Mitigating ER stress and oxidative stress is beneficial after traumatic brain injury
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1
University of Wisconsin, Department of Neurological Surgery, United States
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2
University of Wisconsin, Department of Pediatrics, United States
Endoplasmic reticulum (ER) stress and oxidative stress are known proponents of secondary neuronal damage and neurological dysfunction following traumatic brain injury (TBI). A moderate controlled cortical impact-induced TBI in adult mice significantly induced the phosphorylation of PERK and eIF2α and also increased the expression of the down-stream CHOP and ATF4 indicating activation of PERK signaling pathway that kills neurons if uncontrolled. We further show that treating adult mice with salubrinal (an inhibitor of PERK pathway) leads to a significant decrease in the secondary cortical contusion with a good window of efficacy (5 min to 4h after injury). In the cohort of mice treated with salubrinal at 2h after TBI, there was a significant improvement in the motor function recovery measured by rotarod test and beam walk test. TBI also increased the expression NADPH oxidase subunit NOX2 (gp91phox; promotes formation of reactive oxygen species) and the transcription factor Nrf2 (induces down-stream anti-oxidant enzymes). We tested apocynin (an inhibitor of NOX2; 10 mg/Kg) and TBHQ (an activator of Nrf2; 25 mg/Kg) alone or in combination in cohorts of mice subjected to CCI injury. Either apocynin or TBHQ treatment alone significantly improved the motor function after TBI compared to vehicle control. The drug treated mice stayed longer on rotarod and made fewer foot faults in beam walk test between day 1 to 7 after injury. The combination therapy (apocynin + TBHQ) also significantly improved the post-TBI motor function compared to vehicle control, but there was no additive effect of the 2 drugs. Following the combination therapy, mice spent significantly greater time with higher frequency in the platform quadrant as compared to vehicle control when tested for cognition by Morris Water maze test at 3 weeks after injury. The cortical contusion volume was also significantly lower in the combo therapy group compared to vehicle control. In conclusion, these studies show that controlling either ER stress or oxidative stress significantly improves the functional outcome and tissue sparing after TBI.
Keywords:
Endoplasmic Reticulum Stress,
Oxidative Stress,
Motor function,
in vivo,
Brain Injury
Conference:
14th Meeting of the Asian-Pacific Society for Neurochemistry, Kuala Lumpur, Malaysia, 27 Aug - 30 Aug, 2016.
Presentation Type:
Free Paper Session 2: Molecular Mechanisms of the Nervous System
Topic:
14th Meeting of the Asian-Pacific Society for Neurochemistry
Citation:
Vemuganti
R,
Mehta
SL,
Bodden
L,
Nakka
V,
Kim
TH,
Chandran
R,
Udho
E,
Cengiz
P and
Dempsey
RJ
(2016). Mitigating ER stress and oxidative stress is beneficial after traumatic brain injury.
Conference Abstract:
14th Meeting of the Asian-Pacific Society for Neurochemistry.
doi: 10.3389/conf.fncel.2016.36.00105
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Received:
04 Aug 2016;
Published Online:
11 Aug 2016.
*
Correspondence:
Prof. Raghu Vemuganti, University of Wisconsin, Department of Neurological Surgery, Madison, WI, United States, vemuganti@neurosurgery.wisc.edu