated (PPAR) agonists (Figure 6) that have been given to patients for years to treat other syndromes (Derosa, 2010; McKeage and Keating, 2011). PPARα, δ, and γ are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors that heterodimerize with the retinoid X receptor to regulate gene expression (Blumberg and Evans, 1998). A growing body of evidence suggests that PPARs regulate inflammatory signaling and are neuroprotective in a variety of CNS diseases (Bright et al., 2008; Stahel et al., 2008; Ramanan et al., 2010). Administering the PPARγ agonist, pioglitazone (Pio), to young adult male rats starting 3 days prior to, during, and for 4 or 54 weeks after the completion of a total 40 Gy dose of fWBI delivered twice a week for 4 weeks, prevented the radiation-induced cognitive impairment measured 52 weeks after fWBI (Figure 6; Zhao et al., 2007b). However, administration of Pio for 54 weeks starting after the completion of fWBI did not significantly modulate radiation-induced cognitive impairment. Based on these data, a phase I/II trial has been initiated to determine the dose of Pio that can be given safely to brain tumor patients and obtain preliminary data on the ability of Pio to prevent/ameliorate radiation-induced cognitive impairment.


Radiation-induced brain injury: A review.

Greene-Schloesser D, Robbins ME, Peiffer AM, Shaw EG, Wheeler KT, Chan MD - Front Oncol (2012)

Both RAS inhibitors and PPAR agonists prevent radiation-induced cognitive impairment in young adult male rats that received a total 40 Gy dose of fWBI delivered in 5 Gy fractions, twice/week for 4 weeks, and then tested for cognition at 6–12 months post-irradiation using the NOR task. Rats were administered, (A) the ARB, L-158,809 before, during, and for 54 weeks post-fWBI; tested at 52 weeks, (B) the ACEI, ramipril, before, during, and for 28 weeks post-fWBI; tested at 26 weeks, (C) the PPARγ agonist, pioglitazone, before, during, and for 54 weeks post-fWBI; tested at 52 weeks, and (D) the PPARα agonist, fenofibrate, before, during, and for 29 weeks post-fWBI; tested at 26 weeks. *P <0.05, **P <0.01, ***P <0.001 compared to sham-irradiated rats.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3400082&req=5

Figure 6: Both RAS inhibitors and PPAR agonists prevent radiation-induced cognitive impairment in young adult male rats that received a total 40 Gy dose of fWBI delivered in 5 Gy fractions, twice/week for 4 weeks, and then tested for cognition at 6–12 months post-irradiation using the NOR task. Rats were administered, (A) the ARB, L-158,809 before, during, and for 54 weeks post-fWBI; tested at 52 weeks, (B) the ACEI, ramipril, before, during, and for 28 weeks post-fWBI; tested at 26 weeks, (C) the PPARγ agonist, pioglitazone, before, during, and for 54 weeks post-fWBI; tested at 52 weeks, and (D) the PPARα agonist, fenofibrate, before, during, and for 29 weeks post-fWBI; tested at 26 weeks. *P <0.05, **P <0.01, ***P <0.001 compared to sham-irradiated rats.
Mentions: Several rodent studies designed to prevent or ameliorate radiation-induced cognitive impairment have shown promise using anti-inflammatory peroxisome proliferator-activated (PPAR) agonists (Figure 6) that have been given to patients for years to treat other syndromes (Derosa, 2010; McKeage and Keating, 2011). PPARα, δ, and γ are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors that heterodimerize with the retinoid X receptor to regulate gene expression (Blumberg and Evans, 1998). A growing body of evidence suggests that PPARs regulate inflammatory signaling and are neuroprotective in a variety of CNS diseases (Bright et al., 2008; Stahel et al., 2008; Ramanan et al., 2010). Administering the PPARγ agonist, pioglitazone (Pio), to young adult male rats starting 3 days prior to, during, and for 4 or 54 weeks after the completion of a total 40 Gy dose of fWBI delivered twice a week for 4 weeks, prevented the radiation-induced cognitive impairment measured 52 weeks after fWBI (Figure 6; Zhao et al., 2007b). However, administration of Pio for 54 weeks starting after the completion of fWBI did not significantly modulate radiation-induced cognitive impairment. Based on these data, a phase I/II trial has been initiated to determine the dose of Pio that can be given safely to brain tumor patients and obtain preliminary data on the ability of Pio to prevent/ameliorate radiation-induced cognitive impairment.

Bottom Line: Irradiating pediatric and young adult rodent brains leads to several hippocampal changes including neuroinflammation and a marked reduction in neurogenesis.Studies using older rodents, that more closely match the adult human brain tumor population, indicate that, unlike pediatric and young adult rats, older rats fail to show a radiation-induced decrease in neurogenesis or a loss of mature neurons.Recently developed techniques in neuroscience and neuroimaging provide not only an opportunity to accomplish this, but they also offer the opportunity to identify new biomarkers and new targets for interventions to prevent or ameliorate these late effects.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiation Oncology, Wake Forest School of Medicine, Winston-Salem, NC, USA.

ABSTRACT
Approximately 100,000 primary and metastatic brain tumor patients/year in the US survive long enough (>6 months) to experience radiation-induced brain injury. Prior to 1970, the human brain was thought to be highly radioresistant; the acute CNS syndrome occurs after single doses >30 Gy; white matter necrosis occurs at fractionated doses >60 Gy. Although white matter necrosis is uncommon with modern techniques, functional deficits, including progressive impairments in memory, attention, and executive function have become important, because they have profound effects on quality of life. Preclinical studies have provided valuable insights into the pathogenesis of radiation-induced cognitive impairment. Given its central role in memory and neurogenesis, the majority of these studies have focused on the hippocampus. Irradiating pediatric and young adult rodent brains leads to several hippocampal changes including neuroinflammation and a marked reduction in neurogenesis. These data have been interpreted to suggest that shielding the hippocampus will prevent clinical radiation-induced cognitive impairment. However, this interpretation may be overly simplistic. Studies using older rodents, that more closely match the adult human brain tumor population, indicate that, unlike pediatric and young adult rats, older rats fail to show a radiation-induced decrease in neurogenesis or a loss of mature neurons. Nevertheless, older rats still exhibit cognitive impairment. This occurs in the absence of demyelination and/or white matter necrosis similar to what is observed clinically, suggesting that more subtle molecular, cellular and/or microanatomic modifications are involved in this radiation-induced brain injury. Given that radiation-induced cognitive impairment likely reflects damage to both hippocampal- and non-hippocampal-dependent domains, there is a critical need to investigate the microanatomic and functional effects of radiation in various brain regions as well as their integration at clinically relevant doses and schedules. Recently developed techniques in neuroscience and neuroimaging provide not only an opportunity to accomplish this, but they also offer the opportunity to identify new biomarkers and new targets for interventions to prevent or ameliorate these late effects.

No MeSH data available.


Related in: MedlinePlus