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We examined the neuro/axono-protective potential of a novel poly (ADP-ribose) polymerase (PARP) inhibitor L-2286 in a rat impact acceleration brain injury model. Male Wistar rats (n = 70) weighing 300-350 grams were used to determine the most effective intracerebroventricular (i.c.v.) dose of L-2286 administered 30 min after injury, and to test the neuroprotective effect at two time points (immediately, and 30 min after injury). The neuroprotective effect of L-2286 was tested using immunohistochemical (amyloid precursor protein and mid-sized mouse anti-neurofilament clone RMO-14.9 antibody) and behavioral tests (beam-balance, open-field and elevated plus maze). At both time-points, a 100 µg/rat dose of i.c.v. L-2286 significantly (p < 0.05) reduced the density of damaged axons in the corticospinal tract and medial longitudinal fascicle compared to controls. In the behavioral tests, treatment 30 min post-injury improved motor function, while the level of anxiety was reduced in both treatment protocols.

Abstract: Impaired axoplasmic transport (IAT) and neurofilament compaction (NFC), two common axonal pathology processes involved in traumatic axonal injury (TAI), have been well characterized. TAI is found clinically and in animal models in brainstem white matter (WM) tracts and in the corpus callosum (CC), optic chiasm (Och), and internal capsule. Previous published quantitative studies of the time course of TAI expression induced by the Marmarou impact acceleration model have been limited to the brainstem. Accordingly, this study assessed the extent of IAT and NFC in the CC and Och at 8h, 28h, 3days and 7days after traumatic brain injury (TBI) induction by the Marmarou impact acceleration model. IAT peak density was observed at 8h in the CC and 28h in the Och post-TBI. NFC peak density was observed at 28h in both structures. The density of IAT and NFC decreased with increasing survival time in both structures. The NFC density time profile followed a similar trend in both the Och and CC, whereas the IAT density time profile was variable between the Och and CC. Furthermore, a strong linear relationship was observed between IAT and NFC in the CC but not in the Och. These findings highlight the heterogeneity of TAI as evidenced by variable IAT and NFC injury time profiles in each anatomical structure. This variability indicates the requirement of multiple markers for a comprehensive TAI evaluation and multiple targeted treatments for TAI polypathology within its therapeutic window time frame. [Copyright &y& Elsevier]

We examined the neuro/axono-protective potential of a novel poly (ADP-ribose) polymerase (PARP) inhibitor L-2286 in a rat impact acceleration brain injury model. Male Wistar rats (n = 70) weighing 300-350 grams were used to determine the most effective intracerebroventricular (i.c.v.) dose of L-2286 administered 30 min after injury, and to test the neuroprotective effect at two time points (immediately, and 30 min after injury). The neuroprotective effect of L-2286 was tested using immunohistochemical (amyloid precursor protein and mid-sized mouse anti-neurofilament clone RMO-14.9 antibody) and behavioral tests (beam-balance, open-field and elevated plus maze). At both time-points, a 100 μg/rat dose of i.c.v. L-2286 significantly (p < 0.05) reduced the density of damaged axons in the corticospinal tract and medial longitudinal fascicle compared to controls. In the behavioral tests, treatment 30 min post-injury improved motor function, while the level of anxiety was reduced in both treatment protocols. [ABSTRACT FROM AUTHOR]