RETRACTED ARTICLE: Decreased neuroinflammation and increased brain energy homeostasis following environmental enrichment after mild traumatic brain injury is associated with improvement in cognitive function

Teresita L Briones,Julie Woods,Magdalena Rogozinska

doi:10.1186/2051-5960-1-57

Abstract

BackgroundPersistent neuroinflammation and disruptions in brain energy metabolism is commonly seen in traumatic brain injury (TBI). Because of the lack of success of most TBI interventions and the documented benefits of environmental enrichment (EE) in enhancing brain plasticity, here we focused our study on use of EE in regulating injury-induced neuroinflammation and disruptions in energy metabolism in the prefrontal cortex and hippocampus. Adult male Wistar rats were used in the study and randomly assigned to receive either: mild TBI (mTBI) using the controlled cortical injury model or sham surgery. Following surgery, rats from each group were further randomized to either: EE housing or standard laboratory housing (CON). After 4 weeks of recovery, cognitive testing was performed using the non-matching-to-sample and delayed non-matching-to-sample tasks. After completion of behavioral testing, levels of the pro-inflammatory cytokines IL-1β and TNF-α and the anti-inflammatory cytokine IL-10 were measured. In addition, levels of AMPK (adenosine monophosphate-activated protein kinase), phosphorylated AMPK and uMtCK (ubiquitous mitochondrial creatine kinase) were assessed as measures of brain energy homeostasis.ResultsOur results showed that EE: (1) decreased the pro-inflammatory cytokines IL-1β and TNF-α and enhanced levels of the anti-inflammatory cytokine IL-10 after mTBI; (2) mitigated mTBI-induced cognitive impairment; and (3) attenuated mTBI-induced downregulation in pAMPK/AMPK ratio and uMtCK levels.ConclusionsOur data demonstrated the potential of EE to modulate the persistent: (1) neuroinflammatory response seen following mTBI, and (2) persistent disturbance in brain energy homeostasis. It is possible that through the mechanism of modulating neuroinflammation, EE housing was able to restore the disruption in energy metabolism and enhanced functional recovery after mTBI.

Highlights

Persistent neuroinflammation and disruptions in brain energy metabolism is commonly seen in traumatic brain injury (TBI)
Our results showed significant main effects on IL-1β (F(3,30) = 9.21, p < 0.05) and TNF-α (F(3,30) = 9.67, p < 0.05) in the prefrontal cortex where mild TBI (mTBI) led to the upregulation of these inflammatory cytokines even after more than a month of recovery from injury (Figure 1A and B)
IL-10 level in the mTBI rats housed in EE was 41% higher when compared to the mTBI animals housed in regular laboratory cages

Summary

Introduction

Persistent neuroinflammation and disruptions in brain energy metabolism is commonly seen in traumatic brain injury (TBI). The acute effects of mTBI stemming from the primary insult can cause secondary injuries that can evolve over minutes to days and even months after the initial traumatic event Secondary injury events such as neuroinflammation can cause neurodegeneration and persistent cognitive impairment [7]. When microglia become over-activated or reactive they can induce detrimental neurotoxic effects by releasing multiple cytotoxic substances, such as proinflammatory cytokines (e.g. interleukin-1 beta and tumor necrosis factor-alpha) and arachidonic acid metabolites [12,13,14] These reports suggest that clear beneficial effects can be achieved if neuroinflammation is controlled in a regulated manner and for a defined period of time. There is increasing number of evidence that chronic microglial activation is present in most cases of TBI leading to neuroinflammation that can persist for months or years after injury [14,15]

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