Abstract
Calcium-induced, calpain-mediated proteolysis (CMSP) has recently been implicated to the pathogenesis of diffuse (traumatic) axonal injury (TAI). Some studies suggested that subaxolemmal CMSP may contribute to axolemmal permeability (AP) alterations observed in TAI. Seeking direct evidence for this premise we investigated whether subaxolemmal CMSP may contribute to axolemmal permeability alterations (APA) and pre-injury calpain-inhibition could reduce AP in a rat model of TAI. Horseradish peroxidase (HRP, a tracer that accumulates in axons with APA) was administered one hour prior to injury into the lateral ventricle; 30 min preinjury a single tail vein bolus injection of 30 mg/kg MDL-28170 (a calpain inhibitor) or its vehicle was applied in Wistar rats exposed to impact acceleration brain injury. Histological detection of traumatically injured axonal segments accumulating HRP and statistical analysis revealed that pre-injury administration of the calpain inhibitor MDL-28170 significantly reduced the average length of HRP-labeled axonal segments. The axono-protective effect of pre-injury calpain inhibition recently demonstrated with classical immunohistochemical markers of TAI was further corroborated in this experiment; significant reduction of the length of labeled axons in the drug-treated rats implicate CMSP in the progression of altered AP in TAI.
Highlights
Traumatic brain injury (TBI) generates widespread traumatic axonal injury (TAI) in animals and man significantly contributing to mortality and morbidity [1]
These changes include focal axolemmal permeability alterations (APA), induction of calpain-mediated proteolysis (CMSP) and neurofilament sidearm modification leading to neurofilament compaction (NFC) long associated with impaired axoplasmatic transport and axonal swelling that concludes in axonal disconnection [4]
In a recently published paper we have reported the application of a cell permeable peptidylaldehyde calpain inhibitor (MDL-28170) in an attempt to determine whether this drug attenuates traumatically induced axonal damage to provide further evidence of the role of calpain-mediated spectrin proteolysis (CMSP) in the pathogenesis of TAI, while setting the stage for additional therapeutic studies on the utility of calpaininhibitors for the treatment of TAI
Summary
Traumatic brain injury (TBI) generates widespread traumatic axonal injury (TAI) in animals and man significantly contributing to mortality and morbidity [1]. In the last two decades, detailed investigation of the pathobiology of TAI has revealed that the majority of injured axons are not mechanically severed at the time of impact as it had been proposed previously, but instead these axons show progressive changes gradually evolving towards axonal disconnection [2,3,4] These changes include focal axolemmal permeability alterations (APA), induction of calpain-mediated proteolysis (CMSP) and neurofilament sidearm modification leading to neurofilament compaction (NFC) long associated with impaired axoplasmatic transport and axonal swelling that concludes in axonal disconnection [4]. Hong et al [9] demonstrated the neuroprotective effect of a cell-penetrating calpain inhibitor administrated systematically Their findings suggest that targeting of intracellular Ca2+-activated mechanisms, such as proteolysis, represents a viable therapeutic strategy for limiting neurological damage. Posmantur et al [14]
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