Oxypurinol inhibits free radical release from the cerebral cortex of closed head injured rats

Sen, Souvik; Goldman, Harold; Morehead, Marilyn; Murphy, Sharon; Phillis, John W.

doi:10.1016/0304-3940(93)90574-5

Cited by 15 publications

(10 citation statements)

References 12 publications

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“…In contrast with this transient period of • OH formation, severe CCI-injured rats showed a 250% increase in • OH production, which was sustained above baseline for 90 minutes (Marklund et al, 2001). A similar pattern in • OH production has been observed after impact injury in the adult rat (Sen et al, 1993; Sen et al, 1994). Acute increases in NOS have also been reported after FP and CCI injury.…”

Section: The Role Of Free Radicals In Tbisupporting

confidence: 77%

The pathophysiology of traumatic brain injury at a glance

Prins¹,

Greco²,

Alexander³

et al. 2013

Disease Models &Amp; Mechanisms

328

284

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Traumatic brain injury (TBI) is defined as an impact, penetration or rapid movement of the brain within the skull that results in altered mental state. TBI occurs more than any other disease, including breast cancer, AIDS, Parkinson’s disease and multiple sclerosis, and affects all age groups and both genders. In the US and Europe, the magnitude of this epidemic has drawn national attention owing to the publicity received by injured athletes and military personnel. This increased public awareness has uncovered a number of unanswered questions concerning TBI, and we are increasingly aware of the lack of treatment options for a crisis that affects millions. Although each case of TBI is unique and affected individuals display different degrees of injury, different regional patterns of injury and different recovery profiles, this review and accompanying poster aim to illustrate some of the common underlying neurochemical and metabolic responses to TBI. Recognition of these recurrent features could allow elucidation of potential therapeutic targets for early intervention.

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Section: The Role Of Free Radicals In Tbisupporting

confidence: 77%

The pathophysiology of traumatic brain injury at a glance

Prins¹,

Greco²,

Alexander³

et al. 2013

Disease Models &Amp; Mechanisms

328

284

View full text Add to dashboard Cite

show abstract

“…Various pathways have been implicated in the generation of oxygen free radical molecules: arachidonic acid metabolism, calcium-induced release from mitochondria, auto-oxidation of catecholamines, breakdown of extravasated hemoglobin, and activation of xanthine oxidase (Hall, 1993a,b;McCord, 1985;Muizelaar, 1993;Sen et al, 1993;Siesjo, 1993). Based on such sources of free radicals, there have been different approaches proposed to inhibit or reduce free radical-induced brain damage; enzymatic agents such as superoxide dismutase and catalase; indirect-acting antioxidants that inhibit formation of eicosanoids such as ibuprofen and indomethacin; xanthine oxidase inhibitors such as allopurinol; spin-traps such as a-phenyl t-butyl nitrone (PBN); a-tocopherol, and the 21-aminosteroid tirilazad mesylate, which inhibits lipid peroxidation; and iron-chelating agents such as deferoxamine (Hall, 1997).…”

Section: Discussionmentioning

confidence: 98%

Tempol, a Novel Stable Nitroxide, Reduces Brain Damage and Free Radical Production, after Acute Subdural Hematoma in the Rat

Kwon

Chao²,

Malloy³

et al. 2003

Journal of Neurotrauma

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Recent studies have shown that there is increased production of deleterious free radicals following acute subdural hematoma (ASDH). Scavenging them may therefore be of therapeutic benefit. Nitroxides are new, low molecular weight, cell permeable superoxide dismutase mimics. This study investigated the neuroprotective effect of 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (Tempol) following ASDH in the rat. Twenty-one male Sprague-Dawley rats were used in two studies: (1) a volumetric study of ischemic brain damage (n = 10); and (2) a microdialysis study measuring free radical generation after ASDH (n = 11). Ten minutes after induction of hematoma, the animals received 10 mg/kg Tempol or vehicle intravenously. In the volumetric study, 4 h after treatment, the rats were perfused, the brain removed, cut into serial 12-microm coronal sections, and stained. Ischemic areas were measured in eight predetermined stereotactic planes. In the microdialysis study, free radical production was measured using the salicylate trapping technique by quantifying 2,3-dihydrobenzoic acid (2,3-DHBA) and 2,5-DHBA using HPLC. In the volumetric study, Tempol treatment significantly reduced infarct volumes; 100.2 +/- 15.7 mm3 in Tempol-treated animals compared with 171.5 +/- 13.6 mm3 in controls (42% reduction, p = 0.0005). The microdialysis study demonstrated an early twofold increase of free radical production at 30 min, and returning to the baseline levels in controls. However, in Tempol-treated animals, this early surge was attenuated, and all measured values remained around the baseline levels throughout the experiments. Tempol thus provides significant neuroprotective effect in a rat model of ASDH, related to attenuation of superoxide radical production. The use of these low molecular weight, cell-permeable agents, which readily cross the blood-brain barrier and enter cells, thus appears indicated for acute pathologies, ASDH.

