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Sub-Chronic Neuropathological and Biochemical Changes in Mouse Visual System after Repetitive Mild Traumatic Brain Injury.

Tzekov R, Dawson C, Orlando M, Mouzon B, Reed J, Evans J, Crynen G, Mullan M, Crawford F - PLoS ONE (2016)

Bottom Line: These changes were accompanied by a ~25% decrease in the total number of Brn3a-positive RGCs.Proteomic analysis of the optic nerves demonstrated various changes consistent with a negative effect of r-mTBI on major cellular processes like depolymerization of microtubules, disassembly of filaments and loss of neurons, manifested by decrease of several proteins, including neurofilaments (NEFH, NEFM, NEFL), tubulin (TUBB2A, TUBA4A), microtubule-associated proteins (MAP1A, MAP1B), collagen (COL6A1, COL6A3) and increased expression of other proteins, including heat shock proteins (HSP90B1, HSPB1), APOE and cathepsin D.The overall amount of some ether phospholipids, like ether LPC, ether phosphatidylcholine and ether lysophosphatidylethanolamine were also increased, while the majority of individual molecular species of ester phospholipids, like phosphatidylcholine and phosphatidylethanolamine, were decreased.

View Article: PubMed Central - PubMed

Affiliation: The Roskamp Institute, Sarasota, FL, United States of America.

ABSTRACT
Repetitive mild traumatic brain injury (r-mTBI) results in neuropathological and biochemical consequences in the human visual system. Using a recently developed mouse model of r-mTBI, with control mice receiving repetitive anesthesia alone (r-sham) we assessed the effects on the retina and optic nerve using histology, immunohistochemistry, proteomic and lipidomic analyses at 3 weeks post injury. Retina tissue was used to determine retinal ganglion cell (RGC) number, while optic nerve tissue was examined for cellularity, myelin content, protein and lipid changes. Increased cellularity and areas of demyelination were clearly detectable in optic nerves in r-mTBI, but not in r-sham. These changes were accompanied by a ~25% decrease in the total number of Brn3a-positive RGCs. Proteomic analysis of the optic nerves demonstrated various changes consistent with a negative effect of r-mTBI on major cellular processes like depolymerization of microtubules, disassembly of filaments and loss of neurons, manifested by decrease of several proteins, including neurofilaments (NEFH, NEFM, NEFL), tubulin (TUBB2A, TUBA4A), microtubule-associated proteins (MAP1A, MAP1B), collagen (COL6A1, COL6A3) and increased expression of other proteins, including heat shock proteins (HSP90B1, HSPB1), APOE and cathepsin D. Lipidomic analysis showed quantitative changes in a number of phospholipid species, including a significant increase in the total amount of lysophosphatidylcholine (LPC), including the molecular species 16:0, a known demyelinating agent. The overall amount of some ether phospholipids, like ether LPC, ether phosphatidylcholine and ether lysophosphatidylethanolamine were also increased, while the majority of individual molecular species of ester phospholipids, like phosphatidylcholine and phosphatidylethanolamine, were decreased. Results from the biochemical analysis correlate well with changes detected by histological and immunohistochemical methods and indicate the involvement of several important molecular pathways. This will allow future identification of therapeutic targets for improving the visual consequences of r-mTBI.

No MeSH data available.


Related in: MedlinePlus

Quantitative assessment of ether phosphatidylcholine (ePC), ether lysophosphatidylcholine (eLPC) and ether lysophosphatidylethanolamine (LPE) species in optic nerve samples at 3 weeks after injury.Significant changes in individual molecular species together with changes in the total amount of lipids in the respective classes are shown. Upper panel—changes in ePC, middle panel—changes in eLPC, lower panel—changes in eLPE species. Blue bars represent total amount of phospholipids (μg/sample) in mice after r-sham, red bars—after r-mTBI. Asterisks indicate statistical significance between groups: *—p < 0.05; **—p <,0.01; ***—p < 0.001.
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pone.0153608.g005: Quantitative assessment of ether phosphatidylcholine (ePC), ether lysophosphatidylcholine (eLPC) and ether lysophosphatidylethanolamine (LPE) species in optic nerve samples at 3 weeks after injury.Significant changes in individual molecular species together with changes in the total amount of lipids in the respective classes are shown. Upper panel—changes in ePC, middle panel—changes in eLPC, lower panel—changes in eLPE species. Blue bars represent total amount of phospholipids (μg/sample) in mice after r-sham, red bars—after r-mTBI. Asterisks indicate statistical significance between groups: *—p < 0.05; **—p <,0.01; ***—p < 0.001.

Mentions: Ether phosphatidylcholines (ePC). Despite the fact that the overall amount of ePC was increased by only 8.1% and this change was not statistically significant (p>0.05, t-test), the majority of the ePC species (14 out of 21, or 66.7%) were increased (Fig 4), and for three species: ePC(36:4), ePC(36:5), and ePC(38:5), this increase was statistically significant, while one species—ePC(36:2) was significantly decreased (Fig 5, S4 Table, Fig 7).


