The Immunophilin Ligand FK506 Attenuates Axonal Injury in an Impact-Acceleration Model of Traumatic Brain Injury

Abstract

The immunophilin ligand, cyclosporin A (CsA), is effective in reducing the axonal damage associated with traumatic brain injury (TBI). Based upon extensive ultrastructural and immunohistochemical studies, the neuroprotection afforded by CsA appeared to be mediated via mitochondrial protection, specifically, the prevention of mitochondrial swelling and inhibition of mitochondrial permeability transition (MPT). However, the potential that CsA could also be neuroprotective via the immunophilin-mediated inhibition of the protein phosphatase, calcineurin (CN) has not been directly assessed. To address this issue, the current study assessed the ability of FK506, another immunophilin ligand that inhibits CN with no effect on MPT, to attenuate axonal damage in a rat impact-acceleration model of TBI. Traumatic axonal injury (TAI), detected via an antibody against beta-amyloid precursor protein (APP), a specific marker of axonal injury, was significantly reduced at 24 hr postinjury in Sprague-Dawley rats receiving intravenous FK506 (2 mg/kg; n = 5) 30 min prior to injury compared to vehicle controls (n = 3). While not rejecting the established efficacy of CsA in providing neuroprotection via its targeting of MPT, this study does underscore the potential importance of CN in the progressive pathobiology of TAI, suggesting that CN may constitute another important therapeutic target.

Evidence for the Therapeutic Efficacy of Either Mild Hypothermia or Oxygen Radical Scavengers after Repetitive Mild Traumatic Brain Injury

“…19 Specifically, through using either the delayed administration of FK506 or induction of postrepetitive moderate hypothermia (32-33°C), we achieved remarkable axonal and vascular protection after the repetitive mTBI. 19 Consistent with previous observations from our lab, [20][21][22][23][24] we assume that use of the immunophilin ligand, FK506, as well as moderate hypothermia acted on multiple targets, including, but not limited to, calcineurin-mediated, oxygen radical-linked, and metabolically regulated cascades attenuating their genesis of both axonal and microvascular damage. 19 Although it remains to be determined, such protective effects suggest that these therapies may ultimately prove of use in those patient populations sustaining increased morbidity subsequent to secondary insults or those manifesting a second impact syndrome.…”

Status Epilepticus-Induced Somatostatinergic Hilar Interneuron Degeneration Is Regulated by Striatal Enriched Protein Tyrosine Phosphatase

“…Given that STEP is expressed in the hilus, but not in the GCL, these data indicate the effect of FK506 was the specific result of STEP inhibition. It should be noted that FK506 has been shown to have neuroprotective effects in a number of brain injury models (Butcher et al, 1997;Singleton et al, 2001). However, the mechanism by which FK506 provides protection has not been established.…”

Identification and Characterization of Heterogeneous Neuronal Injury and Death in Regions of Diffuse Brain Injury: Evidence for Multiple Independent Injury Phenotypes

“…Given the established utility of intra-axonal ␤-amyloid precursor protein (APP) pooling to identify axonal injury (Blumbergs et al, 1994;Sherriff et al, 1994a,b;Gentleman et al, 1995;Bramlett et al, 1997;Geddes et al, 1997;Okonkwo and Povlishock, 1999;Buki et al, 1999;Finnie et al, 2000;Stone et al, 2000;Singleton et al, 2001), antibodies targeting the C terminus of the APP protein were used as previously described to identify perisomatic axonal injury (Singleton et al, 2002) and to explore the relationship, if any, between those cells manifesting axotomy and those revealing somatic membrane perturbation. Because our previous study also identified the presence of terminal deoxynucleotidyl transferasemediated biotinylated UTP nick end-labeling-negative, necrotic neurons in close relation to other neurons sustaining in perisomatic axotomy, we also used the histochemical marker Fluoro-Jade (FJ), which selectively stains degenerating neurons independent of the mechanism of cell death (Schmued et al, 1997;Schmued and Hopkins, 2000).…”