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Updated: May 17, 2026
Induction of Diffuse Axonal Brain Injury in Rats Based on Rotational Acceleration
Published on: May 9, 2020
Differential effects of FK506 on structural and functional axonal deficits after diffuse brain injury in the immature
Ann Mae Dileonardi1, Jimmy W Huh, Ramesh Raghupathi
1Program in Neuroscience, Drexel University College of Medicine, Philadelphia, PA, USA.
Insights
Diffuse axonal injury in young rats impairs nerve function and causes axonal damage. A calcineurin inhibitor did not improve outcomes, suggesting this pathway is not involved in young brain injury recovery.
Area of Science:
- Neuroscience
- Pediatric Traumatic Brain Injury Research
Background:
- Diffuse axonal injury (DAI) is a key component of pediatric traumatic brain injury (TBI), often leading to cognitive deficits.
- While DAI effects on adult rodent corpus callosum compound action potential (CAP) are known, data on immature rodents are scarce.
Purpose of the Study:
- To investigate the impact of closed head injury on corpus callosum CAP in 17-day-old rats.
- To explore the role of calcineurin in DAI-induced axonal dysfunction in immature brains.
Main Methods:
- Induction of closed head injury in 17-day-old rats.
- Electrophysiological assessment of CAP in the corpus callosum at various post-injury days.
- Histological analysis of axonal integrity and neurofilament phosphorylation (NF200).
- Pharmacological intervention using a calcineurin inhibitor (FK506).
Main Results:
- Closed head injury caused significant CAP deficits in both myelinated and unmyelinated fibers up to 14 days post-injury.
- Injury led to NF200 dephosphorylation, decreased total NF200, and axonal degeneration.
- FK506 treatment reduced NF200 dephosphorylation and axonal degeneration but did not improve CAP deficits or axonal transport.
- FK506 exacerbated CAP deficits in myelinated fibers at 7 days post-injury.
Conclusions:
- In immature rats, DAI impairs axonal function and integrity.
- Calcineurin inhibition does not ameliorate DAI-induced axonal dysfunction in young animals, unlike in adults.
- These findings suggest calcineurin plays a limited role in the axonal dysfunction following TBI in immature rodents.
Abstract:
Diffuse 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.
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