The sigma-1 receptor agonist 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) protects against newborn excitotoxic brain injury by stabilizing the mitochondrial membrane potential in vitro and inhibiting microglial activation in vivo

Wegleiter, K; Hermann, Michael; Posod, Anna; Wechselberger, Karina; Stanika, Ruslan I.; Obermair, Gerald J.; Kiechl‐Kohlendorfer, Ursula; Urbanek, M; Griesmaier, Elke

doi:10.1016/j.expneurol.2014.07.022

Cited by 23 publications

(24 citation statements)

References 32 publications

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“…Both S1R and BDNF were present in BV-2 microglial cells, yet treating these cells with an S1R agonist did not facilitate BDNF secretion. Although activated microglia (Nakajima et al, 2001; Sun et al, 2014), including a murine N9 microglial cell line (Gomes et al, 2013), are capable of secreting BDNF, our finding is in agreement with numerous studies indicating that the S1R is present in microglia and can modulate injury or toxicant-induced microgliosis by various mechanisms not involving BDNF (Behensky et al, 2013; Cuevas et al, 2011; Dong et al, 2015; Gekker et al, 2006; Hall et al, 2009; Mancuso et al, 2012; Moritz et al, 2015; Robson et al, 2013; Wegleiter et al, 2014; Wu et al, 2015; Zhao et al, 2014). Alternatively, the BV-2 cell line may lack the necessary machinery for investigating S1R-BDNF interactions in microglia or the microglia may need to be activated in order to study the effect.…”

Section: Discussionsupporting

confidence: 91%

Activation of the sigma-1 receptor by haloperidol metabolites facilitates brain-derived neurotrophic factor secretion from human astroglia

Dalwadi

Kim

Schetz

2017

Neurochemistry International

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Glial cells play a critical role in neuronal support which includes the production and release of the neurotrophin brain-derived neurotrophic factor (BDNF). Activation of the sigma-1 receptor (S1R) has been shown to attenuate inflammatory stress-mediated brain injuries, and there is emerging evidence that this may involve a BDNF-dependent mechanism. In this report we studied S1R-mediated BDNF release from human astrocytic glial cells. Astrocytes express the S1R, which mediates BDNF release when stimulated with the prototypical S1R agonists 4-PPBP and (+)-SKF10047. This effect could be antagonized by a selective concentration of the S1R antagonist BD1063. Haloperidol is known to have high affinity interactions with the S1R, yet it was unable to facilitate BDNF release. Remarkably, however, two metabolites of haloperidol, haloperidol I and haloperidol II (reduced haloperidol), were discovered to facilitate BDNF secretion and this effect was antagonized by BD1063. Neither 4-PPBP, nor either of the haloperidol metabolites affected the level of BDNF mRNA as assessed by qPCR. These results demonstrate for the first time that haloperidol metabolites I and II facilitate the secretion of BDNF from astrocytes by acting as functionally selective S1R agonists.

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Section: Discussionsupporting

confidence: 91%

Activation of the sigma-1 receptor by haloperidol metabolites facilitates brain-derived neurotrophic factor secretion from human astroglia

Dalwadi

Kim

Schetz

2017

Neurochemistry International

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“…The sigma agonist PPBP appears to stabilize mitochondrial membrane potential in neurons undergoing excitotoxic stress through glutamate exposure. This stabilization was associated with decreased neuronal death [95]. Another agonist, BHDP ( N -benzyl- N -(2-hydroxy-3,4-dimethoxybenzyl)-piperazine), appeared to have “mitochondrial protective” effects in a liver model of ischemia/reperfusion [96].…”

Section: 3 Sigma-1 Receptor Mediated Mechanisms Of Neuroprotectionmentioning

confidence: 99%

Sigma-1 Receptors and Neurodegenerative Diseases: Towards a Hypothesis of Sigma-1 Receptors as Amplifiers of Neurodegeneration and Neuroprotection

