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Fractionated Radiation Exposure of Rat Spinal Cords Leads to Latent Neuro-Inflammation in Brain, Cognitive Deficits, and Alterations in Apurinic Endonuclease 1.

Suresh Kumar MA, Peluso M, Chaudhary P, Dhawan J, Beheshti A, Manickam K, Thapar U, Pena L, Natarajan M, Hlatky L, Demple B, Naidu M - PLoS ONE (2015)

Bottom Line: As radiation research on the central nervous system has predominantly focused on neurons, with few studies addressing the role of glial cells, we have focused our present research on identifying the latent effects of single/ fractionated -low dose of low/ high energy radiation on the role of base excision repair protein Apurinic Endonuclease-1, in the rat spinal cords oligodendrocyte progenitor cells' differentiation.Our studies show for the first time, that fractionation of protons cause latent damage to spinal cord architecture while fractionation of HZE (28Si) induce increase in APE1 with single dose, which then decreased with fractionation.The oligodendrocyte progenitor cells differentiation was skewed with increase in immature oligodendrocytes and astrocytes, which likely cause the observed decrease in white matter, increased neuro-inflammation, together leading to the observed significant cognitive defects.

View Article: PubMed Central - PubMed

Affiliation: Center for Radiological Research, Columbia University, New York, New York, United States of America.

ABSTRACT
Ionizing radiation causes degeneration of myelin, the insulating sheaths of neuronal axons, leading to neurological impairment. As radiation research on the central nervous system has predominantly focused on neurons, with few studies addressing the role of glial cells, we have focused our present research on identifying the latent effects of single/ fractionated -low dose of low/ high energy radiation on the role of base excision repair protein Apurinic Endonuclease-1, in the rat spinal cords oligodendrocyte progenitor cells' differentiation. Apurinic endonuclease-1 is predominantly upregulated in response to oxidative stress by low- energy radiation, and previous studies show significant induction of Apurinic Endonuclease-1 in neurons and astrocytes. Our studies show for the first time, that fractionation of protons cause latent damage to spinal cord architecture while fractionation of HZE (28Si) induce increase in APE1 with single dose, which then decreased with fractionation. The oligodendrocyte progenitor cells differentiation was skewed with increase in immature oligodendrocytes and astrocytes, which likely cause the observed decrease in white matter, increased neuro-inflammation, together leading to the observed significant cognitive defects.

No MeSH data available.


Related in: MedlinePlus

(A) Representative autoradiograms from control and irradiated (protons and X-rays) rats were pseudo-colored using the rainbow spectrum (scale on right). The neuro-inflammatory marker TSPO binding with [³H] PK11195 in rat brain sections is shown. A bilateral regional increase in inflammation is observed. (B) Statistical analysis is performed by 2-way ANOVA (treatment, time) with repeated measures (region). Alpha is preset at p<0.05. Regions of interest are grouped in four levels by distance from the impact (CHI), as follows: level 1 (mice, anterior striatal level, Bregma 1.7 to 0.02) contained sections in the direct path of the impact; level 2 (posterior striatal level, Bregma -0.22 to -0.82) contained regions directly posterior to the impact; and levels 3 and 4 (dorsal hippocampal level, bregma -1.2 to -2.06, ventral hippocampus/midbrain level, bregma –2.4 to– 3.6) contain regions relatively remote from the site of injury.
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pone.0133016.g005: (A) Representative autoradiograms from control and irradiated (protons and X-rays) rats were pseudo-colored using the rainbow spectrum (scale on right). The neuro-inflammatory marker TSPO binding with [³H] PK11195 in rat brain sections is shown. A bilateral regional increase in inflammation is observed. (B) Statistical analysis is performed by 2-way ANOVA (treatment, time) with repeated measures (region). Alpha is preset at p<0.05. Regions of interest are grouped in four levels by distance from the impact (CHI), as follows: level 1 (mice, anterior striatal level, Bregma 1.7 to 0.02) contained sections in the direct path of the impact; level 2 (posterior striatal level, Bregma -0.22 to -0.82) contained regions directly posterior to the impact; and levels 3 and 4 (dorsal hippocampal level, bregma -1.2 to -2.06, ventral hippocampus/midbrain level, bregma –2.4 to– 3.6) contain regions relatively remote from the site of injury.

Mentions: We were able to study these effects only 9 months post exposure, hence we have data from those rats brains, which indicate a clear increase in the microglial marker translocator protein (TSPO) binding in all brain regions including the hippocampus as shown in Fig 5A, with significant inflammation induced by X-rays and Protons with small number of rats (3 rats each for control, X-rays and Protons as 2 were sacrificed 3 months post exposure for spinal cord inflammation studies). Sections from control animals showed the known distribution of TSPO in the brain, with high density in ependymal cell layers associated with ventricles and relatively low and uniform levels in most brain regions (Table 1 and Fig 5B. ANOVA results showed a highly significant effect of treatment (F = 11.8, p<0.0001) as well as a significant effect of region (p = 0.0069) (Fig 4B). There was no treatment x region interaction (F = 0.19, p = 0.99) (Table 1).


