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Dive into the research topics where Joseph E. Levasseur is active.

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Featured researches published by Joseph E. Levasseur.


Stroke | 1975

Detailed Description of a Cranial Window Technique for Acute and Chronic Experiments

Joseph E. Levasseur; Enoch P. Wei; A. Jarrell Raper; Hermes A. Kontos; John L. Patterson

Methods for implantation of cranial windows for the direct observation of the pial microcirculation in experimental animals are described in detail. These techniques are suitable for both acute experiments in anesthetized animals and chronic implantation permitting several months of observation in awake animals. Experience over several years shows that these techniques have an acceptably low rate of failure, are low in cost and can easily be mastered in most laboratories. They make possible observation of the microcirculation and accurate measurement of the diameter of pial vessels, and permit study of the effects on the microcirculation of a variety of maneuvers and vasoactive agents which can be studied by direct application as well as by intravascular administration. Because they preserve the integrity of the skull, the techniques permit study of the cerebral microcirculation under conditions closely approximating the normal environment of these vessels.


Circulation | 2000

Inducible nitric oxide synthase mediates delayed myocardial protection induced by activation of adenosine A(1) receptors: evidence from gene-knockout mice.

Tingcun Zhao; Lei Xi; Jeya Chelliah; Joseph E. Levasseur; Rakesh C. Kukreja

BACKGROUND The mechanism of delayed preconditioning induced by activation of adenosine A(1) receptors (A(1)ARs) is not fully understood. We determined the role of inducible nitric oxide synthase (iNOS) in mediating adenosine-induced late cardioprotection using pharmacological inhibitors and iNOS gene-knockout mice. METHODS AND RESULTS Adult male mice were treated with saline or an A(1)AR agonist, 2-chloro-N(6)-cyclopentyladenosine (CCPA). Twenty-four hours later, the hearts were perfused in Langendorff mode and subjected to 30 minutes of global ischemia followed by 30 minutes of reperfusion. 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX; 0.1 mg/kg IP) and S-methylisothiourea (SMT; 3 mg/kg IP) were used to block A(1)ARs and iNOS, respectively. Infarct size (IS) was measured by triphenyltetrazolium chloride staining, and iNOS expression was measured by Western blots. Myocardial IS was reduced from 24.0+/-3. 2% in the saline group to 12.2+/-2.5% in CCPA-treated mice (P<0.05). The infarct-reducing effect of CCPA was abrogated by DPCPX (29.3+/-3. 4%) and SMT (32.3+/-2.6%) and was absent in mice with targeted ablation of iNOS (23.9+/-1.6%). CCPA produced improvement in postischemic end-diastolic pressure, developed pressure, and rate-pressure product, which was also blocked by DPCPX and SMT. Increased iNOS protein expression observed in CCPA-treated hearts was diminished by DPCPX. CONCLUSIONS Selective activation of A(1)ARs produces delayed cardioprotection against ischemia/reperfusion injury in the mouse. Increased iNOS expression concomitant with the lack of protective effect of A(1)AR activation in iNOS gene-knockout mice suggests a direct cause-and-effect relationship of iNOS in adenosine-induced late cardioprotection.


Acta Neurochirurgica | 2007

Effect of lactate therapy upon cognitive deficits after traumatic brain injury in the rat.

R. Holloway; Zhengwen Zhou; H. B. Harvey; Joseph E. Levasseur; Ann C. Rice; Dong Sun; Robert J. Hamm; M. R. Bullock

SummaryBackground. In previous studies, it has been shown that intravenous lactate therapy can improve brain neurochemistry, adenosine triphosphate (ATP) generation and outcome after traumatic brain injury (TBI) in rats. In this study, we examined: (1) four L-lactate concentrations to determine the optimal therapeutic dose post TBI in terms of cognitive function; (2) ATP production after TBI for the L-lactate concentration found to be the optimal dose; (3) the possible production of lactic acidosis with the highest L-lactate concentration tested. Methods. Thirty minutes following a fluid percussion injury (FPI) over the left cerebral hemisphere, the animals received an intravenous infusion of 10, 28, 100, or 280 mM L-lactate (n = 10 for each group) for 3 h at a rate of 0.65 ml/h. Shams and control injured animals received a saline infusion. At 11–15 days post injury, cognitive deficits were examined using the Morris Water Maze (MWM) test. Three groups of rats were used for ATP analysis: shams, injured + saline infusion, and injury + the optimal lactate dose as determined by the MWM (n = 4/group). Additionally, a group receiving 280 mM L-lactate (n = 5) and one receiving a saline infusion (n = 3) were monitored for arterial blood variables and blood pressures. Findings. In the MWM test, only the 100 mM L-lactate-treated injured animals showed a significant reduction in cognitive deficits when compared to saline-treated injured animals (p ≤ 0.05). In the ATP study, injured animals without treatment had a 53% reduction in ATP level in the ipsilateral cortex, while animals with 100 mM lactate treatment had a 28% reduction. (p ≤ 0.05). No lactic acidosis was induced by the intravenous infusion of 280 mM L-lactate. Conclusions. This study indicates that the intravenous infusion of 100 mM L-lactate provided the optimal concentration of the substrate to ameliorate cognitive impairment, probably via the regeneration of ATP following TBI in rats.


