Treatment with afobazole at delayed time points following ischemic stroke improves long-term functional and histological outcomes

Katnik, Christopher; García, Ángel; Behensky, Adam; Yasny, Ilya E; Shuster, Alexander M.; Seredenin, S. B.; Petrov, Andrey V.; Seifu, Solomon A.; McAleer, J. J.; Willing, Alison E.; Cuevas, Javier

doi:10.1016/j.nbd.2013.10.011

Cited by 25 publications

(37 citation statements)

References 31 publications

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“…However, the differences in the effects of afobazole and M-11 indicate that in case of afobazole, other drug targets also contribute to the protective effect. This statement corresponds to a series of papers proving the involvement of σ 1 receptors, one of the main targets of afobazole, in its protective action when simulating the various pathological conditions in vitro [8,9,11]. The work was supported by the Russian Foundation for Basic Research (State Contract No.13-04-01014).…”

Section: Resultsmentioning

confidence: 74%

Cytoprotective Effect of Afobazole and Its Main Metabolite M-11

2015

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Cell damage depending on activity of quinone reductase 2 (MT3 receptor) was simulated in experiments on bone marrow cell suspension and assessed by menadione-induced DNA breaks measured by comet assay. We analyzed the protective effect of afobazole interacting with MT1, MT3, σ1 receptors, and monoamine oxidase A and its main metabolite M11 that specifi cally binds to MT3 receptors. Both compounds reduced the level of menadione-induced DNA damage (afobazole was effective in lower concentrations in comparison with M-11). Conclusion was made on the contribution of MT3 receptors to the protective effect of afobazole, but the observed concentration differences indicate possible contribution of other targets of anxiolytic drug to the protective mechanisms.

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Section: Resultsmentioning

confidence: 74%

Cytoprotective Effect of Afobazole and Its Main Metabolite M-11

2015

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“…Neuroprotective and neurorestorative effects of sigma-1 agonists (e.g., decreasing cell death, protecting against tissue damage, and increasing synaptic protein expression) have been shown in multiple animal models of stroke, including mouse [10], rat [11–16], gerbil [17] and cat [18]. In rat models of stroke, for example, decreased infarct volume as well as enhanced neuronal survival were observed following acute treatment with a sigma agonist 24 h after the onset of ischemia [14, 15]. In addition, functional recovery with or without changes in infarct volume was observed when sigma agonists were administered as late as 2 days post-stroke [15, 19].…”

Section: 2 Sigma-1 Receptor Ligands In Animal Models Of Neurodegenmentioning

confidence: 99%

“…In rat models of stroke, for example, decreased infarct volume as well as enhanced neuronal survival were observed following acute treatment with a sigma agonist 24 h after the onset of ischemia [14, 15]. In addition, functional recovery with or without changes in infarct volume was observed when sigma agonists were administered as late as 2 days post-stroke [15, 19]. The potential to treat at extended times following the initial embolic injury warrants further investigation, as the only available post-stroke treatment approved for use in humans is thrombolytics, which is limited to 4 h post-stroke due to the risk of hemorrhagic transformation (i.e., conversion of an ischemic stroke to a hemorrhagic one following reperfusion) [20].…”

Section: 2 Sigma-1 Receptor Ligands In Animal Models Of Neurodegenmentioning

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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“…Neuroprotection by Sig-1R agonists could therefore be provided by preventing detrimental elevations of intracellular Ca 2þ -mediated effects by these channels. Under these conditions, activated Sig-1Rs are involved in normalizing intracellular ischaemia-or acidosis-evoked Ca 2þ overloads (46,47), an effect blocked by selective Sig-1R antagonists BD1047 and BD1063 (46).…”

Section: Influence Of Sig-1r On Ca 2þ Homeostasismentioning

confidence: 99%

The involvement of the sigma-1 receptor in neurodegeneration and neurorestoration

Ruscher

Wieloch

2015

Journal of Pharmacological Sciences

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The sigma-1 receptor (Sig-1R) is a single 25 kD polypeptide and a chaperone protein immersed in lipid rafts of the endoplasmic reticulum (ER) where it interacts with mitochondria at the mitochondria-associated ER membrane domain (MAM). Upon activation, the Sig-1R binds to the inositol trisphosphate receptor (IP3R), and modulates cellular calcium (Ca(2+)) homeostasis. Also, the activated Sig-1R modulates plasma membrane receptor and ion channel functions, and may regulate cellular excitability. Further, the Sig-1R promotes trafficking of lipids and proteins essential for neurotransmission, cell growth and motility. Activation of the Sig-1R provides neuroprotection and is neurorestorative in cellular and animal models of neurodegenerative diseases and brain ischaemia. Neuroprotection appears to be due to inhibition of cellular Ca(2+) toxicity and/or inflammation, and neurorestoration may include balancing abberant neurotransmission or stimulation of synaptogenesis, thus remodelling brain connectivity. Single nucleotide polymorphisms and mutations of the SIGMAR1 gene worsen outcome in Alzheimer's disease and myotrophic lateral sclerosis supporting a role of Sig-1R in neurodegenerative disease. The combined neuroprotective and neurorestorative actions of the Sig-1R, provide a broad therapeutic time window of Sig-1R agonists. The Sig-1R is therefore a strong therapeutic target for the development of new treatments for neurodegenerative diseases and stroke.

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Treatment with afobazole at delayed time points following ischemic stroke improves long-term functional and histological outcomes

Cited by 25 publications

References 31 publications

Cytoprotective Effect of Afobazole and Its Main Metabolite M-11

Cytoprotective Effect of Afobazole and Its Main Metabolite M-11

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

The involvement of the sigma-1 receptor in neurodegeneration and neurorestoration

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