FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2527097966> ?p ?o ?g. }

• W2527097966 endingPage "1392" @default.
• W2527097966 startingPage "1392" @default.
• W2527097966 abstract "Oxidative stress plays a major role in neurodegenerative disease since central nervous system is particularly vulnerable to reactive oxygen species (ROS) due to several reasons: high consumption of O2; high production of ROS and nitrosative species, which originate from specific neurochemical reactions (e.g., dopamine oxidation); high deposition of metal ions in the brain with aging leading to Fenton's reactions; high abundance of lipids which are particularly sensitive to oxidation. Therefore, we evaluated several pharmacological strategies directed at investigating the role of various antioxidants to prevent or treating neurodegenerative disorders in various experimental models (Caccamo et al., 2004; Campisi et al., 2004). However, despite several studies performed both in vitro and in vivo have shown promising results, none of them appear to be of great clinical significance. One possible explanation for such pharmacological profile of antioxidants may be dependent on the complex biochemical cascade underlying neuronal injury. In fact, oxidative stress represents just one of several mechanisms triggered by the pathogenic noxa and it may occur also as a late mechanism of injury. Therefore, several other strategies have been developed in order to obtain a broad range of effects, including the antioxidant effect, and which may also impact on early mechanisms underlying neuronal degeneration. Among such pharmacological strategies possessing pleiotropic effects, sigma receptors seem to play a major role. Sigma receptors were initially proposed as a subtype of opioid receptors and are classified into two subtypes, σ1 and σ2 (Quirion et al., 1992). Sigma-1 receptor is considered to be involved in aging and various diseases, such as schizophrenia, depression, Alzheimer's disease and ischemia. Confirmed σ1 receptor ligand functions are neuroprotective, anti-amnestic and antidepressant (Maurice et al., 2001). Recently, Schmidt et al. (2016) elegantly reported crystal structures of the human σ1 receptor in complex with two chemically divergent ligands, PD144418 and 4-IBP. In particular these authors showed that the structures revealed a trimeric architecture with a single transmembrane domain in each protomer. Some studies suggested that σ1 receptors are involved in modulating the synthesis and release of dopamine (Booth and Baldessarini, 1991). Finally, σ1 receptor has been shown to act as a molecular chaperone at the mitochondrion-associated endoplasmic reticulum (ER) membrane where it regulates calcium signaling between the two organelles (Hayashi and Su, 2007). Sigma-1 receptor activity modulates intracellular calcium mobilization via interacting with inositol triphosphate receptors (IP3R), L-type voltage-dependent calcium channels and N-methyl-D-aspartate (NMDA) receptors (Figure 1). Sigma-1 receptor ligands show neuroprotective effects against cerebral ischemia. For example, intravenous administration of 4-phenyl-1-(4-phenylbutyl) piperidine attenuates infarction volume in rat cortex and striatum following middle cerebral artery occlusion (MCAO) by preventing ischemia-evoked nitric oxide production (Harukuni et al., 2000). Treatment with a different σ1 receptor ligand, PRE-084, also reduces MCAO-induced infarct volume and prevents neurological deficits by inhibiting pro-inflammatory cytokines and enhancing anti-inflammatory cytokines (Allahtavakoli and Jarrott, 2011). Finally, σ1 receptor has been shown to mediate antioxidant and anti-inflammatory effects. In particular, Wu et al. (2015) showed that SKF83959, a potent allosteric modulator of σ1 receptor, significantly suppressed the expression/release of the pro-inflammatory mediators, such as tumor necrosis factor-α, interleukin-1β, inducible nitric oxide synthase, and inhibited the generation of reactive oxygen species (Figure 1). Furthermore, they showed that the protective effects of SKF83959 were abolished by concomitant treatment with selective σ1 receptor antagonists (BD1047 or BD1063). Furthermore, Pal et al. (2012) showed that σ1 receptor knockout mice exhibited higher levels of oxidative stress. Several molecular mechanisms underlying such antioxidant and anti-inflammatory effects. In particular, σ1 receptor regulates the activation of antioxidant responsive element (ARE). ARE promoters are under transcriptional control of the transcription factor NF-E2-related factor 2 (Nrf2) which indicates that the sigma-1 receptor is capable of signaling through this transcriptional pathway in an as yet unknown mechanism. To this regard, previous studies showed that (+)-pentazocine, a sigma-1 receptor agonist, leads to the increase of two important Nrf2 targets: NAD(P)H quinone oxidoreductase 1 (NQO1) and superoxide dismutase 1 (SOD1). Consistently with these evidences, our recent report (Heiss et al., 2016) suggests that (+)-pentazocine restores cell viability and inhibits apoptosis in microglia cells via extracellular signal-regulated kinase 1/2 (ERK1/2) pathway in a model of hypoxia/reoxygenation.Figure 1: Schematic representation of pleiotropic protective effects of σ1 receptor.Molecular protective effects include so far antioxidant effect via ERK1/2 pathway, chaperone effect and Nrf2 activation.ERK1/2: Extracellular signal-regulated kinase 1/2; IL-6: interleukin-6; IL-1β: interleukin-1β; Nrf2: nuclear factor E2-related factor-2; TNF-α: tumor necrosis factor-α.Conclusions and future directions: Taken all together, the above mentioned studies suggest that sigma-1 receptor is a suitable target for pharmacological strategies for neuroprotection since they possess pleiotropic protective effects: chaperone activity reducing ER stress; inhibition of cell signaling cascade triggering the inflammatory response; activation of ARE and activating antioxidant and anti-inflammatory enzymes. Given the intracellular localization of sigma-1, this molecular target may be exploited to selectively deliver additional molecules to further potentiate the effect of sigma-1 agonists. Such new class of compounds, defined as bi-functional sigma-1 ligands, has been already available in our laboratories and we are looking forward to test their biological and pharmacological properties under various experimental conditions." @default.
