Cerebral Oxidative Stress and Depression of Energy Metabolism Correlate with Severity of Diffuse Brain Injury in Rats

Tavazzi, Barbara; Signoretti, Stefano; Lazzarino, Giuseppe; Amorini, Angela Maria; Delfini, Roberto; Cimatti, Marco; Marmarou, Anthony; Vagnozzi, Roberto

doi:10.1227/01.neu.0000156715.04900.e6

Cited by 132 publications

(124 citation statements)

References 47 publications

(48 reference statements)

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“…Studies on traumatic brain injury have consistently shown decreased NAA levels in the brain using different model systems, and the decreases in NAA and ATP were temporally correlated, suggesting that the NAA reductions are related to energetic impairment Signoretti et al, 2001;Signoretti et al, 2004;Tavazzi et al, 2005;Vagnozzi et al, 2005). The reductions in NAA and ATP were positively correlated with the severity of the brain injury.…”

Section: Impairments In Energy Metabolism Decrease Naa Levels In Brainmentioning

confidence: 85%

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

Moffett

Ross

Arun

et al. 2007

Progress in Neurobiology

1,183

1,126

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The brain is unique among organs in many respects, including its mechanisms of lipid synthesis and energy production. The nervous system-specific metabolite N-acetylaspartate (NAA), which is synthesized from aspartate and acetyl-coenzyme A in neurons, appears to be a key link in these distinct biochemical features of CNS metabolism. During early postnatal CNS development, the expression of lipogenic enzymes in oligodendrocytes, including the NAA-degrading enzyme aspartoacylase (ASPA), is increased along with increased NAA production in neurons. NAA is transported from neurons to the cytoplasm of oligodendrocytes, where ASPA cleaves the acetate moiety for use in fatty acid and steroid synthesis. The fatty acids and steroids produced then go on to be used as building blocks for myelin lipid synthesis. Mutations in the gene for ASPA result in the fatal leukodystrophy Canavan disease, for which there is currently no effective treatment. Once postnatal myelination is completed, NAA may continue to be involved in myelin lipid turnover in adults, but it also appears to adopt other roles, including a bioenergetic role in neuronal mitochondria. NAA and ATP metabolism appear to be linked indirectly, whereby acetylation of aspartate may facilitate its removal from neuronal mitochondria, thus favoring conversion of glutamate to alpha ketoglutarate which can enter the tricarboxylic acid cycle for energy production. In its role as a mechanism for enhancing mitochondrial energy production from glutamate, NAA is in a key position to act as a magnetic resonance spectroscopy marker for neuronal health, viability and number. Evidence suggests that NAA is a direct precursor for the enzymatic synthesis of the neuron specific dipeptide N-acetylaspartylglutamate, the most concentrated neuropeptide in the human brain. Other proposed roles for NAA include neuronal osmoregulation and axon-glial signaling. We propose that NAA may also be involved in brain nitrogen balance. Further research will be required to more fully understand the biochemical functions served by NAA in CNS development and activity, and additional functions are likely to be discovered.

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Section: Impairments In Energy Metabolism Decrease Naa Levels In Brainmentioning

confidence: 85%

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

Moffett

Ross

Arun

et al. 2007

Progress in Neurobiology

1,183

1,126

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“…Of particular relevance is the finding that N-acetylaspartate (NAA), an abundant brain-specific compound involved in several relevant biological functions including water homeostasis 14 and lipid myelin biosynthesis, 15 clearly mirrors TBI-induced changes in ATP, showing the same pattern of decrease and recovery following mTBI and no recovery in severe TBI or repeat mTBIs. 8,10,11 The strict correlation between NAA and ATP ensures that this compound may be used as a valid surrogate marker to monitor cerebral energy metabolism. 8,10,11 Recently, particular attention has been given to compounds, noninvasively detectable in vivo by proton magnetic resonance (MR) spectroscopy ( 1 H MRS), that may be used as markers of brain metabolism following mTBI.…”

mentioning

confidence: 99%

“…8,10,11 The strict correlation between NAA and ATP ensures that this compound may be used as a valid surrogate marker to monitor cerebral energy metabolism. 8,10,11 Recently, particular attention has been given to compounds, noninvasively detectable in vivo by proton magnetic resonance (MR) spectroscopy ( 1 H MRS), that may be used as markers of brain metabolism following mTBI. 1 H MRS allows the routine measurement of NAA, creatine (Cr), and choline (Cho) in a single set of spectral acquisition, 16 although the low magnetic field currently used in the clinical setting (1.5 or 3 T) does not allow to resolve the N-acetylaspartatylglutamate signal in the NAA peak 17 or the creatine phosphate (CrP) signal in the Cr peak, 17 or to resolve about 10 different compounds containing the choline moiety in their molecule in the Cho peak.…”

mentioning

confidence: 99%

“…Differently, since the Cho peak is mainly composed of phosphocholine, glycerophosphocholine, and phosphatidylcholine, quantification of this peak area is not in direct correlation with one compound only. However, since these compounds are related to phospholipid metabolism, the Cho peak area is generally considered as a good indicator of the cell membrane turnover, 17,19 that of NAA is used as a marker of energy state and neuronal integrity, 8,10,11,17 and that of Cr is thought to be a marker of cellular energy. 17 Since the period of brain vulnerability following an mTBI is mainly characterized by evident biochemical, metabolic, and molecular changes, 3,5,6,20 it is questionable whether the tests currently adopted in the clinical practice to monitor mTBI patients (neuropsychological tests, balance tests, etc), because of their inability to evaluate cerebral biochemical changes, are of utility to determine the end of brain vulnerability.…”

