Abstract
Objective
The antioxidant potential N-Acetylcysteine (NAC) and its improvement of posttraumatic mitrochondrial dysfunction have been reported. This study investigated the effect of NAC on posttraumatic changes after controlled cortical Impact (CCI) injury.
Design and setting
Prospective randomized controlled animal study.
Methods
A moderate left focal cortical contusion was induced using CCI. Either NAC (163 mg/kg bw) or physiological saline was administered intraperitoneally immediately and 2 and 4 h after trauma. Blood gases, temperature, mean arterial blood pressure (MABP), and intracranial pressure (ICP) were monitored. Twenty-four hours after trauma brains were removed and either posttraumatic edema was quantified gravimetrically (n=24], or contusion volume was determined morphometrically using slices staining and computerized image analysis (n=24]. Laser Doppler flowmetry was used to assess pericontusional cortical perfusion before trauma, 30 min and 4 and 24 h after trauma (n=14].
Measurements and results
Physiological parameters remained within normal limits. ICP measurements and water content in traumatized hemispheres did not differ between the groups. Relative contusion volume of the left hemisphere was slightly but nonsignificantly diminished in NAC-treated animals (4.7±0.4% vs. 5.9±0.5% in controls). In both groups pericontusional perfusion was significantly reduced at 4 h followed by a state of hyperperfusion at 24 h with no differences between the groups.
Conclusions
Despite previously reported neuroprotective abilities of NAC, no positive effect on posttraumatic perfusion, brain edema formation, or contusion volume after focal brain injury was observed in this study.
Similar content being viewed by others
References
Enblad P, Nilsson P, Chambers, I, Citerio, G, Fiddes, H, Howells, T, Kiening, K, Ragauskas, A, Sahuquillo, J, Yau, YH, Contant, C, Piper, IR (2004) Survey of traumatic brain injury management in European brain IT centres year 2001. Intensive Care Med 30:1058–1065
Clausen, F, Lundqvist, H, Ekmark, S, Lewen, A, Ebendal, T, Hillered, L (2004) Oxygen free radical-dependent activation of extracellular signal-regulated kinase mediates apoptosis-like cell death after traumatic brain injury. J Neurotrauma 21:1168–1182
Gilgun-Sherki, Y, Rosenbaum, Z, Melamed, E, Offen, D (2002) Antioxidant therapy in acute central nervous system injury: current state. Pharmacol Rev 54:271–284
Hall ED (1995) Inhibition of lipid peroxidation in central nervous system trauma and ischemia. J Neurol Sci 134 Suppl:79–83
Smith SL, Andrus PK, Zhang JR, Hall ED (1994) Direct measurement of hydroxyl radicals, lipid peroxidation, and blood-brain barrier disruption following unilateral cortical impact head injury in the rat. J Neurotrauma 11:393–404
Aruoma OI, Halliwell B, Hoey BM, Butler J (1989) The antioxidant action of N-acetylcysteine: its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid. Free Radic Biol Med 6:593–597
Cuzzocrea S, Mazzon E, Costantino G, Serraino I, Dugo L, Calabro G, Cucinotta G, De Sarro A, Caputi AP (2000) Beneficial effects of N-acetylcysteine on ischaemic brain injury. Br J Pharmacol 130:1219–1226
Hart AM, Terenghi G, Kellerth JO, Wiberg M (2004) Sensory neuroprotection, mitochondrial preservation, and therapeutic potential of N-acetyl-cysteine after nerve injury. Neuroscience 125:91–101
Khan M, Sekhon B, Jatana M, Giri S, Gilg AG, Sekhon C, Singh I, Singh AK (2004) Administration of N-acetylcysteine after focal cerebral ischemia protects brain and reduces inflammation in a rat model of experimental stroke. J Neurosci Res 76:519–527
Knuckey NW, Palm D, Primiano M, Epstein MH, Johanson CE (1995) N-Acetylcysteine enhances hippocampal neuronal survival after transient forebrain ischemia in rats. Stroke 26:305–310
Sekhon B, Sekhon C, Khan M, Patel SJ, Singh I, Singh AK (2003) N-Acetyl cysteine protects against injury in a rat model of focal cerebral ischemia. Brain Res 971:1–8
Wagner R, Heckman HM, Myers RR (1998) Wallerian degeneration and hyperalgesia after peripheral nerve injury are glutathione-dependent. Pain 77:173–179
Yi JH, Hazell AS (2005) N-Acetylcysteine attenuates early induction of heme oxygenase-1 following traumatic brain injury. Brain Res 1033:13–19
Hall ED, Andrus PK, Yonkers PA (1993) Brain hydroxyl radical generation in acute experimental head injury. J Neurochem 60:588–594
Al Moutaery K, Al Deeb S, Ahmad Khan H, Tariq M (2003) Caffeine impairs short-term neurological outcome after concussive head injury in rats. Neurosurgery 53:704–711
Sullivan PG, Thompson MB, Scheff SW (1999) Cyclosporin A attenuates acute mitochondrial dysfunction following traumatic brain injury. Exp Neurol 160:226–234
Sullivan PG, Bruce-Keller AJ, Rabchevsky AG, Christakos S, Clair DK, Mattson MP, Scheff SW (1999) Exacerbation of damage and altered NF-kappaB activation in mice lacking tumor necrosis factor receptors after traumatic brain injury. J Neurosci 19:6248–6456
Aoyama N, Katayama Y, Kawamata T, Maeda T, Mori T, Yamamoto T, Kikuchi T, Uwahodo Y (2002) Effects of antioxidant, OPC-14117, on secondary cellular damage and behavioral deficits following cortical contusion in the rat. Brain Res 934:117–124
