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: 4.11). 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 0
 · 
0 Bookmarks
 · 
87 Views
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: Aims. We asked whether the neuroprotective effect of cholinergic microglia stimulation during an ischemic event acts via a mechanism involving the activation of nuclear factor erythroid 2 related factor 2 (Nrf2) and/or the expression of its target cytoprotective gene, heme oxygenase-1 (HO-1). Specifically, the protective effect of the pharmacologic alpha-7 nicotinic receptor (α7 nAChR) agonist PNU282987 was analyzed in organotypic hippocampal cultures (OHCs) subjected to oxygen and glucose deprivation in vitro as well as in photothrombotic stroke in vivo. Results. OHCs exposed to oxygen and glucose deprivation (OGD) followed by re-oxygenation, elicited cell death, measured by propidium iodide and MTT staining. Activation of α7 nAChR by PNU282987, after OGD, reduced cell death, ROS production and TNF release. This was associated with induction of HO-1 expression; an effect reversed by the α-bungarotoxin and by tin protoporhyrin IX (SnPP). The protective effect of PNU282987 was lost in microglia-depleted OHCs as well as in OHCs from Nrf2 deficient vs. wild type mice, an effect associated with suppression of HO-1 expression in microglia. Administration of PNU282987 1 h after induction of photothrombotic stroke in vivo reduced infarct size and improved motor skills in Hmox1lox/lox mice, that express normal levels of HO-1 but not in LysMCreHmox1∆/∆ in which HO-1 expression is inhibited in myeloid cells, including the microglia. Innovation. This study suggests the participation of the microglial α7 nAChR in the "brain cholinergic anti-inflammatory pathway". Conclusion. Activation of the α7 nAChR/Nrf2/HO-1 axis in microglia regulates neuroinflammation and oxidative stress affording neuroprotection under brain ischemic conditions.
    Antioxidants & Redox Signaling 01/2013; · 8.20 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: The alkaloids characteristically produced by the subfamily Amaryllidoideae of the Amaryllidaceae, bulbous plant species that include well know genera such as Narcissus (daffodils) and Galanthus (snowdrops), are a source of new pharmaceutical compounds. Presently, only the Amaryllidaceae alkaloid galanthamine, an acetylcholinesterase inhibitor used to treat symptoms of Alzheimer's disease, is produced commercially as a drug from cultivated plants. However, several Amaryllidaceae alkaloids have shown great promise as anti-cancer drugs, but their further clinical development is restricted by their limited commercial availability. Amaryllidaceae species have a long history of cultivation and breeding as ornamental bulbs, and phytochemical research has focussed on the diversity in alkaloid content and composition. In contrast to the available pharmacological and phytochemical data, ecological, physiological and molecular aspects of the Amaryllidaceae and their alkaloids are much less explored and the identity of the alkaloid biosynthetic genes is presently unknown. An improved molecular understanding of Amaryllidaceae alkaloid biosynthesis would greatly benefit the rational design of breeding programs to produce cultivars optimised for the production of pharmaceutical compounds and enable biotechnology based approaches.
    International Journal of Molecular Sciences 01/2013; 14(6):11713-11741. · 2.46 Impact Factor
  • 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; · 4.07 Impact Factor

Full-text

View
32 Downloads
Available from
Sep 25, 2012