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confidence: 99%

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Decrease in N-Acetylaspartate Following Concussion May Be Coupled to Decrease in Creatine

Vagnozzi¹,

Signoretti²,

Floris³

et al. 2013

Journal of Head Trauma Rehabilitation

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Objectives:To assess the time course changes in N-acetylaspartate (NAA) and creatine (Cr) levels in the brain of athletes who suffered a sport-related concussion. Participants: Eleven nonconsecutive athletes with concussive head injury and 11 sex-and age-matched control volunteers Main outcome measures: At 3, 15, 30, and 45 days postinjury, athletes were examined by proton magnetic resonance spectroscopy for the determination of NAA, Cr, and choline (Cho) levels. Proton magnetic resonance spectroscopic data recorded for the control group were used for comparison. Results: Compared with controls (2.18 ± 0.19), athletes showed an increase in the NAA/Cr ratio at 3 (2.71 ± 0.16; P < .01) and 15 (2.54 ± 0.21; P < .01) days postconcussion, followed by a decrease and subsequent normalization at 30 (1.95 ± 0.16, P < .05) and 45 (2.17 ± 0.20; P < .05) days postconcussion. The NAA/Cho ratio decreased at 3, 15, and 30 days postinjury (P < .01 compared with controls), with no differences observed in controls at 45 days postconcussion. Compared with controls, significant increase in the Cho/Cr ratio after 3 (+33%, P < .01) and 15 (+31.5%, P < .01) days postinjury was observed whereas no differences were recorded at 30 and 45 days postinjury. Conclusions: This cohort of athletes indicates that concussion may cause concomitant decrease in cerebral NAA and Cr levels. This provokes longer time for normalization of metabolism, as well as longer time for resolution of concussion-associated clinical symptoms. Geology and Environmental Sciences, Viale A. Doria 6, 95125 Catania, Italy (lazzarig@unict.it). DOI: 10.1097/HTR.0b013e3182795045C ONCUSSION is defined as a biomechanically induced brain injury characterized by the absence of gross anatomic damages. Supported by the absence of structural lesions on traditional neuroimaging, a general and broadly accepted view is that mild traumatic brain injury (mTBI) is indeed a very frequent entity but is not a very serious injury, leading only to transient disturbances, and that no intervention other than observation is typically required. However, mTBI triggers molecular changes in neuronal cells involving a complex cascade of neurometabolic alterations 1-3 that reversibly modify the concentrations of several low-molecular-weight compounds actively involved in functions crucial for cell homeostasis and survival. 3,4 Such a cascade of molecular events is considered as the determinant of the so-called state of metabolic brain vulnerability, 5,6 which transiently exposes cerebral tissue to the cumulative effect of a second mTBI occurring during this particular period. 7,8 High-energy phosphates, 9,10 coenzyme A metabolites, 11 ATP catabolites, 11 and neurotransmitters, 12,13 are some of the substances whose concentrations are temporarily affected as a result of a traumatic insult. Of

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“…In rats subjected to TBI, the extent of oxidative damage was directly proportionate to the severity of the insult (Petronilho et al, 2009;Tavazzi et al, 2005). The total antioxidant reserves of brain homogenates such as tissue concentrations of ascorbate, glutathione, and sulfhydryl proteins were reduced after TBI in rats (Singh et al, 2007).…”

Section: Oxidative Stress In Penetrating Tbimentioning

confidence: 99%

Common biochemical defects linkage between post-traumatic stress disorders, mild traumatic brain injury (TBI) and penetrating TBI

Prasad¹,

Bondy

2015

Brain Research

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AnxietyPsychological damage a b s t r a c t Post-traumatic stress disorder (PTSD) is a complex mental disorder with psychological and emotional components, caused by exposure to single or repeated extreme traumatic events found in war, terrorist attacks, natural or man-caused disasters, and by violent personal assaults and accidents. Mild traumatic brain injury (TBI) occurs when the brain is violently rocked back and forth within the skull following a blow to the head or neck as in contact sports, or when in close proximity to a blast pressure wave following detonation of explosives in the battlefield. Penetrating TBI occurs when an object penetrates the skull and damages the brain, and is caused by vehicle crashes, gunshot wound to the head, and exposure to solid fragments in the proximity of explosions, and other combat-related head injuries. Despite clinical studies and improved understanding of the mechanisms of cellular damage, prevention and treatment strategies for patients with PTSD and TBI remain unsatisfactory. To develop an improved plan for treating and impeding progression of PTSD and TBI, it is important to identify underlying biochemical changes that may play key role in the initiation and progression of these disorders. This review identifies three common biochemical events, namely oxidative stress, chronic inflammation and excitotoxicity that participate in the initiation and progression of these conditions. While these features are separately discussed, in many instances, they overlap. This review also addresses the goal of developing novel treatments and drug regimens, aimed at combating this triad of events common to, and underlying, injury to the brain.

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Cerebral Oxidative Stress and Depression of Energy Metabolism Correlate with Severity of Diffuse Brain Injury in Rats

Cited by 132 publications

References 47 publications

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

Decrease in N-Acetylaspartate Following Concussion May Be Coupled to Decrease in Creatine

Common biochemical defects linkage between post-traumatic stress disorders, mild traumatic brain injury (TBI) and penetrating TBI

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