Potential Neuroprotective Mechanisms of Methamphetamine Treatment in Traumatic Brain Injury Defined by Large-Scale IonStar-Based Quantitative Proteomics

Abstract

Although traumatic brain injury (TBI) causes hospitalizations and mortality worldwide, there are no approved neuroprotective treatments, partly due to a poor understanding of the molecular mechanisms underlying TBI neuropathology and neuroprotection. We previously reported that the administration of low-dose methamphetamine (MA) induced significant functional/cognitive improvements following severe TBI in rats. We further demonstrated that MA mediates neuroprotection in part, via dopamine-dependent activation of the PI3K-AKT pathway. Here, we further investigated the proteomic changes within the rat cortex and hippocampus following mild TBI (TM), severe TBI (TS), or severe TBI plus MA treatment (TSm) compared to sham operated controls. We identified 402 and 801 altered proteins (APs) with high confidence in cortical and hippocampal tissues, respectively. The overall profile of APs observed in TSm rats more closely resembled those seen in TM rather than TS rats. Pathway analysis suggested beneficial roles for acute signaling through IL-6, TGFβ, and IL-1β. Moreover, changes in fibrinogen levels observed in TSm rats suggested a potential role for these proteins in reducing/preventing TBI-induced coagulopathies. These data facilitate further investigations to identify specific pathways and proteins that may serve as key targets for the development of neuroprotective therapies.

Translational and Posttranslational Dynamics in a Model Peptidergic System

“…Statistical significance was then determined using Welch’s t-tests between the conditions of interest. Since it has been discussed that the use of multiple testing–corrected false discovery rate maybe too blunt and restrictive for proteomic analysis ( 26 ), especially when analyzing such a heterogeneous and complex tissue as the brain ( 27 , 28 , 29 , 30 , 31 , 32 ), we considered uncorrected p < 0.05 as differentially produced proteins and phosphosites in all our SON and NIL analysis. All data have been deposited at the ProteomeXchange Consortium via the PRIDE partner repository ( 33 ) with the dataset identifier PXD040870 .…”

Exosomes Derived from Nerve Stem Cells Loaded with FTY720 Promote the Recovery after Spinal Cord Injury in Rats by PTEN/AKT Signal Pathway

“…The result showed that FYT720-NSCS-Exos can availably protect the endothelial barrier and promote the expression of ZO-1 under the hypoxic circumstance. PI3K/AKT pathway is a regulator of apoptosis and survival, and PTEN is considered to be a negative regulator of the PI3K/AKT pathway [47]. p-Akt is a key protein in PI3K/AKT pathway and could inhibit cell apoptosis and improve cell survival [48].…”