Paeonol Attenuates Isoflurane Anesthesia-induced Hippocampal Neurotoxicity Via Modulation of JNK/ERK/P38MAPK Pathway and Regulates Histone Acetylation in Neonatal Rat

Volatile anesthetic such as isoflurane causes widespread neurodegeneration in the developing animal brains and also induces cognitive impairments. Paeonol is a plant-derived phenolic compound possessing numerous bioactive properties. The study investigates the neuroprotective effects of paeonol against isoflurane-induced neurodegeneration and cognitive disturbances in neonatal rats. Paeonol (50, 100, and 150 mg/kg body weight/day) was given orally to separate groups of neonatal rats from postnatal day 3 (P3) to P21 and were exposed to isoflurane (0.75%; 6 h) on P7. Neuroapoptosis following isoflurane exposure was remarkably reduced by paeonol. Isoflurane-induced elevated cleaved caspase-3, Bad, and Bax expression, were down-regulated on paeonol administration. Paeonol significantly enhanced expression of antiapoptotic proteins (Bcl-2, Bcl-xL, xIAP, c-IAP-1, c-IAP-2, and survivin) and improved acetylation of HK39 and HK412. The expression of histone deacetylases (HDACs)-HDAC2 and HDAC-3 were down-regulated. Isoflurane-induced activation of JNK/p38MAPK signaling and suppressed ERK signaling and were effectively regulated by paeonol. General behavior and freezing responses of the rats were improved. Results of the Morris Water Maze tests revealed improved learning and memory retention on paeonol treatment. Paeonol effectively inhibited neuroapoptosis and improved isoflurane-induced cognitive dysfunctions regulating histone acetylation and JNK/ERK1/2/p38MAPK signaling pathways.