Thioredoxin-Mimetic-Peptides Protect Cognitive Function after Mild Traumatic Brain Injury (mTBI).
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.
Department of Anatomy and Anthropology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Renana
R
Baratz-Goldstein
Department of Anatomy and Anthropology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Hanna
H
Deselms
Department of Anatomy and Anthropology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Leore Raphael
LR
Heim
Department Biological Chemistry, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, 91904, Israel.
Lena
L
Khomski
Department of Neurosurgery, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
Barry J
BJ
Hoffer
Department Biological Chemistry, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, 91904, Israel.
Daphne
D
Atlas
Department of Anatomy and Anthropology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.|Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
Chaim G
CG
Pick
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D032701:Biomimetics; D001924:Brain Concussion / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology / Q000523:psychology; D003071:Cognition / Q000187:drug effects*; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D013879:Thioredoxins / Q000737:chemistry* / Q000494:pharmacology
D018696:Neuroprotective Agents; D010455:Peptides; D013879:Thioredoxins