P7C3 neuroprotective chemicals block axonal degeneration and preserve function after traumatic brain injury.
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ABSTRACT:
SUBMITTER: Yin TC
PROVIDER: S-EPMC4206693 | biostudies-literature | 2014 Sep
REPOSITORIES: biostudies-literature
Publications
P7C3 neuroprotective chemicals block axonal degeneration and preserve function after traumatic brain injury.
Yin Terry C TC Britt Jeremiah K JK De Jesús-Cortés Héctor H Lu Yuan Y Genova Rachel M RM Khan Michael Z MZ Voorhees Jaymie R JR Shao Jianqiang J Katzman Aaron C AC Huntington Paula J PJ Wassink Cassie C McDaniel Latisha L Newell Elizabeth A EA Dutca Laura M LM Naidoo Jacinth J Cui Huxing H Bassuk Alexander G AG Harper Matthew M MM McKnight Steven L SL Ready Joseph M JM Pieper Andrew A AA
Cell reports 20140915 6
The P7C3 class of neuroprotective aminopropyl carbazoles has been shown to block neuronal cell death in models of neurodegeneration. We now show that P7C3 molecules additionally preserve axonal integrity after injury, before neuronal cell death occurs, in a rodent model of blast-mediated traumatic brain injury (TBI). This protective quality may be linked to the ability of P7C3 molecules to activate nicotinamide phosphoribosyltransferase, the rate-limiting enzyme in nicotinamide adenine dinucleot ...[more]
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Project description:Diffuse axonal injury (DAI) is a common feature of severe traumatic brain injury (TBI) and may also be a predominant pathology in mild TBI or "concussion". The rapid deformation of white matter at the instant of trauma can lead to mechanical failure and calcium-dependent proteolysis of the axonal cytoskeleton in association with axonal transport interruption. Recently, a proteolytic fragment of alpha-II spectrin, "SNTF", was detected in serum acutely following mild TBI in patients and was prognostic for poor clinical outcome. However, direct evidence that this fragment is a marker of DAI has yet to be demonstrated in either humans following TBI or in models of mild TBI. Here, we used immunohistochemistry (IHC) to examine for SNTF in brain tissue following both severe and mild TBI. Human severe TBI cases (survival <7d; n = 18) were compared to age-matched controls (n = 16) from the Glasgow TBI archive. We also examined brains from an established model of mild TBI at 6, 48 and 72 h post-injury versus shams. IHC specific for SNTF was compared to that of amyloid precursor protein (APP), the current standard for DAI diagnosis, and other known markers of axonal pathology including non-phosphorylated neurofilament-H (SMI-32), neurofilament-68 (NF-68) and compacted neurofilament-medium (RMO-14) using double and triple immunofluorescent labeling. Supporting its use as a biomarker of DAI, SNTF immunoreactive axons were observed at all time points following both human severe TBI and in the model of mild TBI. Interestingly, SNTF revealed a subpopulation of degenerating axons, undetected by the gold-standard marker of transport interruption, APP. While there was greater axonal co-localization between SNTF and APP after severe TBI in humans, a subset of SNTF positive axons displayed no APP accumulation. Notably, some co-localization was observed between SNTF and the less abundant neurofilament subtype markers. Other SNTF positive axons, however, did not co-localize with any other markers. Similarly, RMO-14 and NF-68 positive axonal pathology existed independent of SNTF and APP. These data demonstrate that multiple pathological axonal phenotypes exist post-TBI and provide insight into a more comprehensive approach to the neuropathological assessment of DAI.
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Project description:OBJECTIVES:We investigated an approach for the diagnosis of traumatic axonal injury (TAI) of the spinothalamic tract (STT) that was based on diffusion tensor tractography (DTT) results and a statistical comparison of individual patients who showed central pain following mild traumatic brain injury (mTBI) with the control group. METHODS:Five right-handed female patients in their forties and with central pain following mTBI and 12 age-, sex-, and handedness-matched healthy control subjects were recruited. After DTT reconstruction of the STT, we analyzed the STT in terms of three DTT parameters (fractional anisotropy (FA), mean diffusivity (MD), and fiber number (FN)) and its configuration (narrowing and tearing). To assess narrowing, we determined the area of the STT on an axial slice of the subcortical white matter. RESULTS:the FN values were significantly lower in at least one hemisphere of each patient when compared to those of the control subjects (p < 0.05). Significant decrements from the STT area in the control group were observed in at least one hemisphere of each patient (p < 0.05). Regarding configurational analysis, the STT showed narrowing and/or partial tearing in at least one hemisphere of each of the five patients. CONCLUSIONS:Herein, we demonstrate a DTT-based approach for the diagnosis of TAI of the STT. The approach involves a statistical comparison between DTT parameters of individual patients who show central pain following mTBI and those of an age-, gender-, and handedness-matched control group. We think that the method described in this study can be useful in the diagnosis of TAI of the STT in individual mTBI patients.
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