The protective effect of PARP inhibitor PJ34 in traumatic brain injury

Abstract

Objective To investigate whether PARP inhibitor, PJ34, participates in the inflammation related to PARP-NF-κB pathway in a mouse model of controlled cortical impact (CCI). Methods One hundred and thirty-six BALB/c male mice were divided into 3 groups: sham-operated group, vehicle-treated group and PJ34-treated group. Injury to the cerebral cortex was produced with controlled cortical impact.Evaluation of the neurological deficits was performed at 6 h and 24 h after CCI, which included the motor, sensory, reflex testing and beam balance testing.The contusion volumes were measured after HE staining at 6 h and 24 h after CCI.The activities of MPO in contusion cortex were examined by using MPO ELISA kit. Western blot was performed to detect the levels of NF-κB p65 in cytosolic and nuclear fractions and to detect TNF-α and IL-1β in cytosolic fractions. Results Neurological severity scores at 6 h and 24 h after CCI in PJ34-treated group(8.20 ±0.25 and 7.80 ±0.25, respectively) are less than those in vehicle-treated group(12.40 ±0.38 and 11.70 ±0.22, respectively)( all P<0.01). The contusion volume at 6 h and 24 h after CCI in PJ34-treated group[(10.25 ±0.61) mm3and (11.55 ±1.16) mm3, respectively] is less than that in vehicle-treated group[(25.07 ±1.45) mm3and (27.24± 1.51) mm3, respectively]( all P<0.01). The activities of MPO at 6 h and 24 h after CCI in PJ34-treated group[(0.013 ±0.001) U/g and (0.018 ±0.001) U/g, respectively] is less than those in vehicle-treated group[(0.024 ±0.001) U/g and (0.023± 0.001) U/g, respectively]( all P<0.05). Moreover, the expression level of NF-κB p65 in cytoplasm at 6 h and 24 h after CCI in PJ34-treated group is less than that in vehicle-treated group ( all P<0.05). Compared with vehicle-treated group, the expression level of NF-κB p65 in cell nuclei at 24 h after CCI in PJ34-treated group is higher (P<0.01). There is no significant difference between the expression level of NF-κB p65 in cell nuclei at 6 h after CCI in PJ34-treated group and in vehicle-treated group. PJ34 also reduced the expression level of TNF-α and IL-1β at 6 h or 24 h after CCI(P<0.05 or P<0.01). Conclusions PARP-NF-κB inflammatory pathway plays an important role during the secondary injury after traumatic brain injury(TBI). PJ34 could block the pathway, inhibit inflammatory response and protect the brain against TBI. Key words: Craniocerebral trauma; Poly(ADP-ribose)polymerase; Nuclear factor-κB; Inflammatory response; Mice