Efficacy of N-acetyl cysteine in traumatic brain injury

In this study, using two different injury models in two different species, we found that early post-injury treatment with NAcetyl Cysteine (NAC) reversed the behavioral deficits associated with the TBI. These data suggest generalization of a protocol similar to our recent clinical trial with NAC in blast-induced mTBI in a battlefield setting [1], to mild concussion from blunt trauma. This study used both weight drop in mice and fluid percussion injury in rats. These were chosen to simulate either mild or moderate traumatic brain injury (TBI). For mice, we used novel object recognition and the Y maze. For rats, we used the Morris water maze. NAC was administered beginning 30-60 minutes after injury. Behavioral deficits due to injury in both species were significantly reversed by NAC treatment. We thus conclude NAC produces significant behavioral recovery after injury. Future preclinical studies are needed to define the mechanism of action, perhaps leading to more effective therapies in man

Efficacy of N-Acetyl Cysteine in Traumatic Brain Injury

Abstract In this study, using two different injury models in two different species, we found that early post-injury treatment with NAcetyl Cysteine (NAC) reversed the behavioral deficits associated with the TBI. These data suggest generalization of a protocol similar to our recent clinical trial with NAC in blast-induced mTBI in a battlefield settin

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

Restoration of learning ability by AD4 (100 mg/kg) 30 days post injury.

<p>Thirty days post injury, the mTBI mice showed a decline in cognitive performance both in <b>(A</b>) the Y-maze test and in the (<b>B</b>) NOR test (*p<0.001). Treatment with AD4 (100mg/kg) improved these impairments, revealed by LSD post hoc (p<0.001). Values are mean ± SEM.</p

Restoration of learning ability by TXM-CB3, AD4, and DY-70 (50mg/kg) 7 days post injury.

<p>Seven days post injury, the mTBI mice showed a decline in cognitive performance both in the (<b>A</b>) Y-maze test and in the (<b>B</b>) NOR test (***p<0.001, *p<0.05). Treatment with TXM-CB3 and DY-70 (50mg/kg) improved and AD4 did not improve the cognitive performance, revealed by LSD post. Values are mean ± SEM.</p

Restoration of learning ability by AD4 (100 mg/kg) 30 days post injury.

<p>Thirty days post injury, the mTBI mice showed a decline in cognitive performance both in <b>(A</b>) the Y-maze test and in the (<b>B</b>) NOR test (*p<0.001). Treatment with AD4 (100mg/kg) improved these impairments, revealed by LSD post hoc (p<0.001). Values are mean ± SEM.</p

Administration of thiol reagnets alone did not affect leaning ability 30 days post injection.

<p>Mice administered AD4 and the TXM-peptides did not induce any learning deficit. All groups showed the same performance as the sham group <b>(A</b>) Spatial learning was tested using the Y-maze (N.S) and (<b>B</b>) Visual learning was tested using the NOR test (N.S). Values are mean ± SEM.</p

Restoration of learning ability by TXM-CB3, AD4, and DY-70 (50mg/kg) 30 days post injury.

<p>Thirty days post injury the mTBI mice showed a decline in cognitive performance both in (<b>A</b>) Y-maze test and in the (<b>B</b>) NOR test (***p<0.001). Treatment with TXM-CB3 (50 mg/kg) improved the cognitive performance. DY-70 (50mg/kg) did not improve the cognitive performance, revealed by LSD post. AD4 (50mg/kg) improved performance only in the Y maze test. Values are mean ± SEM.</p

Thioredoxin-Mimetic-Peptides Protect Cognitive Function after Mild Traumatic Brain Injury (mTBI) - Fig 3

<p>The chemical structures of AD4 (top), TXM-CB3 (middle), and DY-70 (bottom).</p

Restoration of learning ability by AD4 (100mg/kg) 7 days post injury.

<p>Seven days post injury mTBI mice exhibit lower learning ability both (<b>A</b>) in the Y-maze test and in <b>(B</b>) the NOR test (*p<0.05). Treatment with AD4 (100mg/kg) improved this impairment, revealed by LSD post hoc (p<0. 01). Values are mean ± SEM.</p