Abstract
Oxidative stress is implicated in the pathogenesis of neurodegenerative disorders and hydrogen peroxide (H2O2) plays a central role in the stress. Huprines, a group of potent acetylcholinesterase inhibitors (AChEIs), have shown a broad cholinergic pharmacological profile. Recently, it has been observed that huprine X (HX) improves cognition in non transgenic middle aged mice and shows a neuroprotective activity (increased synaptophysin expression) in 3xTg-AD mice. Consequently, in the present experiments the potential neuroprotective effect of huprines (HX, HY, HZ) has been analyzed in two different in vitro conditions: undifferentiated and NGF-differentiated PC12 cells. Cells were subjected to oxidative insult (H2O2, 200 µM) and the protective effects of HX, HY and HZ (0.01 µM–1 µM) were analyzed after a pre-incubation period of 24 and 48 hours. All huprines showed protective effects in both undifferentiated and NGF-differentiated cells, however only in differentiated cells the effect was dependent on cholinergic receptors as atropine (muscarinic antagonist, 0.1 µM) and mecamylamine (nicotinic antagonist, 100 µM) reverted the neuroprotection action of huprines. The decrease in SOD activity observed after oxidative insult was overcome in the presence of huprines and this effect was not mediated by muscarinic or nicotinic receptors. In conclusion, huprines displayed neuroprotective properties as previously observed in in vivo studies. In addition, these effects were mediated by cholinergic receptors only in differentiated cells. However, a non-cholinergic mechanism, probably through an increase in SOD activity, seems to be also involved in the neuroprotective effects of huprines.
Highlights
Alzheimer’s disease (AD) is the most common neurodegenerative disorder and the most prevalent cause of dementia with ageing
Values are expressed as percentage of protection obtained from at least three independent experiments run in triplicate. *P,0.05 as compared with H2O2–treated group (Dunnett’s test).a,b,c No significant changes compared with huprine X, Y and Z (1 mM), respectively. doi:10.1371/journal.pone.0074344.t001
Besides the pathological hallmarks of AD, which include the accumulation of protein deposits in the brain as Ab plaques and neurofibrillary tangles (NFT), AD brains exhibit constant evidence of reactive oxygen species (ROS) - and reactive nitrogen species (RNS)-mediated injury [37]
Summary
Alzheimer’s disease (AD) is the most common neurodegenerative disorder and the most prevalent cause of dementia with ageing. The AD aetiology and pathogenesis are still unknown, several reports point out that excitotoxicity, reduced energy metabolism, mitochondrial dysfunctions, and oxidative stress are very important mechanisms involved in cell death in AD [2]. This hypothesis is supported by the finding that Ab peptides are associated with free-radical oxidative stress and are the main cause of cellular dysfunctions [3],[4],[5],[6],[7]. AChEI might be able to act as disease-modifying anti-Alzheimer drugs rather than as mere palliative drugs [22]
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