Sub-Chronic Neuropathological and Biochemical Changes in Mouse Visual System after Repetitive Mild Traumatic Brain Injury.

Tzekov R, Dawson C, Orlando M, Mouzon B, Reed J, Evans J, Crynen G, Mullan M, Crawford F - PLoS ONE (2016)

Quantitative assessment of ether phosphatidylcholine (ePC), ether lysophosphatidylcholine (eLPC) and ether lysophosphatidylethanolamine (LPE) species in optic nerve samples at 3 weeks after injury.Significant changes in individual molecular species together with changes in the total amount of lipids in the respective classes are shown. Upper panel—changes in ePC, middle panel—changes in eLPC, lower panel—changes in eLPE species. Blue bars represent total amount of phospholipids (μg/sample) in mice after r-sham, red bars—after r-mTBI. Asterisks indicate statistical significance between groups: *—p < 0.05; **—p <,0.01; ***—p < 0.001.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4835061&req=5

pone.0153608.g005: Quantitative assessment of ether phosphatidylcholine (ePC), ether lysophosphatidylcholine (eLPC) and ether lysophosphatidylethanolamine (LPE) species in optic nerve samples at 3 weeks after injury.Significant changes in individual molecular species together with changes in the total amount of lipids in the respective classes are shown. Upper panel—changes in ePC, middle panel—changes in eLPC, lower panel—changes in eLPE species. Blue bars represent total amount of phospholipids (μg/sample) in mice after r-sham, red bars—after r-mTBI. Asterisks indicate statistical significance between groups: *—p < 0.05; **—p <,0.01; ***—p < 0.001.
Mentions: Ether phosphatidylcholines (ePC). Despite the fact that the overall amount of ePC was increased by only 8.1% and this change was not statistically significant (p>0.05, t-test), the majority of the ePC species (14 out of 21, or 66.7%) were increased (Fig 4), and for three species: ePC(36:4), ePC(36:5), and ePC(38:5), this increase was statistically significant, while one species—ePC(36:2) was significantly decreased (Fig 5, S4 Table, Fig 7).

Bottom Line: These changes were accompanied by a ~25% decrease in the total number of Brn3a-positive RGCs.Proteomic analysis of the optic nerves demonstrated various changes consistent with a negative effect of r-mTBI on major cellular processes like depolymerization of microtubules, disassembly of filaments and loss of neurons, manifested by decrease of several proteins, including neurofilaments (NEFH, NEFM, NEFL), tubulin (TUBB2A, TUBA4A), microtubule-associated proteins (MAP1A, MAP1B), collagen (COL6A1, COL6A3) and increased expression of other proteins, including heat shock proteins (HSP90B1, HSPB1), APOE and cathepsin D.The overall amount of some ether phospholipids, like ether LPC, ether phosphatidylcholine and ether lysophosphatidylethanolamine were also increased, while the majority of individual molecular species of ester phospholipids, like phosphatidylcholine and phosphatidylethanolamine, were decreased.

View Article: PubMed Central - PubMed

Affiliation: The Roskamp Institute, Sarasota, FL, United States of America.

ABSTRACT
Repetitive mild traumatic brain injury (r-mTBI) results in neuropathological and biochemical consequences in the human visual system. Using a recently developed mouse model of r-mTBI, with control mice receiving repetitive anesthesia alone (r-sham) we assessed the effects on the retina and optic nerve using histology, immunohistochemistry, proteomic and lipidomic analyses at 3 weeks post injury. Retina tissue was used to determine retinal ganglion cell (RGC) number, while optic nerve tissue was examined for cellularity, myelin content, protein and lipid changes. Increased cellularity and areas of demyelination were clearly detectable in optic nerves in r-mTBI, but not in r-sham. These changes were accompanied by a ~25% decrease in the total number of Brn3a-positive RGCs. Proteomic analysis of the optic nerves demonstrated various changes consistent with a negative effect of r-mTBI on major cellular processes like depolymerization of microtubules, disassembly of filaments and loss of neurons, manifested by decrease of several proteins, including neurofilaments (NEFH, NEFM, NEFL), tubulin (TUBB2A, TUBA4A), microtubule-associated proteins (MAP1A, MAP1B), collagen (COL6A1, COL6A3) and increased expression of other proteins, including heat shock proteins (HSP90B1, HSPB1), APOE and cathepsin D. Lipidomic analysis showed quantitative changes in a number of phospholipid species, including a significant increase in the total amount of lysophosphatidylcholine (LPC), including the molecular species 16:0, a known demyelinating agent. The overall amount of some ether phospholipids, like ether LPC, ether phosphatidylcholine and ether lysophosphatidylethanolamine were also increased, while the majority of individual molecular species of ester phospholipids, like phosphatidylcholine and phosphatidylethanolamine, were decreased. Results from the biochemical analysis correlate well with changes detected by histological and immunohistochemical methods and indicate the involvement of several important molecular pathways. This will allow future identification of therapeutic targets for improving the visual consequences of r-mTBI.

No MeSH data available.


Related in: MedlinePlus