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.

Molecules comprising the extracellular matrix (ECM), and the family of matrix metalloproteinases (MMPs) that regulate them, perform essential functions during neuroplasticity in both developing and adult nervous systems, including substrate guidance during neuritogenesis and the establishment of boundaries for axonal terminal fields. MMP proteolysis of ECM molecules may perform a permissive or inductive role in fiber remodeling and synaptogenesis initiated by deafferentation. This study examined functional and structural effects of MMP inhibition during the early phases of deafferentation-induced sprouting, characterizing components of the degeneration/proliferation cycle that may be dependent on MMP activity. Adult rats received unilateral lesions of the entorhinal cortex to induce collateral sprouting of the crossed temporodentate fiber pathway. This was followed by intraventricular infusion of the MMP inhibitor FN-439 (2.9 mg/kg) or saline vehicle. After 7 d postlesion, rats underwent in vivo electrophysiological recording or histological processing for electron microscopic analysis. Lesioned rats receiving vehicle exhibited normal sprouting and synaptogenesis, with the emergence of the capacity for long-term potentiation (LTP) within the sprouting pathway, and the successful clearance of degenerating terminals with subsequent synaptic proliferation. In contrast, lesioned rats receiving the MMP inhibitor failed to develop the capacity for LTP and showed persistent cellular debris. Current source density analysis also revealed an FN-439-induced disruption of the current sink, normally localized to the middle region of the granule cell dendrites, corresponding to the terminal field of the crossed temporodentate fibers. These results establish a role for MMP-dependent processes in the deafferentation/sprouting cycle.

The current study demonstrates that Oxycyte can improve cognitive recovery and reduce CA3 neuronal cell loss after traumatic brain injury in rats.