Thioredoxin-Mimetic-Peptides Protect Cognitive Function after Mild Traumatic Brain Injury (mTBI)

PLoS One. 2016 Jun 10;11(6):e0157064. doi: 10.1371/journal.pone.0157064. eCollection 2016.

Abstract

Mild traumatic brain injury (mTBI) is recognized as a common injury among children, sportsmen, and elderly population. mTBI lacks visible objective structural brain damage but patients frequently suffer from long-lasting cognitive, behavioral and emotional difficulties associated with biochemical and cellular changes. Currently there is no effective treatment for patients with mTBI. The thioredoxin reductase/thioredoxin pathway (TrxR/Trx1) has both anti-inflammatory and anti-oxidative properties. If the system is compromised, Trx1 remains oxidized and triggers cell death via an ASK1-Trx1 signal transduction mechanism. We previously showed tri and tetra peptides which were derived from the canonical -CxxC- motif of the Trx1-active site, called thioredoxin mimetic (TXM) peptides, reversed inflammatory and oxidative stress damage mimicking Trx1 activity. Here, TXM-peptides were examined for protecting cognitive function following weight drop closed-head injury in a mouse model of mTBI. TXM-CB3 (AcCys-Pro-CysNH2), TXM-CB13 (DY-70; AcCys-Met-Lys-CysNH2) or AD4 (ACysNH2) were administered at 50 mg/kg, 60 min after injury and cognitive performance was monitored by the novel-object-recognition and Y-maze tests. Behavioral deficits subsequent to mTBI injury were reversed by a single dose of TXM-CB3, TXM-CB13 and, to a lesser extent, by AD4. TXM-CB13 similar to TXM-CB3 and AD4 reversed oxidative stress-induced phosphorylation of mitogen-activated kinases, p38MAPK and c-Jun N-terminal kinase, (JNK) in human neuronal SH-SY5Y cells. We conclude that significantly improved cognitive behavior post mTBI by the TXM-peptides could result from anti-apoptotic, and/or anti-inflammatory activities. Future preclinical studies are required to establish the TXM-peptides as potential therapeutic drugs for brain injuries.

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Biomimetics
  • Brain Concussion / drug therapy*
  • Brain Concussion / pathology
  • Brain Concussion / physiopathology
  • Brain Concussion / psychology
  • Cognition / drug effects*
  • Disease Models, Animal
  • Male
  • Mice
  • Mice, Inbred ICR
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology*
  • Peptides / chemistry
  • Peptides / pharmacology*
  • Thioredoxins / chemistry*
  • Thioredoxins / pharmacology

Substances

  • Neuroprotective Agents
  • Peptides
  • Thioredoxins

Grant support

This research was supported by the Ari and Regine Aprijaskis Fund at Tel-Aviv University, and by The H.L Lauterbach Fund (Hebrew University) to DA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.