Metformin alleviates hydrogen peroxide-induced inflammation and oxidative stress via inhibiting P2X7R signaling in spinal cord tissue cells neurons

Metformin, the first medication that is often prescribed for the treatment of type 2 diabetes mellitus, was recently found to be neuroprotective. To study the mechanism underlying the neuroprotective effect of metformin, we pretreated primary spinal cord neurons with 50 [micro]M or 100 [micro]M metformin for 2 h prior to treatment with hydrogen peroxide ([H.sub.2][O.sub.2]) for up to 48 h. Our results showed that [H.sub.2][O.sub.2] increased the expression of purinergic receptor P2X7 (P2X7R) in spinal cord neurons, which promoted the downstream pro-inflammatory cytokines release and oxidative stress. We found that metformin could reverse these pro-inflammatory and pro-oxidative effects of [H.sub.2][O.sub.2]. Besides, P2X7R knockdown by siRNA suppressed [H.sub.2][O.sub.2]-induced pro-inflammatory cytokine release and oxidative stress response. In conclusion, our results show that metformin can alleviate [H.sub.2][O.sub.2]-induced inflammation and oxidative stress via modulating the P2X7R signaling pathway. Key words: metformin, inflammation, oxidative stress, spinal cord neurons. Recemment, on a montre que la metformine, le medicament contre le diabete sucre de type 2 souvent prescrit en premier, a des effets neuroprotecteurs. En vue d'etudier le mode d'action sous-jacent des effets neuroprotecteurs de la metformine, nous avons mis des neurones de moelle epiniere primaires en presence de peroxyde d'hydrogene ([H.sub.2][O.sub.2]) pendant jusqu'a 48 heures apres les avoir exposes a de la metformine a 50 ou a 100 [micro]M pendant 2 heures. Nos resultats ont montre que le [H.sub.2][O.sub.2] entrainait une augmentation de l'expression du recepteur purinergique de P2X7 (P2X7R) dans les neurones de moelle epiniere, ce qui favorisait la liberation de cytokines proinflammatoires en aval et le stress oxydatif. Nous avons observe que la metformine pouvait inverser ces effets proinflammatoires et pro-oxydatifs du [H.sub.2][O.sub.2]. Par ailleurs, la repression (<< knockdown >>) des P2X7R par siRNA permettait d'inhiber completement la liberation de cytokines proinflammatoires et la reaction de stress oxydatif engendrees par le [H.sub.2][O.sub.2]. En conclusion, nos resultats montrent que la metformine peut attenuer l'inflammation et le stress oxydatif engendres par le [H.sub.2][O.sub.2] par l'intermediaire de la modulation de la voie de signalisation des P2X7R. [Traduit par la Redaction] Mots-cles: metformine, inflammation, stress oxydatif, neurones de moelle epiniere.
Introduction Spinal cord injury (SCI) is one of the devastating injuries that are commonly caused by trauma or conditions such as infection and tumor. The World Health Organization (WHO) estimates [...]