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

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.

Serum metabonomics analysis of quercetin against the toxicity induced by cadmium in rats

“…[46][47][48][49][50] LysoPC levels are drastically elevated in patients with brain injury. [51] COX-2 is widely involved in brain trauma, ischemia-induced neuronal damage, inflammatory responses, and neurodegenerative diseases. The role of COX-2 in neuropathology is related to changes JIA ET AL.…”

From peroxisomal disorders to common neurodegenerative diseases – the role of ether phospholipids in the nervous system

“…Intriguing, in this context, is the impaired phosphorylation of AKT and, therefore, loss of inhibitory phosphorylation of GSK 3b observed in the PNS of plasmalogen-deficient mice [59]. GSK 3b is one of the kinases implicated in tau phosphorylation [217]; and increased GSK 3b activity upon plasmalogen deficiency may well contribute to Increased levels of some ether-bonded species, particularly such with choline head groups in murine optic nerve after repetitive mild traumatic brain injury [262] Reduced PlsEtn levels in spinal cord after laminectomy and spinal cord compression in a cat model [263] Spinal cord ischemia Reduction of PlsEtn levels (and other ethanolamine phospholipids) in spinal cord of rabbits after ischemia [264] Ischemic stroke Reduction of PlsEtn levels in synaptosomes from rat striatum after injection of endothelin-1 (producing an ischemia-like lesion) [265] Increased levels of PAF in blood of patients [266] Correlation between PAF binding to platelets and infarct volume as well as neurological outcome [267] APLP, amyloid precursor protein-like protein; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin; MS, multiple sclerosis; PS, presenilin.…”

Identification of chronic brain protein changes and protein targets of serum auto-antibodies after blast-mediated traumatic brain injury

“…Some proteins identified in our study were previously identified as upregulated in a proteomic analysis of optic nerves from mice subjected to repetitive blunt impact TBI [59]. These proteins included ALB, MAP1A, and TUBA4A.…”

“…Visual dysfunction can be observed immediately following injury [56], with deficits persisting months after the injury [57]. The visual system damage observed after blast exposure is similar to damage observed in weight drop models of TBI [52,58,59], suggesting similar mechanisms. These mechanisms are varied and include axonal damage, activation of microglia, tissue swelling, infiltration of immune cells, upregulation of chemoattractants, and neuroinflammation [8,60,61,62,63,64,65,66,67].…”