Calpain as a Therapeutic Target in Traumatic Brain Injury

Abstract

Summary:The family of calcium-activated neutral proteases, calpains, appears to play a key role in neuropathologic events following traumatic brain injury (TBI). Neuronal calpain activation has been observed within minutes to hours after either contusive or diffuse brain trauma in animals, suggesting that calpains are an early mediator of neuronal damage. Whereas transient calpain activation triggers numerous cell signaling and remodeling events involved in normal physiological processes, the sustained calpain activation produced by trauma is associated with neuron death and axonal degeneration in multiple models of TBI. Nonetheless, the causal relationship between calpain activation and neuronal death is not fully understood. Much remains to be learned regarding the endogenous regulatory mechanisms for controlling calpain activity, the roles of different calpain isoforms, and the in vivo substrates affected by calpain. Detection of stable proteolytic fragments of the submembrane cytoskeletal protein ␣II-spectrin specific for cleavage by calpains has been the most widely used marker of calpain activation in models of TBI. More recently, these protein fragments have been detected in the cerebrospinal fluid after TBI, driving interest in their potential utility as TBIassociated biomarkers. Post-traumatic inhibition of calpains, either direct or indirect through targets related to intracellular calcium regulation, is associated with attenuation of functional and behavioral deficits, axonal pathology, and cell death in animal models of TBI. This review focuses on the current state of knowledge of the role of calpains in TBI-induced neuropathology and effectiveness of calpain as a therapeutic target in the acute post-traumatic period.

The Cysteine Protease Cathepsin B Is a Key Drug Target and Cysteine Protease Inhibitors Are Potential Therapeutics for Traumatic Brain Injury

“…These data suggest that E64d may have some off-target effects during early post-trauma. A likely offtarget candidate may be inhibition of the calpains, which are known TBI drug targets, 43 because calpain-1 KO studies have validated as such. 44 Brain calpain activity spikes within 24 h of trauma, [45][46][47] and E64d administration has been shown to reduce calpain activity and provide neuroprotection after trauma.…”

Short-Duration Treatment with the Calpain Inhibitor MDL-28170 Does Not Protect Axonal Transport in anin VivoModel of Traumatic Axonal Injury

“…It is believed that post-traumatic calpain activity within axons contributes to transport disruption, cytoskeletal degradation, and subsequent axotomy. However, there is also robust calpain activity in neuronal somata and dendrites after TBI (Saatman et al, 2010). Trying to measure the role of axonal calpains in whole brain TBI models is complex because many supra-axonal structures are affected.…”

Family-wide Structural Characterization and Genomic Comparisons Decode the Diversity-oriented Biosynthesis of Thalassospiramides by Marine Proteobacteria

“…CNJ-328, and then, in 2013, we reported an additional 14 thalassospiramides from Thalassospira and Tistrella strains. We found that many of these compounds display a high inhibitive potency (nanomolar levels) of human calpain protease (4), a calcium-dependent enzyme family implicated in neurological disorders (5), muscular dystrophies, cortical cataracts (6), and cancer (7). For example, inflammatory cytokines that lead to neuronal network disruption, increase intracellular calcium, and increase calpain protease activity are a possible trigger for Alzheimer's disease (8).…”