Calpain as a therapeutic target in traumatic brain injury |
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Authors: | Kathryn E Saatman Jennifer Creed Ramesh Raghupathi |
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Institution: | (1) Neuroscience Program, University of Southern California, Los Angeles, CA 90089-2520, USA;(2) Department of Basic Medical Sciences, COMP, Western University of Health Sciences, Pomona, CA 91766, USA;(3) HNB534, University of Southern California, Los Angeles, CA 90089-2520, USA;(4) Present address: DIV BIOL 216-76, Caltech, Pasadena, CA 91125, USA; |
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Abstract: | 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 αII-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 TBI-associated 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. |
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