Nguyen

Lucke‐Wold

Mookerjee

et al. 2017

Advances in Experimental Medicine and Biology

103

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Sigma-1 receptors are molecular chaperones that may act as pathological mediators and targets for novel therapeutic applications in neurodegenerative diseases. Accumulating evidence indicates that sigma-1 ligands can either directly or indirectly modulate multiple neurodegenerative processes, including excitotoxicity, calcium dysregulation, mitochondrial and endoplasmic reticulum dysfunction, inflammation, and astrogliosis. In addition, sigma-1 ligands may act as disease-modifying agents in the treatment for central nervous system (CNS) diseases by promoting the activity of neurotrophic factors and neural plasticity. Here, we summarize their neuroprotective and neurorestorative effects in different animal models of acute brain injury and chronic neurodegenerative diseases, and highlight their potential role in mitigating disease. Notably, current data suggest that sigma-1 receptor dysfunction worsens disease progression, whereas enhancement amplifies pre-existing functional mechanisms of neuroprotection and/or restoration to slow disease progression. Collectively, the data support a model of the sigma-1 receptor as an amplifier of intracellular signaling, and suggest future clinical applications of sigma-1 ligands as part of multi-therapy approaches to treat neurodegenerative diseases.

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“…The receptors non-selective agonists di-orto-tolyl-guanidine (DTG), and 5-ethoxy-2-[2-(morpholino)ethylthio]benzimidazole (afobazole) were shown to decrease microglia migration in response to ATP by reducing ATP-evoked increases in Ca 2+ [4]. While afobazole, was shown to reduce neuronal and glial cell injury in vitro following ischemia, very recently, another 1 receptor agonist 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) has been shown to reduce neonatal excitotoxic brain lesions by inhibiting microglia activation [26]. Therefore, 1 receptors appear to be important targets for modulating microglia responses to brain insults.…”

Section: Introductionmentioning

confidence: 98%

Live imaging reveals a new role for the sigma-1 (σ1) receptor in allowing microglia to leave brain injuries

Moritz

Berardi

Abate

et al. 2015

Neuroscience Letters

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Microglial cells are responsible for clearing and maintaining the central nervous system (CNS) microenvironment. Upon brain damage, they move toward injuries to clear the area by engulfing dying neurons. However, in the context of many neurological disorders chronic microglial responses are responsible for neurodegeneration. Therefore, it is important to understand how these cells can be "switched-off" and regain their ramified state. Current research suggests that microglial inflammatory responses can be inhibited by sigma (σ) receptor activation. Here, we take advantage of the optical transparency of the zebrafish embryo to study the role of σ1 receptor in microglia in an intact living brain. By combining chemical approaches with real time imaging we found that treatment with PB190, a σ1 agonist, blocks microglial migration toward injuries leaving cellular baseline motility and the engulfment of apoptotic neurons unaffected. Most importantly, by taking a reverse genetic approach, we discovered that the role of σ1in vivo is to "switch-off" microglia after they responded to an injury allowing for these cells to leave the site of damage. This indicates that pharmacological manipulation of σ1 receptor modulates microglial responses providing new approaches to reduce the devastating impact that microglia have in neurodegenerative diseases.

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The sigma-1 receptor agonist 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) protects against newborn excitotoxic brain injury by stabilizing the mitochondrial membrane potential in vitro and inhibiting microglial activation in vivo

Cited by 23 publications

References 32 publications

Activation of the sigma-1 receptor by haloperidol metabolites facilitates brain-derived neurotrophic factor secretion from human astroglia

Activation of the sigma-1 receptor by haloperidol metabolites facilitates brain-derived neurotrophic factor secretion from human astroglia

Sigma-1 Receptors and Neurodegenerative Diseases: Towards a Hypothesis of Sigma-1 Receptors as Amplifiers of Neurodegeneration and Neuroprotection

Live imaging reveals a new role for the sigma-1 (σ1) receptor in allowing microglia to leave brain injuries

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