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

Shichen Shen,Ming Zhang,Min Ma,Jun Qu,David Poulsen,Sailee Rasam

doi:10.3390/ijms22052246

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.

Highlights

IntroductionBecause of the highly complex and heterogeneous nature of Traumatic brain injury (TBI) [3], a comprehensive and in-depth systems biology approach is warranted to understand the molecular mechanisms underlying TBI-induced neuropathy and to better facilitate the clinical management of TBI patients and the development of promising therapeutic drug candidates
Traumatic brain injury (TBI) accounts for over 2.8 million emergency department visits and over 56,000 deaths in the United States annually [1]
In an effort to further delineate the putative mechanisms underlying the neuroprotective effects of low-dose MA, we investigated the unique proteomic changes induced by MA administration following severe TBI compared to both mild and severe TBI

Summary

Introduction

Because of the highly complex and heterogeneous nature of TBI [3], a comprehensive and in-depth systems biology approach is warranted to understand the molecular mechanisms underlying TBI-induced neuropathy and to better facilitate the clinical management of TBI patients and the development of promising therapeutic drug candidates. This remains challenging due to the incapability of most experimental techniques to simultaneously target hundreds or thousands of molecules in one single experiment.

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