Effects of tacrolimus on hemispheric water content and cerebrospinal fluid levels of glutamate, hypoxanthine, interleukin-6, and tumor necrosis factor-alpha following controlled cortical impact injury in rats.

OBJECT Disturbance of calcium homeostasis contributes to evolving tissue damage and energetic impairment following traumatic brain injury (TBI). Calcium-mediated activation of calcineurin results in production of tissue-damaging nitric oxide and free oxygen radicals. Inhibition of calcineurin induced by the immunosuppressant tacrolimus (FK506) has been shown to reduce structural and functional damage after ischemia. The aims of the present study were to investigate time- and dose-dependent short-term antiedematous effects of tacrolimus following TBI. METHODS A left temporoparietal contusion (controlled cortical impact injury [CCII]) was induced in 51 male Sprague-Dawley rats. Tacrolimus (1 or 3 mg/kg body weight) was administered by a single intraperitoneal injection at 5 minutes, 30 minutes, or 4 hours after CCII occurred. Control rats received physiological saline. Water contents of traumatized and nontraumatized hemispheres, as well as cerebrospinal fluid (CSF) levels of mediators reflecting tissue damage (the proinflammatory cytokines interleukin [IL]-6 and tumor necrosis factor [TNF]-alpha, the excitotoxin glutamate, and the adenosine triphosphate-degradation product hypoxanthine), were determined 24 hours after trauma. Although CSF levels of IL-6 and TNFalpha were completely suppressed by tacrolimus at all time points and at both concentrations, CSF levels of glutamate and hypoxanthine, as well as edema formation, were only marginally influenced. Significant reduction of cerebral water content was confined to nontraumatized hemispheres. In addition, the higher dose of tacrolimus failed to exert significant antiedematous effects on traumatized hemispheres. CONCLUSIONS Under the present study design, the potency of tacrolimus in reducing edema formation following CCII seems limited. However, its immunosuppressive effects could be of value in influencing the posttraumatic inflammatory response known to aggravate tissue damage.

[1]  A. Unterberg,et al.  Effects of dopamine on posttraumatic cerebral blood flow, brain edema, and cerebrospinal fluid glutamate and hypoxanthine concentrations , 2000, Critical care medicine.

[2]  A. Unterberg,et al.  Riluzole reduces brain swelling and contusion volume in rats following controlled cortical impact injury. , 2000, Journal of neurotrauma.

[3]  A. Unterberg,et al.  Temporal profile of cerebrospinal fluid glutamate, interleukin-6, and tumor necrosis factor-α in relation to brain edema and contusion following controlled cortical impact injury in rats , 2000, Neuroscience Letters.

[4]  A. Unterberg,et al.  Significant reduction in brain swelling by administration of nonpeptide kinin B2 receptor antagonist LF 16-0687Ms after controlled cortical impact injury in rats. , 2000, Journal of neurosurgery.

[5]  T. Mathiesen,et al.  Intracerebral administration of interleukin-1 and induction of inflammation , apoptosis , and vasogenic edema , 2000 .

[6]  S. Scheff,et al.  Cyclosporin A significantly ameliorates cortical damage following experimental traumatic brain injury in rodents. , 1999, Journal of neurotrauma.

[7]  G. Burnstock,et al.  The Effects of FK506 on Dorsal Column Axons Following Spinal Cord Injury in Adult Rats: Neuroprotection and Local Regeneration , 1999, Experimental Neurology.

[8]  T. Kossmann,et al.  Thiopental attenuates energetic impairment but fails to normalize cerebrospinal fluid glutamate in brain-injured patients. , 1999, Critical care medicine.

[9]  J. Hamada,et al.  Potential role of calcineurin for brain ischemia and traumatic injury , 1999, Progress in Neurobiology.

[10]  D. Altavilla,et al.  Tacrolimus suppresses tumour necrosis factor‐α and protects against splanchnic artery occlusion shock , 1999, British journal of pharmacology.

[11]  A. Faden,et al.  Early neuronal expression of tumor necrosis factor-α after experimental brain injury contributes to neurological impairment , 1999, Journal of Neuroimmunology.

[12]  M. Rudin,et al.  Calcineurin inhibitors FK506 and SDZ ASM 981 alleviate the outcome of focal cerebral ischemic/reperfusion injury. , 1999, The Journal of pharmacology and experimental therapeutics.

[13]  M. Mattson,et al.  Traumatic brain injury alters synaptic homeostasis: implications for impaired mitochondrial and transport function. , 1998, Journal of neurotrauma.

[14]  T. Nakamura,et al.  FK506 promotes liver regeneration by suppressing natural killer cell activity , 1998, Journal of gastroenterology and hepatology.

[15]  Y. Ogura,et al.  Tacrolimus (FK506) attenuates leukocyte accumulation after transient retinal ischemia. , 1998, Stroke.

