Reduction of post-traumatic brain injury and free radical production by inhibition of the caspase-1 cascade

doi:10.1016/S0306-4522(99)00345-0

Neuroscience

Volume 94, Issue 4, November 1999, Pages 1213-1218

https://doi.org/10.1016/S0306-4522(99)00345-0 Get rights and content

Abstract

Necrotic and apoptotic cell death both play a role mediating tissue injury following brain trauma. Caspase-1 (interleukin-1β 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-chloromethylketone 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-1β converting enyzme-like caspases and free radical production pathways, implicating free radical production as a downstream mediator of the caspase cell death cascade.

Section snippets

Traumatic brain injury

Brain trauma experiments and lesion quantification were performed essentially as previously described.³ Spontaneously ventilating adult mice were initially anesthetized with halothane in 70% N₂O and 30% O₂, and fixed in a stereotactic frame. Before trauma, an atraumatic craniectomy was performed by removing the right parietal bone posterior to bregma, lateral to the sagittal, and anterior to the lambdoid suture. Laterally, the craniectomy was extended to the insertion of the temporalis muscle.

DNA fragmentation following traumatic brain injury

To determine whether apoptotic cell death develops as a consequence of direct impact brain injury, we examined traumatized tissue for the presence of oligonucleosomal DNA fragmentation. In the lesioned hemisphere we found extensive DNA fragmentation 24 h following trauma. DNA damage was not detected in brain tissue from sham-operated mice which had only been craniectomized but not traumatized (Fig. 1). DNA fragments appeared on agarose gels as a ladder reflecting oligonucleosomal DNA

Discussion

In this study we demonstrate that, first, caspase-1 is activated following traumatic injury. Involvement of apoptotic cell death is shown by DNA laddering and by TUNEL in situ. DNA electrophoresis did not only show laddering suggesting oligonucleosomal DNA fragmentation characteristic for apoptosis but also a smear reflecting random DNA degradation resulting from necrotic cell death. This result indicates that both necrotic as well as apoptotic cell death pathways are activated and probably

Acknowledgements

Studies were supported by the Deutsche Forschungsgemeinschaft (K.B.F., Fi600/2-1 and M.E., En343/1-1, respectively), by Massachusetts General Hospital Interdepartmental Stroke Project Grant (M.A.M., NS10828), by Uehara Memorial Foundation (S.N.) and by a departmental grant (R.M.F.).

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Reduction of post-traumatic brain injury and free radical production by inhibition of the caspase-1 cascade

Abstract

Section snippets

Traumatic brain injury

DNA fragmentation following traumatic brain injury

Discussion

Acknowledgements

Cell

Brain Res.

Neuron

Cell

Cell

Cell

Expl Neurol.

Neurosci. Lett.

Devl Biol.

Cell

Molecular cloning of the interleukin-1β enzyme

Science

SOD-1 transgenic mice as a model for studies of neuroprotection in stroke and brain trauma

Ann. N. Y. Acad. Sci.

Experimental brain injury induces regionally distinct apoptosis during the acute and delayed post-traumatic period

J. Neurosci.

Post-traumatic brain hypothermia reduces histopathological damage following concussive brain injury in the rat

Acta neuropath., Berlin

A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD

Nature

Sequential activation of ICE-like and CPP32-like proteases during Fas-mediated apoptosis

Nature

Attenuation of delayed neuronal death after mild focal ischemia by inhibition of the caspase family

J. cerebr. Blood Flow Metab.

Nitric oxide and superoxide contribute to motor neuron apoptosis induced by trophic factor deprivation

J. Neurosci.

Expression of a dominant negative mutant of ICE in transgenic mice prevents neuronal cell death induced by trophic factor withdrawal and ischemic brain injury

J. exp. Med.

Functional role of interleukin-1β (IL-1β) in converting enzyme-mediated apoptosis

J. exp. Med.

Inhibition of ICE slows ALS in mice

Nature

ICE, neuronal apoptosis and neurodegeneration

Cell Death Diff.

Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation

J. Cell Biol.

Glutamate release and free radical production following brain injury: effects of posttraumatic hypothermia

J. Neurochem.

Attenuation of transient focal cerebral ischemic injury in transgenic mice expressing a mutant ICE inhibitory protein

J. cerebr. Blood Flow Metab.