Traumatic axonal injury (TAI), a consequence of traumatic brain injury (TBI), results from progressive pathologic processes initiated at the time of injury. Studies attempting to characterize the pathology associated with TAI have not succeeded in following damaged and/or disconnected axonal segments back to their individual neuronal somata to determine their fate. To address this issue, 71 adult male Sprague Dawley rats were subjected to moderate central fluid percussion injury and killed between 30 min and 7 d after injury. Antibodies to the C terminus of ␤-amyloid precursor protein (APP) identified TAI in continuity with individual neuronal somata in the mediodorsal neocortex, the hilus of the dentate gyrus, and the dorsolateral thalamus. These somata were followed with immunocytochemical markers of neuronal injury targeting phosphorylated 200 kDa neurofilaments (RMO-24), altered protein translation (phosphorylated eukaryotic translation initiation factor 2␣), and cell death [terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)], with parallel electron microscopic (EM) assessment. Despite the finding of TAI within 20-50 m of the soma, no evidence of cell death, long associated with proximal axotomy, was seen via TUNEL or routine light microscopy/electron microscopy. Rather, there was rapid onset (Ͻ6 hr after injury) subcellular change associated with impaired protein synthesis identified by EM, immunocytochemical, and Western blot analyses. When followed 7 d after injury, these abnormalities did not reveal dramatic progression. Rather, some somata showed evidence of potential reorganization and repair. This study demonstrates a novel somatic response to TAI in the perisomatic domain and also provides insight into the multifaceted pathology associated with TBI.

Diffuse brain injury (DBI) is a consequence of traumatic brain injury evoked via rapid acceleration-deceleration of the cranium, givingrise to subtle pathological changes appreciated best at the microscopic level. DBI is believed to be comprised by diffuse axonal injury and other forms of diffuse vascular change. The potential, however, that the same forces can also directly injure neuronal somata in vivo has not been considered. Recently, while investigating DBI-mediated perisomatic axonal injury, we identified scattered, rapid neuronal somatic necrosis occurring within the same domains. Moving on the premise that these cells sustained direct somatic injury as a result of DBI, we initiated the current study, in which rats were intracerebroventricularly infused with various high-molecular weight tracers (HMWTs) to identify injury-induced neuronal somatic plasmalemmal disruption. These studies revealed that DBI caused immediate, scattered neuronal somatic plasmalemmal injury to all of the extracellular HMWTs used. Through this approach, a spectrum of neuronal change was observed, ranging from rapid necrosis of the tracer-laden neurons to little or no pathological change at the light and electron microscopic level. Parallel double and triple studies using markers of neuronal degeneration, stress, and axonal injury identified additional injured neuronal phenotypes arising in close proximity to, but independent of, neurons demonstrating plasmalemmal disruption. These findings reveal that direct neuronal somatic injury is a component of DBI, and diffuse trauma elicits a heretofore-unrecognized multifaceted neuronal pathological change within the CNS, generating heterogeneous injury and reactive alteration within both axons and neuronal somata in the same domains.

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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.