[16]  J. Kimura,et al.  Dose-dependent, protective effect of FK506 against white matter changes in the rat brain after chronic cerebral ischemia , 1998, Brain Research.

[17]  S. Wisniewski,et al.  Interstitial adenosine, inosine, and hypoxanthine are increased after experimental traumatic brain injury in the rat. , 1998, Journal of neurotrauma.

[18]  G. Schneider,et al.  Protective effects of aptiganel HCl (Cerestat) following controlled cortical impact injury in the rat. , 1998, Journal of neurotrauma.

[19]  S. Snyder,et al.  Neural actions of immunophilin ligands. , 1998, Trends in pharmacological sciences.

[20]  S. Butcher,et al.  Neuroprotective Actions of FK506 in Experimental Stroke: In Vivo Evidence against an Antiexcitotoxic Mechanism , 1997, The Journal of Neuroscience.

[21]  L. Toledo-Pereyra,et al.  Tacrolimus (FK506) down-regulates free radical tissue levels, serum cytokines, and neutrophil infiltration after severe liver ischemia. , 1997, Transplantation.

[22]  F. Vinas,et al.  Mitochondrial dysfunction after experimental and human brain injury and its possible reversal with a selective N-type calcium channel antagonist (SNX-111). , 1997 .

[23]  R. Dempsey,et al.  The biphasic opening of the blood–brain barrier in the cortex and hippocampus after traumatic brain injury in rats , 1997, Neuroscience Letters.

[24]  T. Ben-Hur,et al.  Cytokine production in the brain following closed head injury: dexanabinol (HU-211) is a novel TNF-α inhibitor and an effective neuroprotectant , 1997, Journal of Neuroimmunology.

[25]  C. Lee,et al.  Mitochondrial dysfunction and calcium perturbation induced by traumatic brain injury. , 1997, Journal of neurotrauma.

[26]  S. Butcher,et al.  Tacrolimus (FK506) ameliorates skilled motor deficits produced by middle cerebral artery occlusion in rats. , 1996, Stroke.

[27]  P. Parnet,et al.  When cytokines get on your nerves: cytokine networks and CNS pathologies , 1996, Trends in Neurosciences.

[28]  A. F. Schinder,et al.  Mitochondrial Dysfunction Is a Primary Event in Glutamate Neurotoxicity , 1996, The Journal of Neuroscience.

[29]  K. Nozaki,et al.  Neuroprotective effect of FK506, an immunosuppressant, on transient global ischemia in gerbil , 1996, Neuroscience Letters.

[30]  P. Young,et al.  Experimental brain injury induces differential expression of tumor necrosis factor-alpha mRNA in the CNS. , 1996, Brain research. Molecular brain research.

[31]  T. Kirino,et al.  An immunosuppressant, FK506, protects hippocampal neurons from forebrain ischemia in the Mongolian gerbil , 1996, Neuroscience Letters.

[32]  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.

[33]  P. Kochanek,et al.  Severe controlled cortical impact in rats: assessment of cerebral edema, blood flow, and contusion volume. , 1995, Journal of neurotrauma.

[34]  B. Gold,et al.  The immunosuppressant FK506 increases the rate of axonal regeneration in rat sciatic nerve , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[35]  J. Zhang,et al.  Nitric oxide synthase, immunophilins and poly(ADP-ribose) synthetase: novel targets for the development of neuroprotective drugs. , 1995, Neurological research.

[36]  E. Marbán,et al.  Presynaptic modulation of cortical synaptic activity by calcineurin. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[37]  N. Rothwell,et al.  Cytokines and the nervous system II: actions and mechanisms of action , 1995, Trends in Neurosciences.

[38]  P. Kochanek,et al.  Neutrophil accumulation after traumatic brain injury in rats: comparison of weight drop and controlled cortical impact models. , 1994, Journal of neurotrauma.

[39]  S. Butcher,et al.  Immunophilins mediate the neuroprotective effects of FK506 in focal cerebral ischaemia , 1994, Nature.

[40]  E. Shohami,et al.  Closed Head Injury Triggers Early Production of TNFα and IL-6 by Brain Tissue , 1994 .

[41]  K. Tomizawa,et al.  Immunosupressants and calcineurin inhibitors, cyclosporin A and FK506, reversibly inhibit epileptogenesis in amygdaloid kindled rat , 1994, Brain Research.

[42]  D. Marion,et al.  Traumatic Brain Injury‐Induced Excitotoxicity Assessed in a Controlled Cortical Impact Model , 1993, Journal of neurochemistry.

[43]  S. Snyder,et al.  Immunosuppressant FK506 enhances phosphorylation of nitric oxide synthase and protects against glutamate neurotoxicity. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[44]  Stuart L. Schreiber,et al.  Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes , 1991, Cell.