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. 2010 Mar 26;11(4):1253-68.
doi: 10.3390/ijms11041253.

A novel PARP inhibitor L-2286 in a rat model of impact acceleration head injury: an immunohistochemical and behavioral study

Erzsébet Kövesdi  1 , Péter Bukovics, Valérie Besson, József Nyirádi, János Lückl, József Pál, Balázs Sümegi, Tamás Dóczi, István Hernádi, András Büki
Affiliations

A novel PARP inhibitor L-2286 in a rat model of impact acceleration head injury: an immunohistochemical and behavioral study

Erzsébet Kövesdi et al. Int J Mol Sci. .

Abstract

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 microg/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.

Keywords: PARP-inhibitor; impact acceleration model; traumatic brain injury.

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Figures

Figure 1.
Figure 1.
Chemical structure of L-2286 [9].
Figure 2.
Figure 2.
The effect of i.c.v. L-2286 administered in different doses 30 min after severe impact acceleration head injury on the density of APP immunopositive axons in the CSpT (** p < 0.01 compared to vehicle group).
Figure 3.
Figure 3.
APP-IR axonal profiles (arrows) from CspT two hours post-injury. Note that the density of damaged axons appears reduced in rats treated with 100 μg/rat of i.c.v. L-2286 (B) compared to those treated with vehicle (A).
Figure 4.
Figure 4.
Densities of APP-immunopositive axons in CSpT and MLF in animals treated with 5 μl/rat of i.c.v. vehicle and 100 μg/rat of i.c.v. L-2286 immediately and 30 min post-injury (**p < 0.01 compared to vehicle).
Figure 5.
Figure 5.
Densities of RMO-14 immunopositive axons in CSpT and MLF in animals treated with 5 μl/rat of i.c.v. vehicle and 100 μg/rat of i.c.v. L-2286 immediately and 30 min post-injury (**p < 0.01 compared to vehicle).
Figure 6.
Figure 6.
Effect of 100 μg/rat of i.c.v. L-2286 on beam-balance test scores from one hour to seven days after severe IA head injury (*p < 0.05 and **p < 0.01 compared to vehicle-treated animals).
Figure 7.
Figure 7.
Effect of 100 μg/rat of i.c.v. L-2286 on grooming in open-field test (*p < 0.05 compared to vehicle-treated animals).
Figure 8.
Figure 8.
Effect of 100 μg/rat of i.c.v. L-2286 on head dip in the elevated plus-maze test (*p < 0.05 compared to vehicle-treated animals).
Figure 9.
Figure 9.
Effect of 100 μg/rat of i.c.v. L-2286 on time spent in the closed arm in the elevated plus-maze test (**p < 0.01 compared to vehicle-treated animals).
Figure 10.
Figure 10.
Effect of 100 μg/rat of i.c.v. L-2286 on time spent in the open arm in the elevated plus-maze test (**p < 0.01 compared to vehicle-treated animals).
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