Oxidative stress and mitochondrial dysfunction following traumatic brain injury: From mechanistic view to targeted therapeutic opportunities

Abstract

Traumatic brain injury (TBI) is one of the most prevalent causes of permanent physical and cognitive disabilities. TBI pathology results from primary insults and a multi-mechanistic biochemical process, termed as secondary brain injury. Currently, there are no pharmacological agents for definitive treatment of patients with TBI. This article is presented with the purpose of reviewing molecular mechanisms of TBI pathology, as well as potential strategies and agents against pathological pathways. In this review article, materials were obtained by searching PubMed, Scopus, Elsevier, Web of Science, and Google Scholar. This search was considered without time limitation. Evidence indicates that oxidative stress and mitochondrial dysfunction are two key mediators of the secondary injury cascade in TBI pathology. TBI-induced oxidative damage results in the structural and functional impairments of cellular and subcellular components, such as mitochondria. Impairments of mitochondrial electron transfer chain and mitochondrial membrane potential result in a vicious cycle of free radical formation and cell apoptosis. The results of some preclinical and clinical studies, evaluating mitochondria-targeted therapies, such as mitochondriatargeted antioxidants and compounds with pleiotropic effects after TBI, are promising. As a proposed strategy in recent years, mitochondria-targeted multipotential therapy is a new hope, waiting to be confirmed. Moreover, based on the available findings, biologics, such as stem cell-based therapy and transplantation of mitochondria are novel potential strategies for the

Antioxidant Therapeutic Strategies in Neurodegenerative Diseases

“…Traumatic brain injury research remains a topic of significant research investment and numerous studies have investigated mitochondrial antioxidant molecular targets. A full discussion of these pathways is outside the scope of this review and a comprehensive discussion of animal studies of mitochondrial targets in traumatic brain injury may be found in Hakimina et al [ 93 ].…”

“…Despite this large number of preclinical trials, three clinical trials have been investigated clinically. The GSH-amplifying agent and ROS scavenger N-acetylcysteine, which has been shown to have positive effects on neuronal survival, suppressing oxidative stress, reducing apoptosis and exerting an anti-inflammatory effect in traumatic brain injury [ 93 ] was investigated in a randomized double blind placebo controlled trial in serviceman suffering mild traumatic brain injury following blast injuries in a combat zone, concluding that N-acetylcysteine improved both neuropsychological and medical symptoms following blast injury [ 94 ]. Administration of the flavonoid Enzogenol (a herbal supplement) to patients suffering mild traumatic brain injury demonstrated an improvement in cognitive symptoms compared to a placebo in a pilot randomized clinical trial [ 95 ].…”

Environmental Enrichment Protects Against Cognition Deficits Caused by Sepsis-Associated Encephalopathy

“…We also found that antioxidant activity was suppressed by SAE, and EE could alleviate this suppression, indicating that EE improved the antioxidant system. Increased oxidative stress produces reactive oxygen species in the brain, which play a positive role in modulating the production of pro-inflammatory mediators by preventing MAPK and nuclear factor kappa B (NF-κB) activation in microglia cells [87]. Therefore, we concluded that EE alleviates the SAE-induced increase in oxidative stress and decreased antioxidant system, resulting in a decrease in pro-inflammatory cytokines.…”

Polynitroxylated PEGylated hemoglobin protects pig brain neocortical gray and white matter after traumatic brain injury and hemorrhagic shock

“…Traumatic brain injury (TBI) produces an immediate mechanical injury to brain tissue followed by the secondary injury that evolves over acute, subacute, and chronic stages instigated by imbalances in neurotransmitter signal processing and connectivity, mitochondrial dysfunction, oxidative stress, and neuroinflammation (1)(2)(3)(4)(5). With moderate or severe TBI, early treatment focuses on maintaining mean arterial blood pressure (MABP) and minimizing brain swelling to mitigate intracranial hypertension.…”