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

Stroke and Neurovascular Regulation, Massachusetts General Hospital, Harvard Medical School, Charlestown 02129, USA.
Neuroscience (Impact Factor: 3.36). 02/1999; 94(4):1213-8. DOI: 10.1016/S0306-4522(99)00345-0
Source: PubMed


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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    • "COX-2 catalyzed production of prostaglandin PGE2 results in the production of free radicals. Free radical-induced lipid peroxidation is responsible for massive neuronal death following primary mechanical injury [69], and PGE2 itself is also neurotoxic [70], [71]. In the short term, vascular permeability in response to inflammatory cell signaling leads to edema and intracranial hypertension, which further contributes to cell death [63], [72]. "
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    ABSTRACT: Traumatic brain injury (TBI) is an enormous public health problem, with 1.7 million new cases of TBI recorded annually by the Centers for Disease Control. However, TBI has proven to be an extremely challenging condition to treat. Here, we apply a nanoprodrug strategy in a mouse model of TBI. The novel nanoprodrug contains a derivative of the nonsteroidal anti-inflammatory drug (NSAID) ibuprofen in an emulsion with the antioxidant α-tocopherol. The ibuprofen derivative, Ibu2TEG, contains a tetra ethylene glycol (TEG) spacer consisting of biodegradable ester bonds. The biodegradable ester bonds ensure that the prodrug molecules break down hydrolytically or enzymatically. The drug is labeled with the fluorescent reporter Cy5.5 using nonbiodegradable bonds to 1-octadecanethiol, allowing us to reliably track its accumulation in the brain after TBI. We delivered a moderate injury using a highly reproducible mouse model of closed-skull controlled cortical impact to the parietal region of the cortex, followed by an injection of the nanoprodrug at a dose of 0.2 mg per mouse. The blood brain barrier is known to exhibit increased permeability at the site of injury. We tested for accumulation of the fluorescent drug particles at the site of injury using confocal and bioluminescence imaging of whole brains and brain slices 36 hours after administration. We demonstrated that the drug does accumulate preferentially in the region of injured tissue, likely due to an enhanced permeability and retention (EPR) phenomenon. The use of a nanoprodrug approach to deliver therapeutics in TBI represents a promising potential therapeutic modality.
    PLoS ONE 04/2013; 8(4):e61819. DOI:10.1371/journal.pone.0061819 · 3.23 Impact Factor
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    • "Caspases are activated during post-traumatic cerebral damage process. In addition, previous studies showed that caspase-3 activity is elevated following TBI (Fink et al., 1999). Our results showed that caspase-3 activities increased significantly after TBI at 24 h. "
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    Gene 10/2012; 512(2). DOI:10.1016/j.gene.2012.10.012 · 2.14 Impact Factor
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    • "The images of the stained specimens were captured by a digital photo camera and analyzed by Image Pro for morphometric measurement. The total lesion volume was determined by integrating the volumes at each coronal section interval as reported [41,42]. A blind investigator performed the lesion volume analyses. "
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