NAAG Peptidase Inhibitor Reduces Acute Neuronal Degeneration and Astrocyte Damage following Lateral Fluid Percussion TBI in Rats

Zhong, Chunlong; Zhao, Xueren; Jayaprakash, Sarva; Kozikowski, Alan P.; Neale, Joseph H.; Lyeth, Bruce G.

doi:10.1089/neu.2005.22.266

Cited by 78 publications

(80 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The increase in righting time, response to toe pinch, seizure rate, mortality and FluoroJade labeling of degenerating neurons in the hilus (4 h study) and CA3 hippocampus (24 h study) of pFPI injured rats compared to the sham group, is consistent with previous work using pFPI systems (Gupta et al, 2012;Zhao et al, 2003;Neuberger et al, 2014;Hallam et al, 2004;Zhong et al, 2005). We also see similar outcomes for injuries from the vcFPI device, which demonstrates that both the devices deliver similar injuries.…”

Section: Induction Of Fluid Percussion Injurysupporting

confidence: 89%

Fluid percussion injury device for the precise control of injury parameters

Wahab

Neuberger

Lyeth

et al. 2015

Journal of Neuroscience Methods

Self Cite

View full text Add to dashboard Cite

h i g h l i g h t s• A novel fluid percussion injury (FPI) system was designed and built.• The system generated fluid percussions with independently adjustable peak pressures, rise times and impulses.• Immediate post-injury behavior was similar between the custom FPI system and the commonly used FPI system.• Fluoro-Jade labeling in the hilus and CA2-3 and granule cell population spike amplitude were consistent between systems.• Slow fluid percussion rise times increased mortality and reduced motor function in a subset of adult rats. a r t i c l e i n f o t r a c tBackground: Injury to the brain can occur from a variety of physical insults and the degree of disability can greatly vary from person to person. It is likely that injury outcome is related to the biomechanical parameters of the traumatic event such as magnitude, direction and speed of the forces acting on the head. New method: To model variations in the biomechanical injury parameters, a voice coil driven fluid percussion injury (FPI) system was designed and built to generate fluid percussion waveforms with adjustable rise times, peak pressures, and durations. Using this system, pathophysiological outcomes in the rat were investigated and compared to animals injured with the same biomechanical parameters using the pendulum based FPI system. Results in comparison with existing methods: Immediate post-injury behavior shows similar rates of seizures and mortality in adolescent rats and similar righting times, toe pinch responses and mortality rates in adult rats. Interestingly, post injury mortality in adult rats was sensitive to changes in injury rate. Fluoro-Jade labeling of degenerating neurons in the hilus and CA2-3 hippocampus were consistent between injuries produced with the voice coil and pendulum operated systems. Granule cell population spike amplitude to afferent activation, a measure of dentate network excitability, also showed consistent enhancement 1 week after injury using either system. Conclusions: Overall our results suggest that this new FPI device produces injury outcomes consistent with the commonly used pendulum FPI system and has the added capability to investigate pathophysiology associated with varying rates and durations of injury.

show abstract

Section: Induction Of Fluid Percussion Injurysupporting

confidence: 89%

Fluid percussion injury device for the precise control of injury parameters

Wahab

Neuberger

Lyeth

et al. 2015

Journal of Neuroscience Methods

Self Cite

View full text Add to dashboard Cite

show abstract

“…Regional patterns of neuronal degeneration in the hippocampus have been documented following fluid percussion injury in the rat with differing degrees of detail, revealing that the CA2-CA3 fields, hilus, and the DG granule cells are the most vulnerable populations of neurons (Anderson et al, 2005;Hallam et al, 2004;Sato et al, 2001;Zhong et al, 2005). Several studies have reported that post-traumatic hypoxia increased the number of degenerating neurons in the hippocampus (Bramlett et al, 1999b;Clark et al, 1997;Nawashiro et al, 1995), but they did not compare changes in cell death at acute and chronic time points.…”

