Inactivation of P2YR12 contributes to isoflurane-induced neuronal injury by altering TLR-4/BDNF/TNF-α
The present investigation evaluated the effect of inhibiting the P2Y12 gene on anaesthetic-induced neuronal injury in a rat model. Neuronal injury was induced by exposing the animals for 6 h to 30% oxygen containing 0.75% isoflurane and 1.2 mg/kg prasugrel (a P2Y12 inhibitor) p.o. for 14 days. Cognitive function was determined by the Morris water maze, and the neurological severity score was determined. Enzyme-linked immunosorbent assay was used to estimate the level of oxidative stress and
... ators of inflammation in brain tissues of isoflurane-induced neuronal injury rats. Apoptosis of neuronal cells was estimated by terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) and western blot assays. Real time-polymerase chain reaction was performed to estimate the expression levels of several proteins. The data revealed that inhibiting the P2Y12 gene ameliorated changes in the modified neurological severity score and cognitive function in neuronal injury rats. Moreover the levels of proinflammatory mediators, oxidative stress, and cyclic AMP, and the number of TUNEL-positive cells, decreased significantly (p < 0.01) in the prasugrel-treated group compared to the negative control group. In addition, apoptosis of neuronal cells decreased in the prasugrel-treated group, as it ameliorated expression of the PI3K, Bcl-2, Bad, and Akt proteins in the isoflurane-induced neuronal injury rats. Expression of brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) proteins was enhanced, whereas the Toll-like receptor-4 (TLR-4) and nuclear factor κB (NF-κB) proteins decreased in the brain tissues of the prasugrel-treated group compared to the negative control group of rats. These results suggest that inhibiting the P2YR12 gene protects against neuronal injury in isoflurane-induced neuronal injury rats. Inhibiting the P2YR12 gene ameliorated neuronal apoptosis by regulating the BDNF/TLR-4/TNF-α pathway.