Mitochondrial dysfunctioning and neuroinflammation: Recent highlights on the possible mechanisms involved in Traumatic Brain Injury

Sahel, Deepak Kumar; Kaira, Meenakshi; Raj, Khadga; Sharma, Shakshi; Singh, Shamsher

doi:10.1016/j.neulet.2019.134347

Cited by 51 publications

(40 citation statements)

References 60 publications

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“…The extent to which these mechanisms are damaged in TBI depends on the severity of the impact. There are various systems and scales to assess the severity of TBI, the most commonly used is the Glasgow Coma Scale (GCS) which classifies TBI into mild (GCS range [13][14][15], moderate (GCS range 9-12) and severe (GCS range [3][4][5][6][7][8]. The GCS is obtained by scoring specific clinical assessments, including eye opening, motor and verbal responses [5] (Table 1).…”

Section: Definition/classificationmentioning

confidence: 99%

“…The secondary insult is characterized by the imbalance of ionic homeostasis, release of excitatory neurotransmitters (glutamate, aspartate), glucose dysmetabolism with mitochondrial dysfunction, and free radical overproduction. Final consequences are the activation of different molecular pathways and inflammatory cascades, leading to cellular apoptosis and damage of the BBB permeability [15]. The formation of reactive oxygen species (ROS) and free radicals in brain tissue following TBI is well documented and plays a crucial role in triggering molecular damaging processes (lipid peroxidation, DNA damage, protein oxidation) and in exacerbating glutamate excitotoxicity, mitochondrial dysfunction, ionic dysregulation, and activation of cellular proteases [16][17][18].…”

Section: Tbi and Oxidative/nitrosative Stress: A Rationale For Antioxmentioning

confidence: 99%

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Antioxidant Therapies in Traumatic Brain Injury

et al. 2020

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Due to a multiplicity of causes provoking traumatic brain injury (TBI), TBI is a highly heterogeneous pathology, characterized by high mortality and disability rates. TBI is an acute neurodegenerative event, potentially and unpredictably evolving into sub-chronic and chronic neurodegenerative events, with transient or permanent neurologic, cognitive, and motor deficits, for which no valid standardized therapies are available. A vast body of literature demonstrates that TBI-induced oxidative/nitrosative stress is involved in the development of both acute and chronic neurodegenerative disorders. Cellular defenses against this phenomenon are largely dependent on low molecular weight antioxidants, most of which are consumed with diet or as nutraceutical supplements. A large number of studies have evaluated the efficacy of antioxidant administration to decrease TBI-associated damage in various animal TBI models and in a limited number of clinical trials. Points of weakness of preclinical studies are represented by the large variability in the TBI model adopted, in the antioxidant tested, in the timing, dosages, and routes of administration used, and in the variety of molecular and/or neurocognitive parameters evaluated. The analysis of the very few clinical studies does not allow strong conclusions to be drawn on the real effectiveness of antioxidant administration to TBI patients. Standardizing TBI models and different experimental conditions, as well as testing the efficacy of administration of a cocktail of antioxidants rather than only one, should be mandatory. According to some promising clinical results, it appears that sports-related concussion is probably the best type of TBI to test the benefits of antioxidant administration.

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Section: Definition/classificationmentioning

confidence: 99%

Section: Tbi and Oxidative/nitrosative Stress: A Rationale For Antioxmentioning

confidence: 99%

Antioxidant Therapies in Traumatic Brain Injury

et al. 2020

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“…Mitochondria consume more than 90% of the total respired oxygen and generate ROS from 2% of that oxygen [71]. The inflammatory stimuli mediated by TLR receptors and other factors cause impairment of the mitochondrial electron transport chain, leading to ROS generation accompanied by reduced mitochondrial ATP production [72][73][74]. The MitoROS generated during the acute phase of the brain injury not only directly damage the brain tissues, but also induce pro-inflammatory reactions [75] through the formation of inflammasomes.…”

Section: Oxidative Stress Caused By Microglia and Macrophages In Tbi mentioning

confidence: 99%

Microglia and Macrophages in the Pathological Central and Peripheral Nervous Systems

