Administration of the immunophilin ligand FK506 differentially attenuates neurofilament compaction and impaired axonal transport in injured axons following diffuse traumatic brain injury.
Traumatic axonal injury (TAI) following traumatic brain injury (TBI) remains a clinical problem for which no effective treatment exists. TAI was thought to involve intraaxonal changes that universally led to impaired axonal transport (IAT), disconnection and axonal bulb formation. However, recent, immunocytochemical studies employing antibodies to amyloid precursor protein (APP), a marker of IAT and antibodies to neurofilament compaction (NFC), RM014, demonstrated that NFC typically occurs independent of IAT, indicating the existence of different populations of damaged axons. FK506 administration has been shown to attenuate IAT. However, in light of the above, the ability of FK506 to attenuate axonal damage demonstrating NFC requires evaluation. The current study explored the potential of FK506 to attenuate both populations of damaged axons. Rats were administered FK506 (3 mg/kg) or vehicle 30 min preinjury. Three hours post-TBI, tissue was prepared for the visualization of TAI using antibodies targeting IAT (APP) or NFC (RMO14) or a combined labeling strategy. Confirming previous reports, FK506 treatment reduced the number of axons demonstrating IAT in the CSpT, from 411 +/- 54.70 to 91.00 +/- 33.87 (P <or= 0.05) and in the ML from 78.62 +/- 16.87 to 41.00 +/- 5.80 (P <or= 0.05). FK506 treatment failed to reduce the number of axons demonstrating NFC in either the CSpT or ML. FK506's failure to attenuate NFC suggests that additional therapeutic agents may be necessary to blunt the full burden of TAI. Because FK506 targets IAT, calcineurin appears to be a major target for neuroprotection in damaged axons demonstrating IAT.
Marmarou
Christina R
CR
Department of Anatomy and Neurobiology, Virginia Commonwealth University, PO Box 980709, Richmond, 23298, USA.
Povlishock
John T
JT
D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001370:Axonal Transport / Q000187:drug effects*; D001930:Brain Injuries / Q000150:complications*; D020833:Diffuse Axonal Injury / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D007150:Immunohistochemistry / Q000379:methods; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D008297:Male; D016900:Neurofilament Proteins / Q000378:metabolism*; D009460:Neurologic Examination; D011712:Pyramidal Tracts / Q000378:metabolism / Q000473:pathology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D016559:Tacrolimus / Q000008:administration & dosage*; D013997:Time Factors
D016564:Amyloid beta-Protein Precursor; D007166:Immunosuppressive Agents; D016900:Neurofilament Proteins; D016559:Tacrolimus