Pharmacological inhibition of poly (ADP-ribose) polymerase by olaparib, prevents acute lung injury associated cognitive deficits potentially through suppression of inflammatory response

Abstract

Acute lung injury (ALI) has been reported to be associated with high mortality rate. Moreover, ALI survivors, frequently present chronic cognitive deterioration. We have previously shown that ‘two hit’ (hydrochloric acid + lipopolysaccharide) induced ALI resulted in cognitive dysfunction through the induction of systemic inflammation. The present study was designed to explore the potential anti-inflammatory effects of olaparib (Poly ADP-ribose polymerase-1 inhibitor), on ALI mediated cognitive impairment. Olaparib was administered at dose of 5 mg/kg body weight (i.p.) 30 min before each hit. Data show that olaparib pre-treatment markedly reduced the neutrophil infiltration, alveolar capillary damage, inflammatory cytokines level (TNF-α/IL-1β/IL-6) and oxidative stress in the lungs at 24 h after ALI induction. Also, olaparib pre-treatment ameliorated the ALI associated cognitive impairment as assessed by Morris water maze test on weekly basis for 2 consecutive weeks. Further, restoration of cognitive function was associated with normalization of serum levels of TNF-α/IL-1β and improved the blood brain barrier (BBB) function, as reflected by data on expression of occludin/claudin-5 and extravasation of Evans-blue/FITC dextran in hippocampus at 1 week post injury. Finally, increased mRNA expression of VCAM-1, TNF-α and IL-1β and NF-κB activation in hippocampus indicate induction of neuro-inflammation, which was downregulated upon olaparib administration. Further, olaparib treatment 1 week after ALI induction blunted the systemic inflammation which was associated with improved BBB and cognitive function. Altogether, our results showed that olaparib protects against ALI and associated cognitive deficits in mice, and thus may offer a new treatment avenue in the area.