Impaired cortical mitochondrial function following TBI precedes behavioral changes

William D Watson ,Neil E Grunberg ,Angela M Yarnell ,Jessica J Lucky,John E Buonora ,Michaela I D'acchille ,David C Mcmullen ,Ajay Verma,William S Kean ,Andrew V Kuczmarski ,Andrew G Boston,John T Cole

doi:10.3389/fnene.2013.00012

William D Watson , Neil E Grunberg + Show 10 more

Open Access

https://doi.org/10.3389/fnene.2013.00012

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Abstract

Traumatic brain injury (TBI) pathophysiology can be attributed to either the immediate, primary physical injury, or the delayed, secondary injury which begins minutes to hours after the initial injury and can persist for several months or longer. Because these secondary cascades are delayed and last for a significant time period post-TBI, they are primary research targets for new therapeutics. To investigate changes in mitochondrial function after a brain injury, both the cortical impact site and ipsilateral hippocampus of adult male rats 7 and 17 days after a controlled cortical impact (CCI) injury were examined. State 3, state 4, and uncoupler-stimulated rates of oxygen consumption, respiratory control ratios (RCRs) were measured and membrane potential quantified, and all were significantly decreased in 7 day post-TBI cortical mitochondria. By contrast, hippocampal mitochondria at 7 days showed only non-significant decreases in rates of oxygen consumption and membrane potential. NADH oxidase activities measured in disrupted mitochondria were normal in both injured cortex and hippocampus at 7 days post-CCI. Respiratory and phosphorylation capacities at 17 days post-CCI were comparable to naïve animals for both cortical and hippocampus mitochondria. However, unlike oxidative phosphorylation, membrane potential of mitochondria in the cortical lining of the impact site did not recover at 17 days, suggesting that while diminished cortical membrane potential at 17 days does not adversely affect mitochondrial capacity to synthesize ATP, it may negatively impact other membrane potential-sensitive mitochondrial functions. Memory status, as assessed by a passive avoidance paradigm, was not significantly impaired until 17 days after injury. These results indicate pronounced disturbances in cortical mitochondrial function 7 days after CCI which precede the behavioral impairment observed at 17 days.

Highlights

Traumatic brain injury (TBI) is a leading cause of death and disability in the United States, with an annual average of 53,014 deaths (Coronado et al, 2011)
State 3, state 4, and uncoupler-stimulated rates of oxygen consumption, respiratory control ratios (RCRs) were measured and membrane potential quantified, and all were significantly decreased in 7 day post-TBI cortical mitochondria
As assessed by a passive avoidance paradigm, was not significantly impaired until 17 days after injury. These results indicate pronounced disturbances in cortical mitochondrial function 7 days after cortical impact (CCI) which precede the behavioral impairment observed at 17 days

Summary

Introduction

Traumatic brain injury (TBI) is a leading cause of death and disability in the United States, with an annual average of 53,014 deaths (Coronado et al, 2011). TBI is the most common cause of death or disability in children (Danielle van Pelt et al, 2011). These mortality rates appear to be declining, this is primarily attributed to increasingly effective precautions such as airbags, improved child safety seats, and mandatory seat belt use (Coronado et al, 2011). Changes in energy generation and mitochondrial function are closely related to and interconnected with other delayed secondary manifestations of injury, including potent inflammatory responses (Dalgard et al, 2012) and Ca2+ dystasis (Ahmed et al, 2002; Weber et al, 2002; Louin et al, 2004; Deshpande et al, 2008; Balbino et al, 2010)

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