Neuroprotective effects of the sigma-1 receptor ligand PRE-084 against excitotoxic perinatal brain injury in newborn mice

Griesmaier, Elke; Posod, Anna; Gross, M; Neubauer, Vera; Wegleiter, K; Hermann, Michael; Urbanek, M; Keller, Matthias; Kiechl‐Kohlendorfer, Ursula

doi:10.1016/j.expneurol.2012.06.030

Cited by 44 publications

(34 citation statements)

References 43 publications

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“…The activation of sigma-1 receptors in particular, with agonists such as PRE-084, can protect against microglia reactivity as reported in rodent models of amyotrophic lateral sclerosis (ALS), experimental parkinsonism, and excitotoxic perinatal brain injury (Francardo et al, 2014; Griesmaier et al, 2012; Mancuso et al, 2012). These data indicate that sigma receptor ligands are capable of modulating the functionality of immune cells, including those present within the CNS.…”

Section: Modulation Of Glial Mechanisms That Contribute To Neurodementioning

confidence: 95%

Sigma receptors as potential therapeutic targets for neuroprotection

Nguyen

Kaushal

Robson

et al. 2014

European Journal of Pharmacology

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Sigma receptors comprise a unique family of proteins that have been implicated in the pathophysiology and treatment of many central nervous system disorders, consistent with their high level of expression in the brain and spinal cord. Mounting evidence indicate that targeting sigma receptors may be particularly beneficial in a number of neurodegenerative conditions including Alzheimer's disease, Parkinson's disease, stroke, methamphetamine neurotoxicity, Huntington's disease, amyotrophic lateral sclerosis, and retinal degeneration. In this perspective, a brief overview is given on sigma receptors, followed by a focus on common mechanisms of neurodegeneration that appear amenable to modulation by sigma receptor ligands to convey neuroprotective effects and/or restorative functions. Within each of the major mechanisms discussed herein, the neuroprotective effects of sigma ligands are summarized, and when known, the specific sigma receptor subtype(s) involved are identified. Together, the literature suggests sigma receptors may provide a novel target for combatting neurodegenerative diseases through both neuronal and glial mechanisms.

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Section: Modulation Of Glial Mechanisms That Contribute To Neurodementioning

confidence: 95%

Sigma receptors as potential therapeutic targets for neuroprotection

Nguyen

Kaushal

Robson

et al. 2014

European Journal of Pharmacology

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“…The robust rescue of cone function in rd10 mice treated with (+)-PTZ appears to be attributable (at least in part) to attenuated Müller cell gliosis, reduced microglial activation, and decreased oxidative stress. Sig1R, whose activation also has been reported to attenuate excitotoxicity (13,18), calcium dysregulation (12,17,26), ER stress (12,23,32), and inflammation (15,16,35), constitutes a promising target for pharmacologically treating retinal disease.…”

Section: Discussionmentioning

confidence: 99%

“…Sig1R is bound to ceramide-enriched microdomains in complex with the binding protein/glucose regulated protein 78 (GRP78/BiP) protein and functions as an ER chaperone involved in Ca 2+ mobilization (12). It regulates neuronal nitric oxide synthase, prevents apoptotic neuronal cell death (13,14), and modulates the activity of pleiotropic transcription factors including NFκB (15,16) (27) that is worsened by stress such as optic nerve crush or diabetes (28)(29)(30). Retinal Müller glial cells isolated from Sig1R…”

mentioning

confidence: 99%

Activation of the molecular chaperone, sigma 1 receptor, preserves cone function in a murine model of inherited retinal degeneration

Wang

Saul

Roon

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

119

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Retinal degenerative diseases are major causes of untreatable blindness, and novel approaches to treatment are being sought actively. Here we explored the activation of a unique protein, sigma 1 receptor (Sig1R), in the treatment of PRC loss because of its multifaceted role in cellular survival. We used Pde6β rd10 (rd10) mice, which harbor a mutation in the rod-specific phosphodiesterase gene Pde6β and lose rod and cone photoreceptor cells (PRC) within the first 6 wk of life, as a model for severe retinal degeneration. Systemic administration of the high-affinity Sig1R ligand (+)-pentazocine [(+)-PTZ] to rd10 mice over several weeks led to the rescue of cone function as indicated by electroretinographic recordings using natural noise stimuli and preservation of cone cells upon spectral domain optical coherence tomography and retinal histological examination. The protective effect appears to result from the activation of Sig1R, because rd10/Sig1R

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“…For example, ligands for σ1R can prevent apoptotic cell death in brain-derived neuronal cultures [9–11] as well as in retinal neurons in vitro and in vivo [12–15]. It has been postulated that σ1R functions as a ligand-operated chaperone in complex with the master endoplasmic reticulum (ER) regulatory protein, BiP [16].…”

Section: Introductionmentioning

confidence: 99%

Sigma 1 receptor regulates the oxidative stress response in primary retinal Müller glial cells via NRF2 signaling and system xc−, the Na+-independent glutamate–cystine exchanger

Wang

Shanmugam

Markand

et al. 2015

Free Radical Biology and Medicine

114

112

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Oxidative stress figures prominently in retinal diseases including diabetic retinopathy and glaucoma. Ligands for σ1R, a unique transmembrane protein localized to the ER, mitochondria, nuclear and plasma membrane, have profound retinal neuroprotective properties in vitro and in vivo. Studies to determine the mechanism of σ1R-mediated retinal neuroprotection have focused mainly on neurons. Little is known about effects of σ1R on Müller cell function, yet these radial glial cells are essential for homeostatic support of the retina. Here we investigated whether σ1R mediates the oxidative stress response of Müller cells using wildtype (WT) and σ1R knockout (σ1RKO) mice. We observed increased endogenous ROS levels in σ1RKO Müller cells compared to WT, which was accompanied by decreased expression of Sod1, Catalase, Nqo1, Hmox1, Gstm6 and Gpx1. The protein levels of SOD1, CAT, NQO1 and GPX1 were also significantly decreased. The genes encoding these antioxidants contain an antioxidant response element (ARE), which under stress is activated by NRF2, a transcription factor that typically resides in the cytoplasm bound by KEAP1. In the σ1RKO Müller cells Nrf2 expression was decreased significantly at the gene (and protein) level, while Keap1 gene (and protein) levels were markedly increased. NRF2-ARE binding affinity was decreased markedly in σ1RKO Müller cells. We investigated system xc−, the cystine-glutamate exchanger important for synthesis of GSH, and observed decreased function in σ1RKO Müller cells compared to WT as well as decreased GSH and GSH/GSSG ratios. This was accompanied by decreased gene and protein levels of xCT, the unique component of system xc−. We conclude that Müller glial cells lacking σ1R manifest elevated ROS, perturbation of antioxidant balance, suppression of NRF2 signaling and impaired function of system xc−. The data suggest that the oxidative stress-mediating function of retinal Müller glial cells may be compromised in the absence of σ1R. The neuroprotective role of σ1R may be linked directly to the oxidative stress-mediating properties of supportive glial cells.

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Neuroprotective effects of the sigma-1 receptor ligand PRE-084 against excitotoxic perinatal brain injury in newborn mice

Cited by 44 publications

References 43 publications

Sigma receptors as potential therapeutic targets for neuroprotection

Sigma receptors as potential therapeutic targets for neuroprotection

Activation of the molecular chaperone, sigma 1 receptor, preserves cone function in a murine model of inherited retinal degeneration

Sigma 1 receptor regulates the oxidative stress response in primary retinal Müller glial cells via NRF2 signaling and system xc−, the Na+-independent glutamate–cystine exchanger

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