The neuroprotective effect of nicotine in Parkinson’s disease models is associated with inhibiting PARP-1 and caspase-3 cleavage

Abstract

Clinical evidence points to neuroprotective effects of smoking in Parkinson’s disease (PD), but the molecular mechanisms remain unclear. We investigated the pharmacological pathways involved in these neuroprotective effects, which could provide novel ideas for developing targeted neuroprotective treatments for PD. We used the ETC complex I inhibitor methylpyridinium ion (MPP+) to induce cell death in SH-SY5Y cells as a cellular model for PD and found that nicotine inhibits cell death. Using choline as a nicotinic acetylcholine receptor (nAChR) agonist, we found that nAChR stimulation was sufficient to protect SH-SY5Y cells against cell death from MPP+. Blocking α7 nAChR with methyllycaconitine (MLA) prevented the protective effects of nicotine, demonstrating that these receptors are necessary for the neuroprotective effects of nicotine. The neuroprotective effect of nicotine involves other pathways relevant to PD. Cleaved Poly (ADP-ribose) polymerase-1 (PARP-1) and cleaved caspase-3 were decreased by nicotine in 6-hydroxydopamine (6-OHDA) lesioned mice and in MPP+-treated SH-SY5Y cells. In conclusion, our data indicate that nicotine likely exerts neuroprotective effects in PD through the α7 nAChR and downstream pathways including PARP-1 and caspase-3. This knowledge could be pursued in future research to develop neuroprotective treatments for PD.

Nicotine associated breast cancer in smokers is mediated through high level of EZH2 expression which can be reversed by methyltransferase inhibitor DZNepA

“…Apoptosis is regulated in part by Bcl-2 genes that regulate cell survival 27 . Reduced apoptosis and neuroprotective effect of NIC is marked by reduced cleavage of PARP-1 28 , 29 . NIC treatment resulted into a significant increase in Bcl-2 expression that reduced upon DZNepA treatment.…”

Nicotine is neuroprotective to neonatal neurons of sympathetic ganglion in rat

“…In support of nicotine functioning as a neuroprotectant, several studies have identified different biochemical responses to nicotine that could contribute to its neuroprotective effects in CNS, including increased expression of growth/trophic factors such as NGF and FGF (Belluardo et al,2000, Garrido et al, 2003; Harrod et al, 2011; Takarada et al, 2012), decreased nitric oxide generation (Shimohama et al, 1996, Toborek et al, 2000), decreased arachidonic acid release (Marin et., 1997; Toborek et al,2000) and decreased caspase signalling (Lu et al, 2017). Further increased expression/activation of ERK1/2 has been shown in PC12 cells (Nakayama et al, 2001) and spinal cord neurons (Toborek et al,2007), which is attributed to nicotine-mediated neuroprotection.…”

Targeting the cholinergic system in Parkinson’s disease

“…First, nicotine can prevent aggregation of both wild-type and A53T mutant α-synuclein in tubes [ 181 ]. Second, in several cell culture models of PD, nicotine treatment can significantly decrease cell loss [ 182 , 183 ]. Finally, in both 6-OHDA-induced rodent and MPTP-induced primate models of PD, nicotine administration can slow down dopamine neuron degeneration [ 184 , 185 ].…”