Effects of Injury Severity on Regional and Temporal mRNA Expression Levels of Calpains and Caspases after Traumatic Brain Injury in Rats

Abstract

Despite a preponderance of studies demonstrating gene expression and/or enzymatic activation of calpain and caspase proteases after traumatic brain injury (TBI), no studies have examined the effects of injury magnitude on expression levels of these cell death effectors after TBI. Determination of the degree to which injury severity affects specific expression profiles is critical to understanding the relevant pathways contributing to post-trauma pathology and for developing targeted therapeutics. This investigation tested the hypothesis that different injury magnitudes (1.0, 1.2, and 1.6 mm) cause alterations in the regional and temporal patterns of mRNA expression of calpain-related (calpain-1 and -2, calpastatin) and caspase-related (caspases -3, -8, -9, BID) gene products after cortical impact in rats. Quantitative RT-PCR was used to compare effects of injury severity on mRNA levels in ipsilateral (injured) cortex and hippocampus, 6 h to 5 days post-injury. TBI caused increases in mRNA expression of all proteins examined, with the highest expression detected in the cortex. Generally, injury magnitude and levels of gene expression were positively correlated. High levels of gene induction were observed with BID, caspase-3, and -8, while caspase-9 mRNA had the lowest level of induction. Interestingly, although calpains are activated within minutes of TBI, calpain mRNA expression was highest 72 h to 5 days post-TBI. This study is the first analysis of the regional and temporal expression of calpains and caspases after TBI. These data provide insight into the inter-relationship of these two protease families and on the distinct but overlapping cascades of cell death after TBI.

Cell Death Mechanisms and Modulation in Traumatic Brain Injury

“…A different strategy is to focus on therapies that specifically and/or simultaneously target multiple PCD mechanisms. In this paradigm multifunctional effects can be generated by multi-drug combinations and/or by targeting single factors that modulate multiple secondary injury cascades - such as activation of the cell cycle 48–50, PARP-1 70, 102, 103, calpains 104 or HSP70 among others. Targeting processes such as autophagy represents a more complex issue because of studies that indicate both cell death and neuroprotective activity 105, 106.…”

Serum-Based Protein Biomarkers in Blast-Induced Traumatic Brain Injury Spectrum Disorder

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Calpain as a Therapeutic Target in Traumatic Brain Injury

“…Cortical and hippocampal μ-calpain mRNA levels increase in a delayed fashion, at 72 hr after CCI in rats, and are preceded by increased m-calpain and calpastatin mRNA at 24 hr 36. Although calpains and calpastatin have multiple phosphorylation sites,3 no published studies have examined the effect of phosphorylation on posttraumatic calpain activity.…”