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.

Antioxidative CXXC Peptide Motif From Mesencephalic Astrocyte-Derived Neurotrophic Factor Antagonizes Programmed Cell Death

“…However, we cannot claim that reduction of ROS is a sole caspase-blocking mechanism of the peptide, as ROS are probably not the main cytotoxic mechanism in death receptor pathway. The CXXC motifs can also regulate cellular processes via other activities, such as metal binding, as they are able to chelate zinc and copper ( Collet et al, 2003 ; Wouters et al, 2010 ; Safaei et al, 2012 ), or alleviating the unfolded protein response ( Woycechowsky and Raines, 2003 ; Baratz-Goldstein et al, 2016 ). The cytoprotective activity of CKGC peptide composed of dCKGC suggests that caspase inactivation could not occur via direct interaction with the caspases (or other upstream proteins).…”

The Potential Roles of Redox Enzymes in Alzheimer’s Disease: Focus on Thioredoxin

“…Trx-mimetic peptides represent a new family of potent and selective redox compounds that could act as potential candidates for the prevention and treatment of oxidative stress-related diseases (Bachnoff et al., 2011). The Trx-mimetic peptide could improve cognitive function in a mouse model of mild traumatic brain injury (Baratz-Goldstein et al., 2016). Trx-mimetic peptide, Ac-Cys-Pro-Cys-amide, prevented the expression of TXNIP, inhibited the JNK/p38MAPK-mediated neuronal apoptosis and attenuated the neuro-inflammatory processes (Cohen-Kutner et al., 2014).…”

Elucidating opportunities and pitfalls in the treatment of experimental traumatic brain injury to optimize and facilitate clinical translation

“…Muccigrosso and colleagues (2016) measured cognitive deficits at one month following midline FP injury in adult male BALB/C mice using the Barnes maze. Cognitive deficits as measured by novel object recognition and Y-maze at 30 days post-injury in male mice subjected to weight drop TBI have been reported from several labs (Rachmany et al, 2013; Baratz-Goldstein et al, 2016; Ji et al, 2016). Cheng and colleagues (2012) showed that rats housed in standard (STD) living conditions exhibited spatial learning deficits even up to 6 months after a CCI injury of moderate severity.…”