Journal of Neurotrauma | 2008

Validation of Brain Extracellular Glycerol as an Indicator of Cellular Membrane Damage due to Free Radical Activity after Traumatic Brain Injury

Amedeo Merenda; Marinella Gugliotta; Rebecca Holloway; Joseph E. Levasseur; Beht Alessandri; Dong Sun; M. Ross Bullock

Following severe traumatic brain injury (TBI), increasing oxygen delivery to the brain has been advocated as a useful strategy to reverse mitochondrial dysfunction and improve neurological outcome. However, this might also promote overproduction of free radicals, responsible for lipid peroxidation and hence brain cell damage. Therefore, a method for monitoring this potential adverse effect in humans is desirable. Glycerol, an end product of phospholipid breakdown, easily detectable in the human brain by means of microdialysis, might represent a reliable indicator of free radical-induced cell membrane damage. Brain microdialysates were collected from 24 adult male Sprague-Dawley rats over a 3-hour period following sham operation (n=6), chemical brain injury via administration of Fentons reagent (n=6), a powerful hydroxyl radical generator, and lateral fluid percussion injury (FPI; n=12). In the FPI animals, post-traumatic i.v. administration of either normal saline or the free radical scavenger Tempol (10 mg/kg, followed by an infusion of 30 mg/kg/h over 3 h) was carried out to evaluate the effect of blockade of free radical generation. Samples were analyzed for the presence of glycerol and the marker of hydroxyl radical (OH.) by generation of 2,3-DHBA (dihydroxybenzoic acid). Brain tissue staining with TTC (2,3,5-triphenyltetrazoium chloride) was performed for lesion size assessment. Rats subjected to either Fentons reagent administration or FPI exhibited significantly higher levels of glycerol as compared with shams (p=0.05). However, when the FPI was followed by Tempol administration, concentration of both glycerol and 2,3-DHBA decreased significantly (p=0.05). Furthermore, TCC staining revealed a significant reduction of secondary brain tissue damage in Tempol-treated animals (p=0.05). Our data suggest that injury-induced increases in microdialysate glycerol levels are a valid indicator of free radical activity, and their amelioration following Tempol treatment accords with less histological damage in response to FPI.


Neurosurgery | 2004

Perfluorocarbon emulsion improves cerebral oxygenation and mitochondrial function after fluid percussion brain injury in rats.

Wilson P. Daugherty; Joseph E. Levasseur; Dong Sun; Bruce D. Spiess; M. Ross Bullock; E. Sander Connolly; Charles J. Hodge; R. Loch Macdonald

OBJECTIVE:Cerebral ischemia is a common secondary sequela of traumatic brain injury (TBI). Experimental models of stroke have demonstrated reductions in ischemia after perfluorocarbon (PFC) administration; however, there are no published reports of PFC efficacy after TBI. The current study analyzed the effect of the PFC emulsion Oxygent (AF0144; Alliance Pharmaceutical Corp., San Diego, CA) on cerebral oxygenation, mitochondrial redox potential, and free radical formation after lateral fluid percussion injury. METHODS:After fluid percussion injury, five 2.25 ml/kg doses of PFC or saline were administered to rats breathing 100% O2, and oxygen tension was recorded. In a second experiment, a single bolus (11.25 ml/kg) of PFC or saline was given after injury, and redox potential and free radical formation were measured at 1 or 4 hours with Alamar blue dye and dihydrorhodamine 123, respectively. RESULTS:Cerebral oxygen tension was significantly increased in both injured and sham animals treated with 11.25 ml/kg of PFC as compared with saline (P < 0.05). Likewise, PFC significantly increased mitochondrial redox potential as compared with saline at 4 hours after injury (P < 0.01). Mitochondrial peroxynitrite and peroxide production also increased with the administration of PFC (P < 0.05). CONCLUSION:The current study demonstrates that a PFC emulsion can significantly increase cerebral oxygenation after TBI and enhance mitochondrial function at 4 hours after injury as compared with saline. This study demonstrates a new therapeutic potential for PFC to enhance cerebral oxygenation and aerobic metabolism after TBI. However, the increased free radical formation with high-dose PFCs suggests the need for further studies combining PFCs with free radical scavengers.