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“…Utilizing cerebral ketone metabolism as a therapeutic approach is not only appealing because it can bypass the early glucose metabolic derangements after TBI, but it rats following FP or controlled cortical impact (CCI) injury both show signifi cant ipsilateral decreases in the cerebral metabolic rate of glucose (CMRglc) lasting 7-14 days depending on injury severity. Similarly, 18 F-deoxyglucose positron emission tomography studies in human patients also reveal long-term glucose metabolic depression after TBI . Experimental studies have shown that the magnitude and duration of the glucose metabolic depression increases with injury severity and age ( 8-10 ).…”

Section: Ketones As Alternative Substrate Early After Tbimentioning

confidence: 99%

“…14 C-2-deoxy-D-glucose autoradiography studies in adult instance, proton NMR spectroscopy of [1,2-13 C]-labeled glucose demonstrates a 9-12% increase in glucose processing through the pentose phosphate pathway between 3 and 24 h after CCI injury, thereby decreasing the available glucose supply for energy production ( 14 ). TBI also has been shown to generate early increases in reactive oxygen species (ROS) which damage lipids, protein, and DNA (15)(16)(17)(18)(19). ROS-induced DNA damage activates DNA repair enzymes, such as poly-ADP ribose polymerase (PARP).…”

Section: Metabolic Dysfunctions After Tbimentioning

confidence: 99%

The collective therapeutic potential of cerebral ketone metabolism in traumatic brain injury

Prins

Matsumoto

2014

Journal of Lipid Research

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This article is available online at http://www.jlr.org setting ( 2, 3 ). Thus, there is a signifi cant need to identify better strategies to improve global outcome after TBI. In addition, given the inherent differences between the developing brain in which dynamic processes such as synaptogenesis, myelination, and plasticity are ongoing, and the mature adult brain in which these processes have been completed, any potential neuroprotective treatment must be evaluated in an age-specifi c manner. To that end, we discuss the changes in cerebral glucose metabolism, which have been described in the aftermath of TBI, the age-related variation of this metabolic dysfunction, and the potential of using the natural ketone metabolism mechanisms to ameliorate these problems and improve global outcome. METABOLIC DYSFUNCTIONS AFTER TBIUpon impact, rapid movement of the brain within the skull initiates a series of neurochemical disruptions that alter cerebral metabolism. Within minutes after injury, the ionic equilibrium across the neuronal membranes is disrupted, with injury severity-dependent increases in the concentration of extracellular potassium and glutamate, as well as intracellular calcium accumulation ( 4, 5 ). This disruption of ionic equilibrium requires cellular energy to reestablish homeostasis, which is refl ected by increases in cerebral glucose uptake observed within 30 min after adult rodent fl uid percussion (FP) injury ( 6 ) and within 8 days after human TBI ( 7 ). This transient increase in glucose uptake is also known as "hyperglycolysis" and is followed by a prolonged period of glucose metabolic depression. These cerebral metabolic changes are a hallmark response described in both experimental and clinical brain trauma. Nationally, the incidence of traumatic brain injury (TBI) exceeds that of all other health diseases with an annual incidence of 1.7 million new cases ( 1 ). It is an injury that affects both genders across all age groups, producing long-term disabilities that negatively impact families and society. Recent years have seen a substantial increase in public awareness of the long-term cognitive, emotional, and functional consequences of TBI. However, several potential neuroprotective treatments, such as therapeutic hypothermia, have produced disappointing results when tested in the clinical

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Oxypurinol inhibits free radical release from the cerebral cortex of closed head injured rats

Cited by 15 publications

References 12 publications

The pathophysiology of traumatic brain injury at a glance

The pathophysiology of traumatic brain injury at a glance

Tempol, a Novel Stable Nitroxide, Reduces Brain Damage and Free Radical Production, after Acute Subdural Hematoma in the Rat

The collective therapeutic potential of cerebral ketone metabolism in traumatic brain injury

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