Increased vulnerability of the midly traumatized rat brain to cerebral ischemia: the use of controlled secondary ischemia as a research tool to identify common or different mechanisms contributing to mechanical and ischemic brain injury

Jenkins, Larry W.; Moszyński, K; Lyeth, Bruce G.; Lewelt, W.; DeWitt, Douglas S.; Allen, Anne; Dixon, C. Edward; Povlishock, John T.; Majewski, Tadeusz; Clifton, Guy L.; Young, Harold F.; Becker, Donald P.; Hayes, R. L.

doi:10.1016/0006-8993(89)91409-1

Cited by 268 publications

(113 citation statements)

References 29 publications

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“…During this phase, there is a decrease in cerebral blood flow, resulting in hypoxia and ischemia with an increase of brain oxidative metabolism. 11,12 A shortage of glucose and an acute increase in energy demand results in anaerobic metabolism of glucose (hyperglycolysis) and release of lactate. These exacerbate the effects of the primary physical insult.…”

Section: Pathophysiology Of Traumatic Brain Injurymentioning

confidence: 99%

Use of Magnesium in Traumatic Brain Injury

Sen¹,

Gulati

2010

Neurotherapeutics

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Summary: Depletion of magnesium is observed in animal brain and in human blood after brain injury. Treatment with magnesium attenuates the pathological and behavioral changes in rats with brain injury; however, the therapeutic effect of magnesium has not been consistently observed in humans with traumatic brain injury (TBI). Secondary brain insults are observed in patients with brain injury, which adversely affect clinical outcome. Systemic administration studies in rats have shown that magnesium enters the brain; however, inducing hypermagnesemia in humans did not concomitantly increase magnesium levels in the CSF. We hypothesize that the neuroprotective effects of magnesium in TBI patients could be observed by increasing its brain bioavailability with mannitol. Here, we review the role of magnesium in brain injury, preclinical studies in brain injury, clinical safety and efficacy studies in TBI patients, brain bioavailability studies in rat, and pharmacokinetic studies in humans with brain injury. Neurodegeneration after brain injury involves multiple biochemical pathways. Treatment with a single agent has often resulted in poor efficacy at a safe dose or toxicity at a therapeutic dose. A successful neuroprotective therapy needs to be aimed at homeostatic control of these pathways with multiple agents. Other pharmacological agents, such as dexanabinol and progesterone, and physiological interventions, with hypothermia and hyperoxia, have been studied for the treatment of brain injury. Treatment with magnesium and hypothermia has shown favorable outcome in rats with cerebral ischemia. We conclude that coadministration of magnesium and mannitol with pharmacological and physiological agents could be an effective neuroprotective regimen for the treatment of TBI.

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Section: Pathophysiology Of Traumatic Brain Injurymentioning

confidence: 99%

Use of Magnesium in Traumatic Brain Injury

Sen¹,

Gulati

2010

Neurotherapeutics

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“…Although not producing cell death, the F-P injury may produce a level of ionic flux and metabolic dysfunction that, although sublethal, disrupts cellu lar processes for several days, rendering them vul nerable. An example of this state of an injury induced vulnerability has been reported: When a F-P brain injury is followed in 1 h by a sublethal level of ischemia, cells within the CAl region of the hippocampus that would normally survive either in sult independently now die (Jenkins et al, 1989). Consequently, the hypometabolism beginning 6 h following F-P injury may be due to glutamate and/or glutamate-induced ionic fluxes.…”