Neurosurgery | 2006

Lactate, not glucose, up-regulates mitochondrial oxygen consumption both in sham and lateral fluid percussed rat brains.

Joseph E. Levasseur; Beat Alessandri; Michael Reinert; Tobias Clausen; Zhengwen Zhou; Nabil Altememi; M. Ross Bullock

OBJECTIVEFailure of energy metabolism after traumatic brain injury may be a major factor limiting outcome. Although glucose is the primary metabolic substrate in the healthy brain, the well documented surge in tissue lactate after traumatic brain injury suggests that lactate may provide an energy need that cannot be met by glucose. We hypothesized, therefore, that administration of lactate or the combination of lactate and supraphysiological oxygen may improve mitochondrial oxidative respiration in the brain after rat fluid percussion injury. We measured oxygen consumption (VO2) to determine what effects glucose, lactate, oxygen, and the combination of lactate and oxygen have on mitochondrial respiration in both injured and uninjured rat brain tissue. METHODSAnesthetized Sprague-Dawley rats were intubated and ventilated with either 0.21 or 1.0 fraction of inspired oxygen (FIO2). Brain tissue from acute sham animals was subjected in vitro to 1.1 mM, 12 mM and 100 mM concentrations of glucose and L-lactate. In another group, injury (fluid percussion injury of 2.5 ± 0.02 atmospheres) was induced over the left hemisphere. The VO2 of μg amounts of brain tissues were measured in a microrespirometry system (Cartesian diver). RESULTSThe VO2 was found to be independent of glucose concentrations, but dose-dependent for lactate. Moreover, the lactate dependent VO2s were all significantly higher than those generated by glucose. Injured rats on FIO2 0.21 had brain tissue VO2 rates that were significantly lower than those of shams or preinjury levels. In injured rats treated with FIO2 1.0, the reduction in VO2 levels was prevented. Injured rats that received an intravenous infusion of 100 mM lactate had VO2 rates that were significantly higher than those obtained with FIO2 1.0. Combined treatment further boosted the lactate generated VO2 rates by approximately 15%. CONCLUSIONGlucose sustains mitochondrial respiration at a low level “fixed” rate because, despite increasing its concentration nearly 100-fold, it cannot up-regulate VO2 after fluid percussion injury. Lactate produces a dose-dependent VO2 response, possibly enabling mitochondria to meet the increased energy needs of the injured brain.


Journal of Neurotrauma | 2010

Strain-Related Differences after Experimental Traumatic Brain Injury in Rats

Wendy Reid; Andrew Rolfe; David Register; Joseph E. Levasseur; Severn B. Churn; Dong Sun

The present study directly compares the effects of experimental brain injury in two commonly used rat strains: Fisher 344 and Sprague-Dawley. We previously found that Fisher rats have a higher mortality rate and more frequent seizure attacks at the same injury level than Sprague-Dawley rats. Although strain differences in rats are commonly accepted as contributing to variability among studies, there is a paucity of literature addressing strain influence in experimental neurotrauma. Therefore this study compares outcome measures in two rat strains following lateral fluid percussion injury. Fisher 344 and Sprague-Dawley rats were monitored for changes in physiological measurements, intracranial pressure, and electroencephalographic activity. We further analyzed neuronal degeneration and cell death in the injured brain using Fluoro-Jade-B (FJB) histochemistry and caspase-3 immunostaining. Behavioral studies using the beam walk and Morris water maze were conducted to characterize strain differences in both motor and cognitive functional recovery following injury. We found that Fisher rats had significantly higher intracranial pressure, prolonged seizure activity, increased FJB-positive staining in the injured cortex and thalamus, and increased caspase-3 expression than Sprague-Dawley rats. On average, Fisher rats displayed a greater amount of total recording time in seizure activity and had longer ictal durations. The Fisher rats also had increased motor deficits, correlating with the above results. In spite of these results, Fisher rats performed better on cognitive tests following injury. The results demonstrate that different rat strains respond to injury differently, and thus in preclinical neurotrauma studies strain influence is an important consideration when evaluating outcomes.


Neurosurgery | 2008

Perfluorocarbon emulsions improve cognitive recovery after lateral fluid percussion brain injury in rats.