Fractionated Radiation Exposure of Rat Spinal Cords Leads to Latent Neuro-Inflammation in Brain, Cognitive Deficits, and Alterations in Apurinic Endonuclease 1.

Suresh Kumar MA, Peluso M, Chaudhary P, Dhawan J, Beheshti A, Manickam K, Thapar U, Pena L, Natarajan M, Hlatky L, Demple B, Naidu M - PLoS ONE (2015)

(A) Representative autoradiograms from control and irradiated (protons and X-rays) rats were pseudo-colored using the rainbow spectrum (scale on right). The neuro-inflammatory marker TSPO binding with [³H] PK11195 in rat brain sections is shown. A bilateral regional increase in inflammation is observed. (B) Statistical analysis is performed by 2-way ANOVA (treatment, time) with repeated measures (region). Alpha is preset at p<0.05. Regions of interest are grouped in four levels by distance from the impact (CHI), as follows: level 1 (mice, anterior striatal level, Bregma 1.7 to 0.02) contained sections in the direct path of the impact; level 2 (posterior striatal level, Bregma -0.22 to -0.82) contained regions directly posterior to the impact; and levels 3 and 4 (dorsal hippocampal level, bregma -1.2 to -2.06, ventral hippocampus/midbrain level, bregma –2.4 to– 3.6) contain regions relatively remote from the site of injury.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4514622&req=5

pone.0133016.g005: (A) Representative autoradiograms from control and irradiated (protons and X-rays) rats were pseudo-colored using the rainbow spectrum (scale on right). The neuro-inflammatory marker TSPO binding with [³H] PK11195 in rat brain sections is shown. A bilateral regional increase in inflammation is observed. (B) Statistical analysis is performed by 2-way ANOVA (treatment, time) with repeated measures (region). Alpha is preset at p<0.05. Regions of interest are grouped in four levels by distance from the impact (CHI), as follows: level 1 (mice, anterior striatal level, Bregma 1.7 to 0.02) contained sections in the direct path of the impact; level 2 (posterior striatal level, Bregma -0.22 to -0.82) contained regions directly posterior to the impact; and levels 3 and 4 (dorsal hippocampal level, bregma -1.2 to -2.06, ventral hippocampus/midbrain level, bregma –2.4 to– 3.6) contain regions relatively remote from the site of injury.
Mentions: We were able to study these effects only 9 months post exposure, hence we have data from those rats brains, which indicate a clear increase in the microglial marker translocator protein (TSPO) binding in all brain regions including the hippocampus as shown in Fig 5A, with significant inflammation induced by X-rays and Protons with small number of rats (3 rats each for control, X-rays and Protons as 2 were sacrificed 3 months post exposure for spinal cord inflammation studies). Sections from control animals showed the known distribution of TSPO in the brain, with high density in ependymal cell layers associated with ventricles and relatively low and uniform levels in most brain regions (Table 1 and Fig 5B. ANOVA results showed a highly significant effect of treatment (F = 11.8, p<0.0001) as well as a significant effect of region (p = 0.0069) (Fig 4B). There was no treatment x region interaction (F = 0.19, p = 0.99) (Table 1).

Bottom Line: As radiation research on the central nervous system has predominantly focused on neurons, with few studies addressing the role of glial cells, we have focused our present research on identifying the latent effects of single/ fractionated -low dose of low/ high energy radiation on the role of base excision repair protein Apurinic Endonuclease-1, in the rat spinal cords oligodendrocyte progenitor cells' differentiation.Our studies show for the first time, that fractionation of protons cause latent damage to spinal cord architecture while fractionation of HZE (28Si) induce increase in APE1 with single dose, which then decreased with fractionation.The oligodendrocyte progenitor cells differentiation was skewed with increase in immature oligodendrocytes and astrocytes, which likely cause the observed decrease in white matter, increased neuro-inflammation, together leading to the observed significant cognitive defects.

View Article: PubMed Central - PubMed

Affiliation: Center for Radiological Research, Columbia University, New York, New York, United States of America.

ABSTRACT
Ionizing radiation causes degeneration of myelin, the insulating sheaths of neuronal axons, leading to neurological impairment. As radiation research on the central nervous system has predominantly focused on neurons, with few studies addressing the role of glial cells, we have focused our present research on identifying the latent effects of single/ fractionated -low dose of low/ high energy radiation on the role of base excision repair protein Apurinic Endonuclease-1, in the rat spinal cords oligodendrocyte progenitor cells' differentiation. Apurinic endonuclease-1 is predominantly upregulated in response to oxidative stress by low- energy radiation, and previous studies show significant induction of Apurinic Endonuclease-1 in neurons and astrocytes. Our studies show for the first time, that fractionation of protons cause latent damage to spinal cord architecture while fractionation of HZE (28Si) induce increase in APE1 with single dose, which then decreased with fractionation. The oligodendrocyte progenitor cells differentiation was skewed with increase in immature oligodendrocytes and astrocytes, which likely cause the observed decrease in white matter, increased neuro-inflammation, together leading to the observed significant cognitive defects.

No MeSH data available.


Related in: MedlinePlus