Afobazole Activation of σ-1 Receptors Modulates Neuronal Responses to Amyloid-β25–35

Behensky, Adam; Yasny, Ilya E; Shuster, Alexander M.; Seredenin, S. B.; Petrov, Andrey V.; Cuevas, Javier

doi:10.1124/jpet.113.208330

Cited by 39 publications

(39 citation statements)

References 55 publications

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“…A large body of literature suggests that sigma-1-mediated attenuation of ROS/RNS levels is associated with agonist, rather than antagonist actions. Consistent with this, knockout of the sigma-1 subtype in mice has shown an increased ROS production (Pal et al, 2012), while the application of sigma-1 agonists reduce ROS/RNS production caused by ischemia, diabetes, and amyloid-beta toxicity (Behensky et al, 2013a; Smith et al, 2008; Yang et al, 2010). The specific mechanisms through which sigma ligands mitigate the harmful effects of ROS/RNS are still being elucidated, but include modulation of nitric oxide synthase (NOS) enzyme activity (Vagnerova et al, 2006; Yang et al, 2010) and intrinsic and extrinsic cell death pathways (Kaushal et al, 2014).…”

Section: Modulation Of Excitotoxicity and Oxidative/nitrosative Stmentioning

confidence: 58%

“…The activation of sigma-1 receptors can be targeted to convey neuroprotection by preserving anti-apoptotic genes like bcl-2 (Meunier and Hayashi, 2010), as has been reported in a cerebral focal ischemia model (Yang et al, 2007) and mouse neuronal cultures exposed to HIV-1 envelope protein gp120 (Zhang et al, 2012). Sigma-1 receptor agonists can also regulate intracellular calcium levels and prevent the activation of pro-apoptotic genes and caspases in retinal ganglion cells (Tchedre and Yorio, 2008) as well as in rat cortical neurons with prolonged exposure to amyloid-beta peptide (Behensky et al, 2013a). …”

Section: Modulation Of Mitochondrial Death Cascades and Er Stressmentioning

confidence: 99%

“…Sigma receptor ligands modulate several aspects of microglial activation in vitro and in vivo , including migration and increases in cytokine release or gene expression in response to various activators such as adenosine triphosphate, lipopolysaccharide, amyloid-beta, and methamphetamine (Behensky et al, 2013a; Hall et al, 2009; Robson et al, 2013). 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).…”

Section: Modulation Of Glial Mechanisms That Contribute To Neurodementioning

confidence: 99%

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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 Excitotoxicity and Oxidative/nitrosative Stmentioning

confidence: 58%

Section: Modulation Of Mitochondrial Death Cascades and Er Stressmentioning

confidence: 99%

Section: Modulation Of Glial Mechanisms That Contribute To Neurodementioning

confidence: 99%

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Sigma receptors as potential therapeutic targets for neuroprotection

Nguyen

Kaushal

Robson

et al. 2014

European Journal of Pharmacology

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“…Sigma-1 agonists have been shown to regulate intracellular Ca 2+ levels and prevent the increased expression of pro-apoptotic genes and caspases in RGCs [72], as well as in rat cortical neurons with prolonged exposure to amyloid beta peptide [73]. These molecular effects correspond with phenotypic improvements to memory impairments in animal models [29].…”

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

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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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“…Aβ 25–35 fragments are implicated in the pathophysiology of AD and possess multiple neurotoxic mechanisms including the disruption of calcium homeostasis, production of reactive oxygen species (ROS), hyperactivation of NMDA channels and promotion of proapoptotic signaling through the upregulation of Bax (Figure 1). Injections of Aβ 25–35 fragments in mice and rats induce an increase in intracellular calcium concentrations, memory deficits, and AD-like pathology in brain tissue [40,41]. A selective Sig-1R agonist, afobazole, was reported to prevent Bax increase and promote calcium homeostasis in rat cortical neurons.…”

Section: Neurodegenerative Disordersmentioning

confidence: 99%

Sigma-1 receptor chaperones in neurodegenerative and psychiatric disorders

Tsai¹,

Pokrass²,

Klauer

et al. 2014

Expert Opin. Ther. Targets

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Introduction Sigma-1 receptors (Sig-1Rs) are molecular chaperones that reside mainly in the endoplasmic reticulum (ER) but exist also in the proximity of the plasma membrane. Sig-1Rs are highly expressed in the CNS and are involved in many cellular processes including cell differentiation, neuritogenesis, microglia activation, protein quality control, calcium-mediated ER stress and ion channel modulation. Disturbance in any of the above cellular processes can accelerate the progression of many neurological disorders; therefore, the Sig-1R has been implicated in several neurological diseases. Areas covered This review broadly covers the functions of Sig-1Rs including several neurodegenerative disorders in humans and drug addiction-associated neurological disturbance in the case of HIV infection. We discuss how several Sig-1R ligands could be utilized in therapeutic approaches to treat those disorders. Expert opinion Emerging understanding of the cellular functions of this unique transmembrane chaperone may lead to the use of new agents or broaden the use of certain available ligands as therapeutic targets in those neurological disorders.

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Afobazole Activation of σ-1 Receptors Modulates Neuronal Responses to Amyloid-β_25–35

Cited by 39 publications

References 55 publications

Sigma receptors as potential therapeutic targets for neuroprotection

Sigma receptors as potential therapeutic targets for neuroprotection

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

Sigma-1 receptor chaperones in neurodegenerative and psychiatric disorders

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