John B. Hiebert

Traumatic Brain Injury and Mitochondrial Dysfunction

Abstract:Traumatic brain injury (TBI) is a major cause of death and disability in the United States and causes mitochondrial damage leading to impaired brain function. The purpose of this review is to (1) describe TBI processes and manifestations, (2) examine the mitochondrial alterations after TBI, specifically increased reactive oxygen species production, decreased bioenergetics and apoptosis and (3) current TBI treatments. There are various degrees of severity of TBI, yet all affect mitochondrial function. Currently, health care professionals use various methods to assess TBI severity—from brain imaging to serum biomarkers. The major cause of TBI-associated brain damage is secondary injury, which is mainly from mitochondrial injury dysfunction. Mitochondrial injury leads to oxidative stress and subsequent apoptosis and decreased cellular energy production. These brain cellular alterations impair neurologic functions, which are observed in individuals with TBI. The complex mitochondrial dysfunction after TBI requires treatment that specifically addresses the secondary injury. There are numerous therapies being used, including (1) hypothermia, (2) hyperbaric oxygen, (3) exercise and (4) antioxidants. Researchers are exploring novel approaches to prevent, diagnose and treat TBI focusing on maintaining mitochondrial function.

Systematic Review of Traumatic Brain Injury and the Impact of Antioxidant Therapy on Clinical Outcomes

BACKGROUNDnTraumatic brain injury (TBI) is an acquired brain injury that occurs when there is sudden trauma that leads to brain damage. This acute complex event can happen when the head is violently or suddenly struck or an object pierces the skull or brain. The current principal treatment of TBI includes various pharmaceutical agents, hyperbaric oxygen, and hypothermia. There is evidence that secondary injury from a TBI is specifically related to oxidative stress. However, the clinical management of TBI often does not include antioxidants to reduce oxidative stress and prevent secondary injury.nnnAIMSnThe purpose of this article is to examine current literature regarding the use of antioxidant therapies in treating TBI. This review evaluates the evidence of antioxidant therapy as an adjunctive treatment used to reduce the underlying mechanisms involved in secondary TBI injury.nnnMETHODSnA systematic review of the literature published between January 2005 and September 2015 was conducted. Five databases were searched including CINAHL, PubMed, the Cochrane Library, PsycINFO, and Web of Science.nnnFINDINGSnCritical evaluation of the six studies that met inclusion criteria suggests that antioxidant therapies such as amino acids, vitamins C and E, progesterone, N-acetylcysteine, and enzogenol may be safe and effective adjunctive therapies in adult patients with TBI. Although certain limitations were found, the overall trend of using antioxidant therapies to improve the clinical outcomes of TBI was positive.nnnLINKING EVIDENCE TO ACTIONnBy incorporating antioxidant therapies into practice, clinicians can help attenuate the oxidative posttraumatic brain damage and optimize patients recovery.

Ubiquinol treatment for TBI in male rats: Effects on mitochondrial integrity, injury severity, and neurometabolism

Following traumatic brain injury (TBI), there is significant secondary damage to cerebral tissue from increased free radicals and impaired mitochondrial function. This imbalance between reactive oxygen species (ROS) production and the effectiveness of cellular antioxidant defenses is termed oxidative stress. Often there are insufficient antioxidants to scavenge ROS, leading to alterations in cerebral structure and function. Attenuating oxidative stress following a TBI by administering an antioxidant may decrease secondary brain injury, and currently many drugs and supplements are being investigated. We explored an over‐the‐counter supplement called ubiquinol (reduced form of coenzyme Q10), a potent antioxidant naturally produced in brain mitochondria. We administered intra‐arterial ubiquinol to rats to determine if it would reduce mitochondrial damage, apoptosis, and severity of a contusive TBI. Adult male F344 rats were randomly assigned to one of three groups: (1) Saline‐TBI, (2) ubiquinol 30 minutes before TBI (UB‐PreTBI), or (3) ubiquinol 30 minutes after TBI (UB‐PostTBI). We found when ubiquinol was administered before or after TBI, rats had an acute reduction in brain mitochondrial damage, apoptosis, and two serum biomarkers of TBI severity, glial fibrillary acidic protein (GFAP) and ubiquitin C‐terminal hydrolase‐L1 (UCH‐L1). However, in vivo neurometabolic assessment with proton magnetic resonance spectroscopy did not show attenuated injury‐induced changes. These findings are the first to show that ubiquinol preserves mitochondria and reduces cellular injury severity after TBI, and support further study of ubiquinol as a promising adjunct therapy for TBI.

Study protocol, randomized controlled trial: Reducing symptom burden in patients with heart failure with preserved ejection fraction using ubiquinol and/or D-ribose

