Article

Galantamine elicits neuroprotection by inhibiting iNOS, NADPH oxidase and ROS in hippocampal slices stressed with anoxia/reoxygenation.

Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Spain.
Neuropharmacology (Impact Factor: 4.82). 11/2011; 62(2):1082-90. DOI: 10.1016/j.neuropharm.2011.10.022
Source: PubMed

ABSTRACT Galantamine is a drug currently used to treat Alzheimer's disease (AD); in this group of patients it has been observed that concomitant ischemic brain injury can accelerate their cognitive deficit. We have previously shown that galantamine can afford neuroprotection on in vitro and in vivo models related to brain ischemia. In this context, this study was planned to investigate the intracellular signaling pathways implicated in the protective effect of galantamine on an in vitro brain ischemia-reperfusion model, namely rat hippocampal slices subjected to oxygen and glucose deprivation (OGD) followed by reoxygenation. Galantamine protected hippocampal slices subjected to OGD in a concentration-dependent manner; at 15 μM, cell death was reduced to almost control levels. The neuroprotective effects of galantamine were reverted by mecamylamine and AG490, but not by atropine, indicating that nicotinic receptors and Jak2 participated in this action. Galantamine also prevented p65 translocation into the nucleus induced by OGD; this effect was also linked to nicotinic receptors and Jak2. Furthermore, galantamine reduced iNOS induction and production of NO caused by OGD via Jak2. ROS production by NADPH oxidase (NOX) activation was also inhibited by galantamine. In conclusion, galantamine afforded neuroprotection under OGD-reoxygenation conditions by activating a signaling pathway that involves nicotinic receptors, Jak2 and the consequent inhibition of NOX and NFκB/iNOS. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.

0 Bookmarks
 · 
146 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Oxidative stress is implicated in the pathogenesis of different human diseases: Alzheimer, Parkinson, Huntington, amyotrophic lateral sclerosis (Lou Gehrig's disease), Down's syndrome, atherosclerosis, vascular disease, cancer, diabetes mellitus type 1 and type 2, age-related macular degeneration, psoriatic arthritis. The aim of the current study is to summarize the scientific evidences for the antioxidant and neuroprotective activity of Galantamine and some of its derivatives. Galantamine is a scavenger of reactive oxygen species and causes neuroprotective effect by lowering the oxidative neuronal damage, through the following pathways: 1) prevention of the activation of P2X7 receptors; 2) protection of mitochondrial membrane potential; 3) prevention of the membrane fluidity disturbances. Another mechanism is the decrease of the overproduction of reactive oxygen species, as a result of the increase of acetylcholine level due to: 1) acethylcholinesterase inhibition; 2) allosteric potentiation of α7-subtype of nicotinic acetylcholine receptors. A close relationship between acethylcholinesterase inhibition and reduced oxidative injury is observed. Through allosteric potentiation of the α7-subtype of nicotinic acetylcholine receptors, the drug leads to induction of phosphorylation of serine-threonine protein kinase, stimulates phosphoinositide 3-kinase and elevates the expression of protective protein Bcl-2. Through activation of these important neuroprotective cascades, Galantamine exerts neuroprotection against a variety of cytotoxic agents (ß-amyloid peptide, glutamate, hydrogen peroxide, and oxygen and glucose deprivation). A new trend in the therapy of Alzheimer's disease will be the investigation and application of compounds such as Galantamine derivatives, which possess acethylcholinesterase and γ-secretase inhibitory activity and antioxidant properties.
    Current Medicinal Chemistry 06/2013; · 3.72 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Acetylcholinesterase inhibitors are prominent alternative in current clinical treatment for AD patients. Therefore, there is a continued need to search for novel AChEIs with good clinical efficacy and less side effects. By using our in-house natural product database and AutoDock Vina as a tool in docking study, we have identified twelve phytochemicals (emodin, aloe-emodin, chrysophanol, and rhein in Rhei Radix Et Rhizoma; xanthotoxin, phellopterin, alloisoimperatorin, and imperatorin in Angelicae dahuricae Radix; shikonin, acetylshikonin, isovalerylshikonin, and β,β-dimethylacrylshikonin in Arnebiae Radix) as candidates of AChEIs that were not previously reported in the literature. In addition to AChEI activity, a series of cell-based experiments were conducted for the investigation of their neuroprotective activities. We found that acetylshikonin and its derivatives prevented apoptotic cell death induced by hydrogen peroxide in human and rat neuronal SH-SY5Y and PC12 cells at 10 μM. We showed that acetylshikonin exhibited the most potent antiapoptosis activity through the inhibition of the generation of reactive oxygen species as well as protection of the loss of mitochondria membrane potential. Furthermore, we identified for the first time that the upregulation of heme oxygenase 1 by acetylshikonin is a key step mediating its antiapoptotic activity from oxidative stress in SH-SY5Y cells.
    Evidence-based Complementary and Alternative Medicine 01/2013; 2013:937370. · 2.18 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Creatine is the substrate for creatine kinase in the synthesis of phosphocreatine (PCr). This energetic system is endowed of antioxidant and neuroprotective properties and plays a pivotal role in brain energy homeostasis. The purpose of this study was to investigate the neuroprotective effect of creatine and PCr against 6-hydroxydopamine (6-OHDA)-induced mitochondrial dysfunction and cell death in rat striatal slices, used as an in vitro Parkinson's model. The possible involvement of the signaling pathway mediated by phosphatidylinositol-3 kinase (PI3K), protein kinase B (Akt), and glycogen synthase kinase-3β (GSK3β) was also evaluated. Exposure of striatal slices to 6-OHDA caused a significant disruption of the cellular homeostasis measured as 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide reduction, lactate dehydrogenase release, and tyrosine hydroxylase levels. 6-OHDA exposure increased the levels of reactive oxygen species and thiobarbituric acid reactive substances production and decreased mitochondrial membrane potential in rat striatal slices. Furthermore, 6-OHDA decreased the phosphorylation of Akt (Serine(473)) and GSK3β (Serine(9)). Coincubation with 6-OHDA and creatine or PCr reduced the effects of 6-OHDA toxicity. The protective effect afforded by creatine or PCr against 6-OHDA-induced toxicity was reversed by the PI3K inhibitor LY294002. In conclusion, creatine and PCr minimize oxidative stress in striatum to afford neuroprotection of dopaminergic neurons. © The Author(s) 2014.
    ASN Neuro 10/2014; 6(6). · 4.44 Impact Factor

Full-text

Download
40 Downloads
Available from
Feb 7, 2015