Reduction of post-traumatic brain injury and free radical production by inhibition of the caspase-1 cascade.
ABSTRACT Necrotic and apoptotic cell death both play a role mediating tissue injury following brain trauma. Caspase-1 (interleukin-1beta converting enzyme) is activated and oligonucleosomal DNA fragmentation is detected in traumatized brain tissue. Reduction of tissue injury and free radical production following brain trauma was achieved in a transgenic mouse expressing a dominant negative inhibitor of caspase-1 in the brain. Neuroprotection was also conferred by pharmacological inhibition of caspase-1 by intracerebroventricular administration of the selective inhibitor of caspase-1, acetyl-Tyr-Val-Ala-Asp-chloromethyl-ketone or the non-selective caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone. These results indicate that inhibition of caspase-1-like caspases reduces trauma-mediated brain tissue injury. In addition, we demonstrate an in vivo functional interaction between interleukin-1beta converting enyzme-like caspases and free radical production pathways, implicating free radical production as a downstream mediator of the caspase cell death cascade.
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ABSTRACT: Our aim in this study was to investigate the effect of moderate acute alcohol administration on cysteine protease mediated neuronal apoptosis and nitric oxide production in the traumatic brain injury. A total of 29 adult Sprague-Dawley male rats weighing 250-300g were used. The rats were allocated into four groups. The first group was control (sham-operated) group in which only a craniotomy was performed, the others were alcohol, trauma and trauma+alcohol groups. Caspase-3 enzyme activity in the trauma group increased significantly in comparison with the control group. Alcohol given group showed a decreased caspase-3 enzyme activity compared to the trauma group. The level of caspase-3 enzyme activity in the alcohol+trauma group decreased in comparison to the trauma group. SF/FEL ratio of cathepsin-L enzyme activity in the trauma group was significantly higher than in the control group. Our results indicate that moderate alcohol consumption may have protective effects on apoptotic cell death after traumatic brain injury. Protective effects of moderate ethanol consumption might be related to inhibition of lysosomal protease release and nitric oxide production.Gene 10/2012; DOI:10.1016/j.gene.2012.10.012
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ABSTRACT: We investigated the consequences of transient application of specific stimuli mimicking inflammation to hippocampal tissue on microglia activation and neuronal cell vulnerability to a subsequent excitotoxic insult. Two-week-old organotypic hippocampal slice cultures, from 7-day-old C57BL/6 donor mice, were exposed for 3 h to lipopolysaccharide (LPS; 10 ng/mL) followed by 3 h co-incubation with 1 mM ATP, or 100 microM 2'3'-O-(4-benzoyl-benzoyl) adenosine 5'-triphosphate triethylammonium, a selective P2X(7) receptor agonist. These treatments in combination, but not individually, induced a pronounced activation and apoptotic-like death of macrophage antigen-1 (MAC-1)-positive microglia associated with a massive release of interleukin (IL)-1beta exceeding that induced by LPS alone. Antagonists of P2X(7) receptors prevented these effects. Transient pre-exposure of slice cultures to a combination of LPS and P2X(7) receptor agonists, but not either one or the other alone, significantly exacerbated CA3 pyramidal cell loss induced by subsequent 12 h exposure to 8 microM alpha-amino-3-hydroxy-5-methyl-4-isoxazole propinate (AMPA). Potentiation of AMPA toxicity was prevented when IL-1beta production or its receptor signaling were blocked by an inhibitor of interleukin-converting-enzyme or IL-1 receptor antagonist during application of LPS + ATP. The same treatments did not prevent microglia apoptosis-like death. These findings show that transient exposure to specific pro-inflammatory stimuli in brain tissue can prime neuronal susceptibility to a subsequent excitotoxic insult. P2X(7) receptor stimulation, and the consequent IL-1beta release, is mandatory for exacerbation of neuronal loss. These mechanisms may contribute to determine cell death/survival in acute and chronic neurodegenerative conditions associated with inflammatory events.Journal of Neurochemistry 08/2008; 106(1):271-80. DOI:10.1111/j.1471-4159.2008.05387.x
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ABSTRACT: Apoptosis as a cell death mechanism is important in numerous diseases, including traumatic SCI. We evaluated the neuroprotective effects of Ac.YVAD.cmk and functional outcomes in a rat SCI model. Thirty rats were randomized into 3 groups of 10: sham-operated, trauma only, and trauma plus Ac.YVAD.cmk treatment. Trauma was produced in the thoracic region by a weight-drop technique. Group 3 rats received Ac.YVAD.cmk (1 mg/kg, ip) 1 minute after trauma. The rats were killed at 24 hours and 5 days after injury. Efficacy was evaluated with light microscopy and TUNEL staining. Functional outcomes were assessed with the inclined plane technique and a modified version of the Tarlov grading system. At 24 hours postinjury, the respective mean number of apoptotic cells in groups 1, 2, and 3 were 0, 5.26 +/- 0.19, and 0.97 +/- 0.15. Microscopic examination of group 2 tissues showed widespread hemorrhage, edema, necrosis, and polymorphic nuclear leukocyte infiltration and vascular thrombi. Group 3 tissues revealed similar features, but cavitation and demyelination were less prominent than those in group 2 samples at this period. At 5 days postinjury, the respective mean inclined plane angles in groups 1, 2, and 3 were 65.5 +/- 2.09, 42.00 +/- 2.74, and 52.5 +/- 1.77. Motor grading of animals revealed a similar trend. These differences were statistically significant (P < .05). Ac.YVAD.cmk inhibited posttraumatic apoptosis in a rat SCI model. This may provide the basis for development of new therapeutic strategies for the treatment of SCI.Surgical Neurology 06/2008; 69(6):561-7. DOI:10.1016/j.surneu.2007.03.041