The beta-lactam antibiotic, ceftriaxone, provides neuroprotective potential via anti-excitotoxicity and anti-inflammation response in a rat model of traumatic brain injury

BACKGROUND The beta-lactam antibiotic, ceftriaxone (CTX), has been reported to induce neuroprotection in animal models of diverse neurologic diseases. Currently, no data have explored the potential for CTX to provide neuroprotection in the animal models of traumatic brain injury (TBI). The aim of this study was to investigate the neuroprotective effect by CTX on TBI and to determine the underlying mechanisms. METHODS Rats were immediately subjected to a lateral cortical impact injury caused by a free-falling object and divided randomly into three groups: sham-operated, trauma, and trauma + CTX treatment group. The CTX treatment group was given CTX (200 mg/kg of body weight, intravenously) immediately after injury. The cognitive function was assessed by Y-maze testing and cerebral edema was evaluated. Inflammatory cytokines expression was measured using enzyme-linked immunosorbent assay array. The expression of glutamate transporter-1 protein was identified by Western blot analysis. RESULTS This study shows that the CTX causes attenuation of TBI-induced cerebral edema and cognitive function deficits. CTX treatment significantly reduced levels of the proinflammatory cytokines interleukin-1&bgr;, interferon-&ggr;, and tumor necrosis factor-&agr; and up-regulated glutamate transporter-1 expression after TBI. CONCLUSION Our results provide in vivo evidence that CTX could exert neuroprotective effect against TBI by improving cognitive function and alleviating brain edema via reducing excitotoxicity and inflammation after TBI.

[1]  D. Hovda,et al.  Translational neurochemical research in acute human brain injury: the current status and potential future for cerebral microdialysis. , 2005, Journal of neurotrauma.

[2]  J. Lipski,et al.  Neuroprotective potential of ceftriaxone in in vitro models of stroke , 2007, Neuroscience.

[3]  R. Raghupathi,et al.  Cell Death Mechanisms Following Traumatic Brain Injury , 2004, Brain pathology.

[4]  A. Faden,et al.  Neuroprotection for traumatic brain injury: translational challenges and emerging therapeutic strategies. , 2010, Trends in pharmacological sciences.

[5]  A. von Deimling,et al.  Decreased expression of glutamate transporters in astrocytes after human traumatic brain injury. , 2006, Journal of neurotrauma.

[6]  R. Vink,et al.  The role of excitatory amino acids and NMDA receptors in traumatic brain injury. , 1989, Science.

[7]  I. Bechmann,et al.  Early expression of glutamate transporter proteins in ramified microglia after controlled cortical impact injury in the rat , 2001, Glia.

[8]  P. Kochanek,et al.  Oxidative Stress Following Traumatic Brain Injury in Rats , 2000, Journal of neurochemistry.

[9]  Sonu Bhatia.  Beta-lactam antibiotic offers neuroprotection in a spinal muscular atrophy model by multiple mechanisms , 2011, Annals of Neurosciences.

[10]  C. Mclean,et al.  In situ detection of inflammatory mediators in post mortem human brain tissue after traumatic injury. , 2010, Journal of neurotrauma.

[11]  M. Pickering,et al.  Actions of TNF‐α on glutamatergic synaptic transmission in the central nervous system , 2005 .

[12]  P. Calabresi,et al.  Assemblies of glutamate receptor subunits with post-synaptic density proteins and their alterations in Parkinson's disease. , 2010, Progress in brain research.

[13]  Rajkumar Verma,et al.  Pharmacological evaluation of glutamate transporter 1 (GLT-1) mediated neuroprotection following cerebral ischemia/reperfusion injury. , 2010, European journal of pharmacology.

[14]  A. Villringer,et al.  The β-lactam antibiotic, ceftriaxone, dramatically improves survival, increases glutamate uptake and induces neurotrophins in stroke , 2008, Journal of hypertension.

[15]  M. Pickering,et al.  Actions of TNF-alpha on glutamatergic synaptic transmission in the central nervous system. , 2005, Experimental physiology.

[16]  J. Roh,et al.  Pharmacological Induction of Ischemic Tolerance by Glutamate Transporter-1 (EAAT2) Upregulation , 2007, Stroke.

[17]  A. Hazell,et al.  Excitotoxic mechanisms and the role of astrocytic glutamate transporters in traumatic brain injury , 2006, Neurochemistry International.

[18]  M. Le Moal,et al.  A two-trial memory task with automated recording: study in young and aged rats , 1992, Brain Research.

[19]  M. Gilchrist,et al.  Animal models of traumatic brain injury: a critical evaluation. , 2011, Pharmacology & therapeutics.

[20]  P. Fisher,et al.  β-Lactam antibiotics offer neuroprotection by increasing glutamate transporter expression , 2005, Nature.

[21]  E. Hedlund.  The protective effects of beta-lactam antibiotics in motor neuron disorders , 2011, Experimental Neurology.

[22]  R. Vink,et al.  Traumatic brain injury: Therapeutic challenges and new directions , 2011, Neurotherapeutics.

[23]  P. Chan,et al.  Free radical pathways in CNS injury. , 2000, Journal of neurotrauma.

[24]  R. Bullock,et al.  Clinical Trials in Traumatic Brain Injury: Lessons for the Future , 2004, Journal of neurosurgical anesthesiology.

[25]  Richard T. Linn,et al.  Responses to cortical injury: I. Methodology and local effects of contusions in the rat , 1981, Brain Research.

[26]  Allison A Sande,et al.  Traumatic brain injury: a review of pathophysiology and management. , 2010, Journal of veterinary emergency and critical care.

[27]  E. von Elm,et al.  Pre-hospital tracheal intubation in patients with traumatic brain injury: systematic review of current evidence. , 2009, British journal of anaesthesia.

[28]  P. Biberfeld,et al.  Intracerebral inflammation after human brain contusion. , 1998, Neurosurgery.

[29]  M. Robinson,et al.  The role of glutamate transporters in neurodegenerative diseases and potential opportunities for intervention , 2007, Neurochemistry International.

[30]  T A Gennarelli,et al.  Neuropathological sequelae of traumatic brain injury: relationship to neurochemical and biomechanical mechanisms. , 1996, Laboratory investigation; a journal of technical methods and pathology.

[31]  R. Vink,et al.  Mechanisms of cerebral edema in traumatic brain injury: therapeutic developments , 2010, Current opinion in neurology.

[32]  E. Steyerberg,et al.  Epidemiology, severity classification, and outcome of moderate and severe traumatic brain injury: a prospective multicenter study. , 2011, Journal of neurotrauma.

[33]  D. Sengelaub,et al.  Up-regulation of GLT1 expression increases glutamate uptake and attenuates the Huntington's disease phenotype in the R6/2 mouse , 2008, Neuroscience.

[34]  R. Swanson,et al.  Astrocyte glutamate transport: Review of properties, regulation, and physiological functions , 2000, Glia.

[35]  L. An,et al.  Neuroprotection of catalpol in transient global ischemia in gerbils , 2004, Neuroscience Research.

[36]  L. Eng,et al.  Inflammation in Traumatic Brain Injury: Role of Cytokines and Chemokines , 1998, Neurochemical Research.

[37]  P. Fisher,et al.  Role of Excitatory Amino Acid Transporter‐2 (EAAT2) and glutamate in neurodegeneration: Opportunities for developing novel therapeutics , 2011, Journal of cellular physiology.