• W2527097966 created "2016-10-07" @default.
• W2527097966 creator A5026039152 @default.
• W2527097966 creator A5040846564 @default.
• W2527097966 date "2016-01-01" @default.
• W2527097966 modified "2023-09-23" @default.
• W2527097966 title "Sigma-1 receptor and neuroprotection: current outlook and potential therapeutic effects" @default.
• W2527097966 cites W1821708052 @default.
• W2527097966 cites W1919518154 @default.
• W2527097966 cites W1968153520 @default.
• W2527097966 cites W1992768650 @default.
• W2527097966 cites W2002439304 @default.
• W2527097966 cites W2012298500 @default.
• W2527097966 cites W2019079031 @default.
• W2527097966 cites W2020628417 @default.
• W2527097966 cites W2036156958 @default.
• W2527097966 cites W2049168135 @default.
• W2527097966 cites W2093330856 @default.
• W2527097966 cites W2314811232 @default.
• W2527097966 cites W2398803518 @default.
• W2527097966 doi "https://doi.org/10.4103/1673-5374.191200" @default.
• W2527097966 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/5090828" @default.
• W2527097966 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/27857729" @default.
• W2527097966 hasPublicationYear "2016" @default.
• W2527097966 type Work @default.
• W2527097966 sameAs 2527097966 @default.
• W2527097966 citedByCount "5" @default.
• W2527097966 countsByYear W25270979662017 @default.
• W2527097966 countsByYear W25270979662021 @default.
• W2527097966 crossrefType "journal-article" @default.
• W2527097966 hasAuthorship W2527097966A5026039152 @default.
• W2527097966 hasAuthorship W2527097966A5040846564 @default.
• W2527097966 hasBestOaLocation W25270979661 @default.
• W2527097966 hasConcept C103133801 @default.
• W2527097966 hasConcept C126322002 @default.
• W2527097966 hasConcept C169760540 @default.
• W2527097966 hasConcept C170493617 @default.
• W2527097966 hasConcept C185592680 @default.
• W2527097966 hasConcept C25498285 @default.
• W2527097966 hasConcept C25876315 @default.
• W2527097966 hasConcept C2776151105 @default.
• W2527097966 hasConcept C2776925932 @default.
• W2527097966 hasConcept C2778938600 @default.
• W2527097966 hasConcept C2779134260 @default.
• W2527097966 hasConcept C48349386 @default.
• W2527097966 hasConcept C55493867 @default.
• W2527097966 hasConcept C71924100 @default.
• W2527097966 hasConcept C86803240 @default.
• W2527097966 hasConcept C95444343 @default.
• W2527097966 hasConcept C98274493 @default.
• W2527097966 hasConceptScore W2527097966C103133801 @default.
• W2527097966 hasConceptScore W2527097966C126322002 @default.
• W2527097966 hasConceptScore W2527097966C169760540 @default.
• W2527097966 hasConceptScore W2527097966C170493617 @default.
• W2527097966 hasConceptScore W2527097966C185592680 @default.
• W2527097966 hasConceptScore W2527097966C25498285 @default.
• W2527097966 hasConceptScore W2527097966C25876315 @default.
• W2527097966 hasConceptScore W2527097966C2776151105 @default.
• W2527097966 hasConceptScore W2527097966C2776925932 @default.
• W2527097966 hasConceptScore W2527097966C2778938600 @default.
• W2527097966 hasConceptScore W2527097966C2779134260 @default.
• W2527097966 hasConceptScore W2527097966C48349386 @default.
• W2527097966 hasConceptScore W2527097966C55493867 @default.
• W2527097966 hasConceptScore W2527097966C71924100 @default.
• W2527097966 hasConceptScore W2527097966C86803240 @default.
• W2527097966 hasConceptScore W2527097966C95444343 @default.
• W2527097966 hasConceptScore W2527097966C98274493 @default.
• W2527097966 hasIssue "9" @default.
• W2527097966 hasLocation W25270979661 @default.
• W2527097966 hasLocation W25270979662 @default.
• W2527097966 hasLocation W25270979663 @default.
• W2527097966 hasLocation W25270979664 @default.
• W2527097966 hasOpenAccess W2527097966 @default.
• W2527097966 hasPrimaryLocation W25270979661 @default.
• W2527097966 hasRelatedWork W1969122285 @default.
• W2527097966 hasRelatedWork W1988833851 @default.
• W2527097966 hasRelatedWork W2080416537 @default.
• W2527097966 hasRelatedWork W2124369185 @default.
• W2527097966 hasRelatedWork W2780192089 @default.
• W2527097966 hasRelatedWork W2796692882 @default.
• W2527097966 hasRelatedWork W3046417874 @default.
• W2527097966 hasRelatedWork W4245887746 @default.
• W2527097966 hasRelatedWork W4313472354 @default.
• W2527097966 hasRelatedWork W90797609 @default.
• W2527097966 hasVolume "11" @default.
• W2527097966 isParatext "false" @default.
• W2527097966 isRetracted "false" @default.
• W2527097966 magId "2527097966" @default.
• W2527097966 workType "article" @default.