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

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.

• Authors: Renana Baratz-Goldstein, Hanna Deselms, Leore Raphael Heim, Lena Khomski, Barry J Hoffer, Daphne Atlas, Chaim G Pick
• Journal: PloS one (PLoS One) Vol. 11 Issue 6 Pg. e0157064 ( 2016) ISSN: 1932-6203 [Electronic] United States
• PMID: 27285176 (Publication Type: Journal Article)

Chemical References

• Neuroprotective Agents
• Peptides
• Thioredoxins

Topics

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