BackgroundHeart failure (HF), the leading cause of morbidity and mortality in the US, affects 6.6 million adults with an estimated additional 3 million people by 2030. More than 50% of HF patients have heart failure with preserved left ventricular ejection fraction (HFpEF). These patients have impaired cardiac muscle relaxation and diastolic filling, which investigators have associated with cellular energetic impairment. Patients with HFpEF experience symptoms of: (1) fatigue; (2) shortness of breath; and (3) swelling (edema) of the lower extremities. However, current HF guidelines offer no effective treatment to address these underlying pathophysiologic mechanisms. Thus, we propose a biobehavioral symptom science study using ubiquinol and D-ribose (therapeutic interventions) to target mitochondrial bioenergetics to reduce the complex symptoms experienced by patients with HFpEF.MethodsUsing a randomized, double-blind, placebo-controlled design, the overall objective is to determine if administering ubiquinol and/or D-ribose to HFpEF patients for 12xa0weeks would decrease the severity of their complex symptoms and improve their cardiac function. The measures used to assess patients’ perceptions of their health status and level of vigor (energy) will be the Kansas City Cardiomyopathy Questionnaire (KCCQ) and Vigor subscale of the Profile of Mood States. The 6-min walk test will be used to test exercise tolerance. Left ventricular diastolic function will be assessed using innovative advanced echocardiography software called speckle tracking. We will measure B-type natriuretic peptides (secreted from ventricles in HF) and lactate/ATP ratio (measure of cellular energetics).DiscussionsUbiquinol (active form of Coenzyme Q10) and D-ribose are two potential treatments that can positively affect cellular energetic impairment, the major underlying mechanism of HFpEF. Ubiquinol, the reduced form of CoQ10, is more effective in adults over the age of 50. In patients with HFpEF, mitochondrial deficiency of ubiquinol results in decreased adenosine triphosphate (ATP) synthesis and reduced scavenging of reactive oxygen species. D-ribose is a substrate required for ATP synthesis and when administered has been shown to improve impaired myocardial bioenergetics. Therefore, if the biological underpinning of deficient mitochondrial ATP in HFpEF is not addressed, patients will suffer major symptoms including lack of energy, fatigue, exertional dyspnea, and exercise intolerance.Trial registrationClinicalTrials.gov Identifier: NCT03133793; Data of Registration: April 28, 2017.

A pilot study exploring the effects of ubiquinol on brain genomics after traumatic brain injury

BACKGROUNDnTraumatic brain injury is a major cause of morbidity and mortality that affects military service members and veterans.nnnPURPOSEnExplore the effects of ubiquinol before traumatic brain injury on cerebralxa0gene expression to elucidate molecular mechanisms of ubiquinol neuroprotection.nnnMETHODnIn this experimental study, Fisher rats in the untreated (n = 2) and ubiquinol-treated (n = 2) groups received respectively either normal saline or ubiquinol 30 min before traumatic brain injury induced by controlled cortical impact. Ribonucleic acid sequencing and ingenuity pathway analysis were conducted to detect cerebral gene and signaling expression profiles.nnnDISCUSSIONnIn the ubiquinol-treated group, 67 ingenuity pathway analysis transcripts in the ubiquinol-treated group were statistically different from those in the untreated group (p <.0001).nnnCONCLUSIONSnAdministering ubiquinol 30 min before traumatic brain injury significantly affected cerebral gene expression profiles that may be involved in the most fundamental molecular mechanisms of bioenergetics and free radical production.

The Use of Antioxidants in the Treatment of Traumatic Brain Injury

AIMSnThe aim of this study was to discuss secondary traumatic brain injury, the mitochondria and the use of antioxidants as a treatment.nnnBACKGROUNDnOne of the leading causes of death globally is traumatic brain injury, affecting individuals in all demographics. Traumatic brain injury is produced by an external blunt force or penetration resulting in alterations in brain function or pathology. Often, with a traumatic brain injury, secondary injury causes additional damage to the brain tissue that can have further impact on recovery and the quality of life. Secondary injury occurs when metabolic and physiologic processes alter after initial injury and includes increased release of toxic free radicals that cause damage to adjacent tissues and can eventually lead to neuronal necrosis. Although antioxidants in the tissues can reduce free radical damage, the magnitude of increased free radicals overwhelms the bodys reduced defence mechanisms. Supplementing the bodys natural supply of antioxidants, such as coenzyme Q10, can attenuate oxidative damage caused by reactive oxygen species.nnnDESIGNnDiscussion paper.nnnDATA SOURCESnResearch literature published from 2011-2016 in PubMed, CINAHL and Cochrane.nnnIMPLICATIONS FOR NURSINGnPrompt and accurate assessment of patients with traumatic brain injury by nurses is important to ensure optimal recovery and reduced lasting disability. Thus, it is imperative that nurses be knowledgeable about the secondary injury that occurs after a traumatic brain injury and aware of possible antioxidant treatments.nnnCONCLUSIONnThe use of antioxidants has potential to reduce the magnitude of secondary injury in patients who experience a traumatic brain injury.

Impaired Myocardial Bioenergetics in HFpEF and the Role of Antioxidants

Heart failure with preserved ejection fraction (HFpEF) is a significant cardiovascular condition for more than 50% of patients with heart failure. Currently, there is no effective treatment to decrease morbidity and mortality rates associated with HFpEF because of its pathophysiological heterogeneity. Recent evidence shows that deficiency in myocardial bioenergetics is one of the key pathophysiological factors contributing to diastolic dysfunction in HFpEF. Another known mechanism for HFpEF is an overproduction of free radicals, specifically reactive oxygen species. To reduce free radical formation, antioxidants are often used. This article is a summative review of the recent relevant literature that addresses cardiac bioenergetics, deficiency in myocardial bioenergetics, and increased reactive oxygen species associated with HFpEF and the promising potential use of antioxidants in managing this condition.

Understanding D-Ribose and Mitochondrial Function

Mitochondria are important organelles referred to as cellular powerhouses for their unique properties of cellular energy production. With many pathologic conditions and aging, mitochondrial function declines, and there is a reduction in the production of adenosine triphosphate. The energy carrying molecule generated by cellular respiration and by pentose phosphate pathway, an alternative pathway of glucose metabolism. D-ribose is a naturally occurring monosaccharide found in the cells and particularly in the mitochondria is essential in energy production. Without sufficient energy, cells cannot maintain integrity and function. Supplemental D-ribose has been shown to improve cellular processes when there is mitochondrial dysfunction. When individuals take supplemental D-ribose, it can bypass part of the pentose pathway to produce D-ribose-5-phosphate for the production of energy. In this article, we review how energy is produced by cellular respiration, the pentose pathway, and the use of supplemental D-ribose.