Docosahexaenoic acid and tetracyclines as promising neuroprotective compounds with poly(ADP-ribose) polymerase inhibitory activities for oxidative/genotoxic stress treatment

Abstract

The human genome is exposed to oxidative/genotoxic stress by several endogenous and exogenous compounds. These events evoke DNA damage and activate poly(ADP-ribose) polymerase-1 (PARP-1), the key enzyme involved in DNA repair. The massive stress and over-activation of this DNA-bound enzyme can be responsible for an energy crisis and neuronal death. The last data indicated that product of PARP-1, i.e. poly(ADP-ribose) (PAR), acts as a signalling molecule and plays a significant role in nucleus-mitochondria cross-talk. PAR translocated to the mitochondria can be involved in mitochondrial permeability, the release of an apoptosis-inducing factor (AIF). Its translocation into the nucleus leads to chromatin condensation, fragmentation and cell death. The exact mechanism of this novel death pathway has not yet fully been understood.In this study the relationship between AIF and PARP/PAR in death signalling in the neuronal cell line (HT22) subjected to oxidative/genotoxic stress evoked by N-methyl-N’-nitro-N-nitrosoguanidine (MNNG) was explored. The neuroprotective influence of docosahexaenoic acid (DHA), major dietary ω-3 long-chain polyunsaturated fatty acids as well as the action of tetracyclines, the novel suppressors of PARP-1, were examined. The effect of these all compounds was compared with specific PARP-1 inhibitors.The oxidative/genotoxic stress evoked by MNNG enhanced the level of PAR in a time-dependent manner with a concomitant significant decrease in the mitochondrial AIF protein level. Moreover, the down-regulation of the anti-apoptotic proteins (Bcl-2 and Bcl-xL) and the up-regulation of the Bax pro-apoptotic protein were presented. In these conditions massive HT22 cell death was observed. Both PARP-1 inhibitors: 3-aminobenzamide (3-AB) and PJ 34, tetracycline: doxocycline and minocycline, as well as DHA protected the cells against PAR formation and AIF translocation. Moreover, all of these compounds enhanced Bcl-xL gene expression and protected the cells against MNNG-induced death.Our data show that both DHA and tetracyclines offer a novel neuroprotective strategy for oxidative/genotoxic stress treatment.