Section: Immediate Post-traumatic Hypoxia Exacerbated Hippocampal Neumentioning

confidence: 99%

Post-Traumatic Hypoxia Exacerbates Neuronal Cell Death in the Hippocampus

Feng

Zhao

Gurkoff

et al. 2012

Journal of Neurotrauma

Self Cite

View full text Add to dashboard Cite

Hypoxia frequently occurs in patients with traumatic brain injury (TBI) and is associated with increased morbidity and mortality. This study examined the effects of immediate or delayed post-traumatic hypoxia (fraction of inspired oxygen [FiO 2 ] 11%) on acute neuronal degeneration and long-term neuronal survival in hippocampal fields after moderate fluid percussion injury in rats. In Experiment 1, hypoxia was induced for 15 or 30 min alone or immediately following TBI. In Experiments 2 and 3, 30 min of hypoxia was induced immediately after TBI or delayed until 60 min after TBI. In Experiment 1, acute neurodegeneration was evaluated in the hippocampal fields 24 h after insults using Fluoro-Jade staining and stereological quantification. During hypoxia alone, or in combination with TBI, mean arterial blood pressure was significantly reduced by approximately 30%, followed by a rapid return to normal values upon return to pre-injury FiO 2 . Hypoxia alone failed to cause hippocampal neuronal degeneration when measured at 24 h after insult. TBI alone resulted in neuronal degeneration in each ipsilateral hippocampal field, predominantly in CA2-CA3 and the dentate gyrus. Compared to TBI alone, TBI plus immediate hypoxia for either 15 or 30 min significantly increased neuronal loss in most ipsilateral hippocampal fields and in the contralateral hilus and dentate gyrus. In Experiment 2, TBI plus hypoxia delayed 30 min significantly increased degeneration only in ipsilateral CA2-CA3. In Experiment 3, 30 min of immediate hypoxia significantly reduced the numbers of surviving neurons in the CA3 at 14 days after TBI. The greatly increased vulnerability in all hippocampal fields by immediate 30 min post-traumatic hypoxia provides a relevant model of TBI complicated with hypoxia/hypotension. These data underscore the significance of the secondary insult, the necessity to better characterize the range of injuries experienced by the TBI patient, and the importance of strictly avoiding hypoxia in the early management of TBI patients.

show abstract

“…Unlike NAA, several biological activities were clearly demonstrated for NAAG either under physiological (58) or pathological conditions (3,37). With regard to head injury, the beneficial effects connected to the inhibition of glutamate carboxypeptidase II, also known as N-acetylated alpha-linked acidic dipeptidase, are of particular interest in models of neuropathies, stroke, and focal TBI (36,59). Glutamate carboxypeptidase II, which catalyzes the hydrolysis of NAAG to glutamate and NAA, is activated under these pathological conditions leading to an increase in glutamate release (3,37,50).…”

Section: Significance Of N-acetylaspartylglutamate Variationsmentioning

confidence: 99%

Temporal Window of Metabolic Brain Vulnerability to Concussions

et al. 2007

View full text Add to dashboard Cite

OBJECTIVE:In the present study, we investigate the existence of a temporal window of brain vulnerability in rats undergoing repeat mild traumatic brain injury (mTBI) delivered at increasing time intervals. METHODS: Rats were subjected to two diffuse mTBIs (450 g/1 m height) with the second mTBI delivered after 1 (n ϭ 6), 2 (n ϭ 6), 3 (n ϭ 6), 4 (n ϭ 6), and 5 days (n ϭ 6) and sacrificed 48 hours after the last impact. Sham-operated animals were used as controls (n ϭ 6). Two further groups of six rats each received a second mTBI after 3 days and were sacrificed at 120 and 168 hours postinjury. Concentrations of adenine nucleotides, N-acetylated amino acids, oxypurines, nucleosides, free coenzyme A, acetyl CoA, and oxidized and reduced nicotinamide adenine dinucleotides, oxidized nicotinamide adenine dinucleotide phosphate, and reduced nicotinamide adenine dinucleotide, reduced nicotinamide adenine dinucleotide phosphate nicotinic coenzymes were measured in deproteinized cerebral tissue extracts (three right and three left hemispheres), whereas the gene expression of N-acetylaspartate acylase, the enzyme responsible for N-acetylaspartate (NAA) degradation, was evaluated in extracts of three left and three right hemispheres. RESULTS: A decrease of adenosine triphosphate, adenosine triphosphate /adenosine diphosphate ratio, NAA, N-acetylaspartylglutamate, oxidized and reduced nicotinamide adenine dinucleotide, reduced nicotinamide adenine dinucleotide, and acetyl CoA and increase of N-acetylaspartate acylase expression were related to the interval between impacts with maximal changes recorded when mTBIs were spaced by 3 days. In these animals, protracting the time of sacrifice after the second mTBI up to 1 week failed to show cerebral metabolic recovery, indicating that this type of damage is difficult to reverse. A metabolic pattern similar to controls was observed only in animals receiving mTBIs 5 days apart. CONCLUSION: This study shows the existence of a temporal window of brain vulnerability after mTBI. A second concussive event falling within this time range had profound consequences on mitochondrial-related metabolism. Furthermore, because NAA recovery coincided with normalization of all other metabolites, it is conceivable to hypothesize that NAA measurement by 1 H-NMR spectroscopy might be a valid tool in assessing full cerebral metabolic recovery in the clinical setting and with particular reference to sports medicine in establishing when to return mTBI-affected athletes to play. This study also shows, for the first time, the influence of TBI on acetyl-CoA, N-acetylaspartate acylase gene expression, and N-acetylaspartylglutamate, thus providing novel data on cerebral biochemical changes occurring in head injury.

show abstract

NAAG Peptidase Inhibitor Reduces Acute Neuronal Degeneration and Astrocyte Damage following Lateral Fluid Percussion TBI in Rats

Cited by 78 publications

References 44 publications

Fluid percussion injury device for the precise control of injury parameters

Fluid percussion injury device for the precise control of injury parameters

Post-Traumatic Hypoxia Exacerbates Neuronal Cell Death in the Hippocampus

Temporal Window of Metabolic Brain Vulnerability to Concussions

Contact Info

Product

Resources

About