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.
Highlights
Traumatic brain (TBI) and spinal cord injuries are the largest causes of death and disability within the spectrum of trauma-related injuries
LSD post hoc confirmed that the mild traumatic brain injury (mTBI) group was different from all other groups (p
LSD post hoc analysis confirmed that the mTBI group was different from the AD4-treated groups (p
Summary
Traumatic brain (TBI) and spinal cord injuries are the largest causes of death and disability within the spectrum of trauma-related injuries. Similar to more severe traumatic brain injury [3], [4], [5], mTBI has been characterized as a multi- phase injury, comprised of a primary blunt force injury followed by secondary injuries lasting over an extended period of time [6], [7]. This delayed phase involves glutamate toxicity, permeability of the blood-brain-barrier (BBB), elevated oxidative stress, inflammation, astrocyte reactivity, apoptosis and other processes [8]. Secondary injury effects may potentially be reduced even if primary brain damage cannot be prevented [11]
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