Zhengwen Zhou; Dong Sun; Joseph E. Levasseur; Amedeo Merenda; Robert J. Hamm; Jiepei Zhu; Bruce D. Spiess; M. Ross Bullock

OBJECTIVEPerfluorocarbon emulsions have been shown to improve outcomes in stroke models. This study examined the effect of Oxycyte, a third-generation perfluorocarbon emulsion (04RD33; Synthetic Blood International, Inc., Costa Mesa, CA) treatment on cognitive recovery and mitochondrial oxygen consumption after a moderate lateral fluid percussion injury (LFPI). METHODSAdult male Sprague-Dawley rats (Harlan Bioproducts for Science, Indianapolis, IN) were allocated to 4 groups: 1) LFPI treated with a lower dose of Oxycyte (4.5 mL/kg); 2) LFPI with a higher dose of Oxycyte (9.0 mL/kg); 3) LFPI with saline infusion; and 4) sham animals treated with saline. Fifteen minutes after receiving moderate LFPI or sham surgery, animals were infused intravenously with Oxycyte or saline within 30 minutes while breathing 100% O2. Animals breathed 100% O2 continuously for a total of 4 hours after injury. At 11 to 15 days after LFPI, animals were assessed for cognitive deficits using the Morris water maze test. They were sacrificed at Day 15 after injury for histology to assess hippocampal neuronal cell loss. In a parallel study, mitochondrial oxygen consumption values were measured by the Cartesian diver microrespirometer method. RESULTSWe found that injured animals treated with a lower or higher dose of Oxycyte had significant improvement in cognitive function when compared with injured saline-control animals (P < 0.05). Moreover, injured animals that received either dose of Oxycyte had significantly less neuronal cell loss in the hippocampal CA3 region compared with saline-treated animals (P < 0.05). Furthermore, a lower dose of Oxycyte significantly improved mitochondrial oxygen consumption levels (P < 0.05). CONCLUSIONThe current study demonstrates that Oxycyte can improve cognitive recovery and reduce CA3 neuronal cell loss after traumatic brain injury in rats.


Microvascular Research | 1984

Microvascular responses of intermediate-size arterioles on the cerebral surface of diabetic mice

William I. Rosenblum; Joseph E. Levasseur

Mice were rendered diabetic with streptozotocin. After intervals of approximately 4 weeks and 6 months, the vascular responses of cerebral surface arterioles (pial arterioles) with mean internal diameters of 35-39 micrometers were determined and compared with those of control mice. Norepinephrine, serotonin, prostaglandin F2 alpha, and papaverine were used. Only one agent was tested in a given mouse, each agent being applied to the surface vessels of that mouse at three different doses. Statistically significant dose-response relationships were always observed, but with one exception, no differences were found between the contractile responses (norepinephrine, serotonin, prostaglandin F2 alpha) or the dilating responses (papaverine) in diabetic vs normal mice. The one exception involved responses to serotonin following 4-5 weeks of diabetes. Here diabetic responses were 10-18% less than those of control. Though significant statistically, the difference may nevertheless be a chance occurrence, and is in any case sufficiently small to be of doubtful biological meaning. The overall data indicate no effect of diabetes on the responses of the selected pial arterioles to norepinephrine, serotonin, PGF2 alpha, and papaverine.


Future Neurology | 2009

Lactate and glucose as energy substrates and their role in traumatic brain injury and therapy

Beat Alessandri; Marinella Gugliotta; Joseph E. Levasseur; M. Ross Bullock

Traumatic brain injury is a leading cause of disability and mortality worldwide, but no new pharmacological treatments are clinically available. A key pathophysiological development in the understanding of traumatic brain injury is the energy crisis derived from decreased cerebral blood flow, increased energy demand and mitochondrial dysfunction. Although still controversial, new findings suggest that brain cells try to cope in these conditions by metabolizing lactate as an energy substrate ‘on-demand’ in lieu of glucose. Experimental and clinical data suggest that lactate, at least when exogenously administered, is transported from astrocytes to neurons for neuronal utilization, essentially bypassing the slow, catabolizing glycolysis process to quickly and efficiently produce ATP. Treatment strategies using systemically applied lactate have proved to be protective in various experimental traumatic brain injury studies. However, lactate has the potential to elevate oxygen consumption to high levels and, t...

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M. Ross Bullock

Virginia Commonwealth University

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Dong Sun

Virginia Commonwealth University

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Rakesh C. Kukreja

Virginia Commonwealth University

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Robert J. Hamm

Virginia Commonwealth University

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Lei Xi

Virginia Commonwealth University

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Zhengwen Zhou

Virginia Commonwealth University

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Ann C. Rice

Virginia Commonwealth University

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Beat Alessandri

Virginia Commonwealth University

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Bruce D. Spiess

Virginia Commonwealth University

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