Differential Effects of FK506 on Structural and Functional Axonal Deficits After Diffuse Brain Injury in the Immature Rat

• Published in: Journal of neuropathology and experimental neurology Vol. 71; no. 11; pp. 959 - 972
• Main Authors: DiLeonardi, Ann Mae, Huh, Jimmy W, Raghupathi, Ramesh
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Association of Neuropathologists, Inc 01.11.2012; Lippincott Williams & Wilkins; Oxford University Press
• Subjects: Aging - drug effects; Aging - physiology; Animals; Axons - drug effects; Axons - pathology; Axons - physiology; Biological and medical sciences; Brain damage; Brain Injuries - drug therapy; Brain Injuries - pathology; Brain Injuries - physiopathology; Cranial nerves. Spinal roots. Peripheral nerves. Autonomic nervous system. Gustation. Olfaction; Female; Head injuries; Immunosuppressive Agents - pharmacology; Male; Medical sciences; Nervous system (semeiology, syndromes); Neurology; Proteins; Rats; Rats, Sprague-Dawley; Rodents; Tacrolimus - pharmacology; Nervous system diseases; Traumatic brain injury; Rat; Calcineurin; Rodentia; Electrophysiology; Action potential; Compound action potential; FK506; Cerebral disorder; Vertebrata; Neurofilament; Mammalia; Axonal injury; Immature rat; Animal; Central nervous system disease; Head trauma
• ISSN: 0022-3069; 1554-6578
• DOI: 10.1097/NEN.0b013e31826f5876

ABSTRACTDiffuse axonal injury is a major component of traumatic brain injury in children and correlates with long-term cognitive impairment. Traumatic brain injury in adult rodents has been linked to a decrease in compound action potential (CAP) in the corpus callosum, but information on trauma-associated diffuse axonal injury in immature rodents is limited. We investigated the effects of closed head injury on CAP in the corpus callosum of 17-day-old rats. The injury resulted in CAP deficits of both myelinated and unmyelinated fibers in the corpus callosum between 1 and 14 days postinjury (dpi). These deficits were accompanied by intra-axonal dephosphorylation of the 200-kDa neurofilament subunit (NF200) at 1 and 3 dpi, a decrease in total NF200 at 3 dpi and axonal degeneration at 3 and 7 dpi. Although total phosphatase activity decreased at 1 dpi, calcineurin activity was unchanged. The calcineurin inhibitor, FK506, significantly attenuated the injury-induced NF200 dephosphorylation of NF200 at 3 dpi and axonal degeneration at 3 and 7 dpi but did not affect the decrease in NF200 protein levels or impaired axonal transport. FK506 had no effect on CAP deficits at 3 dpi but exacerbated the deficit in only the myelinated fibers at 7 dpi. Thus, in contrast to adult animals, FK506 treatment did not improve axonal function in brain-injured immature animals, suggesting that calcineurin may not contribute to impaired axonal function.