Abe

Nishihara

Yorozuya

et al. 2020

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Microglia, the immunocompetent cells in the central nervous system (CNS), have long been studied as pathologically deteriorating players in various CNS diseases. However, microglia exert ameliorating neuroprotective effects, which prompted us to reconsider their roles in CNS and peripheral nervous system (PNS) pathophysiology. Moreover, recent findings showed that microglia play critical roles even in the healthy CNS. The microglial functions that normally contribute to the maintenance of homeostasis in the CNS are modified by other cells, such as astrocytes and infiltrated myeloid cells; thus, the microglial actions on neurons are extremely complex. For a deeper understanding of the pathophysiology of various diseases, including those of the PNS, it is important to understand microglial functioning. In this review, we discuss both the favorable and unfavorable roles of microglia in neuronal survival in various CNS and PNS disorders. We also discuss the roles of blood-borne macrophages in the pathogenesis of CNS and PNS injuries because they cooperatively modify the pathological processes of resident microglia. Finally, metabolic changes in glycolysis and oxidative phosphorylation, with special reference to the pro-/anti-inflammatory activation of microglia, are intensively addressed, because they are profoundly correlated with the generation of reactive oxygen species and changes in pro-/anti-inflammatory phenotypes.

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“…The severity of this cellular and molecular damage depends on the impact force acting on the cerebral tissue [12]. Mitochondrial dysfunction occurs in the post-injured brain [13,14], causing an imbalance of ATP production and consumption, with consequent energy crisis [15]. This triggers the intrinsic apoptotic pathway [16], and increasing levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS) with associated decreased levels of cell antioxidants [17] causing an insurgence of oxidative/nitrosative stress [18].…”

Section: Introductionmentioning

confidence: 99%

Low Molecular Weight Dextran Sulfate (ILB®) Administration Restores Brain Energy Metabolism Following Severe Traumatic Brain Injury in the Rat

et al. 2020

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Traumatic brain injury (TBI) is the leading cause of death and disability in people less than 40 years of age in Western countries. Currently, there are no satisfying pharmacological treatments for TBI patients. In this study, we subjected rats to severe TBI (sTBI), testing the effects of a single subcutaneous administration, 30 min post-impact, of a new low molecular weight dextran sulfate, named ILB®, at three different dose levels (1, 5, and 15 mg/kg body weight). A group of control sham-operated animals and one of untreated sTBI rats were used for comparison (each group n = 12). On day 2 or 7 post-sTBI animals were sacrificed and the simultaneous HPLC analysis of energy metabolites, N-acetylaspartate (NAA), oxidized and reduced nicotinic coenzymes, water-soluble antioxidants, and biomarkers of oxidative/nitrosative stress was carried out on deproteinized cerebral homogenates. Compared to untreated sTBI rats, ILB® improved energy metabolism by increasing ATP, ATP/ adenosine diphosphate ratio (ATP/ADP ratio), and triphosphate nucleosides, dose-dependently increased NAA concentrations, protected nicotinic coenzyme levels and their oxidized over reduced ratios, prevented depletion of ascorbate and reduced glutathione (GSH), and decreased oxidative (malondialdehyde formation) and nitrosative stress (nitrite + nitrate production). Although needing further experiments, these data provide the first evidence that a single post-injury injection of a new low molecular weight dextran sulfate (ILB®) has beneficial effects on sTBI metabolic damages. Due to the absence of adverse effects in humans, ILB® represents a promising therapeutic agent for the treatment of sTBI patients.

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Mitochondrial dysfunctioning and neuroinflammation: Recent highlights on the possible mechanisms involved in Traumatic Brain Injury

Cited by 51 publications

References 60 publications

Antioxidant Therapies in Traumatic Brain Injury

Antioxidant Therapies in Traumatic Brain Injury

Microglia and Macrophages in the Pathological Central and Peripheral Nervous Systems

Low Molecular Weight Dextran Sulfate (ILB®) Administration Restores Brain Energy Metabolism Following Severe Traumatic Brain Injury in the Rat

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