Poststress treatment with PNU282987 can rescue SH-SY5Y cells undergoing apoptosis via α7 nicotinic receptors linked to a Jak2/Akt/HO-1 signaling pathway

Most neuroprotection studies with nicotinic agonists have shown efficacy when given before the stressor Here WE have investigated whether the ea nicotinic acetylcholine receptor (nAChR) agonist PNU282987 can prevent cell death once the cells have already undergone an oxidative stress The combination of rotenone (30 mu M) plus oligomycin A (10 mu M) (rot/oligo) has been used as an in vitro model of mitochondrial ROS production SH SY5Y cells incubated with rot/oligo for 8 h and left for another 16 h in MEM/F 12 experienced 30% apoptotic cell death Under these experimental conditions PNU282987 administered after rot/oligo (PST/PNU) prevented cell death in a concentration-dependent manner Co incubation of PNU282987 with 100 nM methyllycaconitine (a selective alpha nAChR antagonist) 10 mu M mecamylamine (a nonselective nAChR antagonist) 3 mu M LY294002 (a PI3K inhibitor) or 10 mu M AG490 (a Jak2 inhibitor) prevented the protection afforded by PST/PNU Moreover the increase in ROS active caspase-3 and apoptosis caused by rot/oligo was also prevented by PST/PNU Furthermore PNU282987 increased the expression of heme oxygenase-1 (HO 1) a critical cell defense enzyme against oxidative stress this Increase was prevented by AG490 or LY294002 The HO 1 inhibitor Sn(IV) protoporphyrin-IX also inhibited the PST/PNU protecting effects These results suggest that activation of ea nAChR linked to the Jak2/PI3K/Akt cascade induces the antioxidant enzyme HO 1 tc provide neuroprotection (C) 2010 Elsevier Inc All rights reserved