Section: Hypometabolismmentioning

confidence: 99%

Hippocampal CA₃Lesion Prevents Postconcussive Metabolic Dysfunction in CA₁

Yoshino¹,

Hovda²,

Katayama³

et al. 1992

J Cereb Blood Flow Metab

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Summary: Immediately following fluid-percussion (F-P) brain injury, the hippocampus exhibits a marked increase in its local CMR g lc (LCMR g l c ; ILmol/lOO g/min) as deter mined using [14C]2-deoxY-D-glucose autoradiography. This injury-induced increase in metabolism is followed in 6 h by a subsequent decrease in LCMR g lc' These two postinjury metabolic states may be the result of ionic dis ruptions following trauma via stimulation of glutamate gated ion channels. To determine if endogenous gluta mate innervation to the CAl region of the hippocampus can provide an anatomical basis for this proposed mech anism, it was removed by kainic-acid-induced destruc tion of CA3, and the effect on CAl metabolism following concussive injury was studied. Five days before a lateral F-P injury (3.5-4.5 atm), kainic acid (0.5 ILg) or vehicle was stereotaxically injected into the left ventricle of 65 rats. Histological inspection indicated that kainic acid produced severe cell loss primarily in the CA3 region of the hippocampus ipsilateral to the injection. The meta bolic results indicated that immediately following injury, animals with an intact hippocampus exhibited an increase Following cerebral concussion in the rat, as pro duced using fluid-percussion (F-P) , the cerebral cortex and hippocampus exhibit pronounced changes in glucose metabolism. During the acute period, these regions exhibit a marked increase in this metabolism as determined by e 4 C]2-deoxY-D-

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“…CBF abnormalities have been shown to be an important mechanism underlying secondary brain damage experimentally (Jenkins et al, 1989;Giri et al, 2000) and clinically have been shown to be strongly associated with poor outcome (Robertson et al, 1992). Although the early decline in CBF typically tends to lie above the threshold level classically associated with ischemic brain injury (Hossmann, 1994), it is possible that this pronounced decrease in postinjury CBF, when associated with increased metabolic demand, as indicated by hyperglycolysis, may contribute to the ongoing injury process and account for the poor outcome seen in patients.…”

mentioning

confidence: 99%

Relationship between Flow-Metabolism Uncoupling and Evolving Axonal Injury after Experimental Traumatic Brain Injury

Chen

Richards

Smielewski

et al. 2004

J Cereb Blood Flow Metab

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Summary: Blood flow-metabolism uncoupling is a welldocumented phenomenon after traumatic brain injury, but little is known about the direct consequences for white matter. The aim of this study was to quantitatively assess the topographic interrelationship between local cerebral blood flow (LCBF) and glucose metabolism (LCMRglc) after controlled cortical impact injury and to determine the degree of correspondence with the evolving axonal injury. LCMRglc and LCBF measurements were obtained at 3 hours in the same rat from 18 Ffluorodeoxyglucose and 14 C-iodoantipyrine coregistered autoradiographic images, and compared to the density of damaged axonal profiles in adjacent sections and in an additional group at 24 hours using beta-amyloid precursor protein (ß-APP) immunohistochemistry. LCBF was significantly reduced over the ipsilateral hemisphere by 48 ± 15% compared with shamcontrols, whereas LCMRglc was unaffected, apart from foci of elevated LCMRglc in the contusion margin. Flow-metabolism was uncoupled, indicated by a significant 2-fold elevation in the LCMRglc/LCBF ratio within most ipsilateral structures. There was a significant increase in ß-APP-stained axons from 3 to 24 hours, which was negatively correlated with LCBF and positively correlated with the LCMRglc/LCBF ratio at 3 hours in the cingulum and corpus callosum. Our study indicates a possible dependence of axonal outcome on flow-metabolism in the acute injury stage.

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Increased vulnerability of the midly traumatized rat brain to cerebral ischemia: the use of controlled secondary ischemia as a research tool to identify common or different mechanisms contributing to mechanical and ischemic brain injury

Cited by 268 publications

References 29 publications

Use of Magnesium in Traumatic Brain Injury

Use of Magnesium in Traumatic Brain Injury

Hippocampal CA₃Lesion Prevents Postconcussive Metabolic Dysfunction in CA₁

Relationship between Flow-Metabolism Uncoupling and Evolving Axonal Injury after Experimental Traumatic Brain Injury

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Increased vulnerability of the midly traumatized rat brain to cerebral ischemia: the use of controlled secondary ischemia as a research tool to identify common or different mechanisms contributing to mechanical and ischemic brain injury

Cited by 268 publications

References 29 publications

Use of Magnesium in Traumatic Brain Injury

Use of Magnesium in Traumatic Brain Injury

Hippocampal CA3Lesion Prevents Postconcussive Metabolic Dysfunction in CA1

Relationship between Flow-Metabolism Uncoupling and Evolving Axonal Injury after Experimental Traumatic Brain Injury

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Hippocampal CA₃Lesion Prevents Postconcussive Metabolic Dysfunction in CA₁