Cherian L, Robertson CS (2003) L-Arginine and free radical scavengers increase cerebral blood flow and brain tissue nitric oxide concentrations after controlled cortical impact injury in Rats. J Neurotrauma 20:77–85
Sarrafzadeh AS, Thomale UW, Kroppenstedt SN, Unterberg AW (2000) Neuroprotective effect of melatonin on cortical impact injury in the rat. Acta Neurochir (Wien) 142:1293–1299
Yunoki M, Kawauchi M, Ukita N, Sugiura T, Ohmoto T (2003) Effects of lecithinized superoxide dismutase on neuronal cell loss in CA3 hippocampus after traumatic brain injury in rats. Surg Neurol 59:156–160
Thomale UW, Griebenow M, Kroppenstedt SN, Unterberg A, Stover JF (2004) The antioxidant properties of N-acethylcysteine after experimental contusion in rats. Acta Neurochir Suppl
Stover JF, Beyer TF, Unterberg AW (2000) Riluzole reduces brain swelling and contusion volume in rats following controlled cortical impact injury. J Neurotrauma 17:1171–1178
Stover JF, Sakowitz OW, Beyer TF, Dohse NK, Kroppenstedt SN, Thomale UW, Schaser KD, Unterberg AW (2003) Effects of LY379268, a selective group II metabotropic glutamate receptor agonist on EEG activity, cortical perfusion, tissue damage, and cortical glutamate, glucose, and lactate levels in brain-injured rats. J Neurotrauma 20:315–326
Thomale UW, Kroppenstedt SN, Beyer TF, Schaser KD, Unterberg AW, Stover JF (2002) Temporal profile of cortical perfusion and microcirculation after controlled cortical impact injury in rats. J Neurotrauma 19:403–413
Xiong Y, Peterson PL, Lee CP (1999) Effect of N-acetylcysteine on mitochondrial function following traumatic brain injury in rats. J Neurotrauma 16:1067–1082
Stover JF, Dohse NK, Unterberg AW (2000) Bradykinin 2 receptor antagonist LF 16-0687Ms reduces posttraumatic brain edema. Acta Neurochir Suppl 76:171–175
Moinard C, Neveux N, Royo N, Genthon C, Marchand-Verrecchia C, Plotkine M, Cynober L (2005) Characterization of the alteration of nutritional state in brain injury induced by fluid percussion in rats. Intensive Care Med 31:281–288
Harrison PM, Wendon JA, Gimson AE, Alexander GJ, Williams R (1991) Improvement by acetylcysteine of hemodynamics and oxygen transport in fulminant hepatic failure. N Engl J Med 324:1852–1857
Wendon JA, Harrison PM, Keays R, Williams R (1994) Cerebral blood flow and metabolism in fulminant liver failure. Hepatology 19:1407–1413
Muir JK, Tynan M, Caldwell R, Ellis EF (1995) Superoxide dismutase improves posttraumatic cortical blood flow in rats. J Neurotrauma 12:179–188
Schaser KD, Bail HJ, Schewior L, Stover JF, Melcher I, Haas NP, Mittlmeier T (2005) Acute effects of N-acetylcysteine on skeletal muscle microcirculation following closed soft tissue trauma in rats. J Orthop Res 23:231–241
Stroop R, Thomale UW, Pauser S, Bernarding J, Vollmann W, Wolf KJ, Lanksch WR, Unterberg AW (1998) Magnetic resonance imaging studies with cluster algorithm for characterization of brain edema after controlled cortical impact injury (CCII). Acta Neurochir Suppl 71:303–305
Unterberg AW, Stroop R, Thomale UW, Kiening KL, Pauser S, Vollmann W (1997) Characterisation of brain edema following “controlled cortical impact injury” in rats. Acta Neurochir Suppl 70:106–108
Farr SA, Poon HF, Dogrukol-Ak D, Drake J, Banks WA, Eyerman E, Butterfield DA, Morley JE (2003) The antioxidants alpha-lipoic acid and N-acetylcysteine reverse memory impairment and brain oxidative stress in aged SAMP8 mice. J Neurochem 84:1173–1183
Baskaya MK, Rao AM, Dogan A, Donaldson D, Dempsey RJ (1997) The biphasic opening of the blood-brain barrier in the cortex and hippocampus after traumatic brain injury in rats. Neurosci Lett 226:33–36
Silbergleit R, Haywood Y, Fiskum G, Rosenthal RE (1999) Lack of a neuroprotective effect from N-acetylcysteine after cardiac arrest and resuscitation in a canine model. Resuscitation 40:181–186
Ellis EF, Dodson LY, Police RJ (1991) Restoration of cerebrovascular responsiveness to hyperventilation by the oxygen radical scavenger N-acetylcysteine following experimental traumatic brain injury. J Neurosurg 75:774–749
Nomoto Y, Yamamoto M, Fukushima T, Kimura H, Ohshima K, Tomonaga M (2001) Expression of nuclear factor kappaB and tumor necrosis factor alpha in the mouse brain after experimental thermal ablation injury. Neurosurgery 48:158–166
Author information
Authors and Affiliations
Corresponding author
Additional information
U.-W. Thomale and M. Griebenow contributed equally to this study
This work was supported in part by research grants from Charité Hospital, Humboldt University, Berlin (89531154 to U.W.T.) and Research Award 2001 of the Deutsche Gesellschaft für Neurotraumatologie und Klinische Neuropsychologie (to J.F.S.)
Rights and permissions
About this article
Cite this article
Thomale, UW., Griebenow, M., Kroppenstedt, SN. et al. The effect of N-acetylcysteine on posttraumatic changes after controlled cortical impact in rats. Intensive Care Med 32, 149–155 (2006). https://doi.org/10.1007/s00134-005-2845-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00134-005-2845-4