Relationship between Sigma-1 receptor and BDNF in the visual system

Mysona, Barbara A.; Zhao, Jing; Smith, Sylvia B.; Bollinger, Kathryn E.

doi:10.1016/j.exer.2017.10.012

Cited by 24 publications

(19 citation statements)

References 53 publications

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“…Immunohistochemistry and quantitative analyses were performed according to established protocols [ 17 , 28 ] using primary antibodies against tyrosine hydroxylase [ 32 ] (rabbit anti-TH antiserum from Pel-Freez, Rogers, AR, 1:1000) and Cluster of Differentiation 68 (CD68) (rat anti-CD68 antiserum from AbD Serotec, Kidlington, Oxfordshire, UK; 1:1000). Quantitative analyses were performed by an experimentally blinded investigator using the following methods.…”

Section: Methodsmentioning

confidence: 99%

Pridopidine Induces Functional Neurorestoration Via the Sigma-1 Receptor in a Mouse Model of Parkinson's Disease

Francardo

Geva²,

Bez

et al. 2019

Neurotherapeutics

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Pridopidine is a small molecule in clinical development for the treatment of Huntington’s disease. It was recently found to have high binding affinity to the sigma-1 receptor, a chaperone protein involved in cellular defense mechanisms and neuroplasticity. Here, we have evaluated the neuroprotective and neurorestorative effects of pridopidine in a unilateral 6-hydroxydopamine (6-OHDA) lesion model of parkinsonism in mice. By 5 weeks of daily administration, a low dose of pridopidine (0.3 mg/kg) had significantly improved deficits in forelimb use (cylinder test, stepping test) and abolished the ipsilateral rotational bias typical of hemiparkinsonian animals. A higher dose of pridopidine (1 mg/kg) significantly improved only the rotational bias, with a trend towards improvement in forelimb use. The behavioral recovery induced by pridopidine 0.3 mg/kg was accompanied by a significant protection of nigral dopamine cell bodies, an increased dopaminergic fiber density in the striatum, and striatal upregulation of GDNF, BDNF, and phosphorylated ERK1/2. The beneficial effects of pridopidine 0.3 mg/kg were absent in 6-OHDA-lesioned mice lacking the sigma-1 receptor. Pharmacokinetic data confirmed that the effective dose of pridopidine reached brain concentrations sufficient to bind S1R. Our results are the first to show that pridopidine promotes functional neurorestoration in the damaged nigrostriatal system acting via the sigma-1 receptor. Electronic supplementary material The online version of this article (10.1007/s13311-018-00699-9) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Pridopidine Induces Functional Neurorestoration Via the Sigma-1 Receptor in a Mouse Model of Parkinson's Disease

Francardo

Geva²,

Bez

et al. 2019

Neurotherapeutics

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“…Researchers from Bollinger’s lab have also interrogated the possible relationship between Sig1R and brain derived neurotrophic factor (BDNF), which is critical for ganglion cell survival. Sig1R activation with (+)-PTZ increased optic nerve head astrocyte secretion of BDNF, though the mechanism of the increased BDNF secretion is not known [Mysona et al, 2018]. It is noteworthy that activation of Sig1R can inhibit osmotic swelling of Müller cell somata (induced by exposure to hypoosmotic solution), though not of bipolar cell somata.…”

Section: Biological Role Of Sig1r and Mechanisms Of Retinal Neuroprotmentioning

confidence: 99%

Sigma 1 receptor: A novel therapeutic target in retinal disease

Smith

Wang

Cui

et al. 2018

Progress in Retinal and Eye Research

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Retinal degenerative diseases are major causes of untreatable blindness worldwide and efficacious treatments for these diseases are sorely needed. A novel target for treatment of retinal disease is the transmembrane protein Sigma 1 Receptor (Sig1R). This enigmatic protein is an evolutionary isolate with no known homology to any other protein. Sig1R was originally thought to be an opioid receptor. That notion has been dispelled and more recent pharmacological and molecular studies suggest that it is a pluripotent modulator with a number of biological functions, many of which are relevant to retinal disease. This review provides an overview of the discovery of Sig1R and early pharmacologic studies that led to the cloning of the Sig1R gene and eventual elucidation of its crystal structure. Studies of Sig1R in the eye were not reported until the late 1990s, but since that time there has been increasing interest in the potential role of Sig1R as a target for retinal disease. Studies have focused on elucidating the mechanism(s) of Sig1R function in retina including calcium regulation, modulation of oxidative stress, ion channel regulation and molecular chaperone activity. Mechanistic studies have been performed in isolated retinal cells, such as Müller glial cells, microglial cells, optic nerve head astrocytes and retinal ganglion cells as well as in the intact retina. Several compelling studies have provided evidence of powerful in vivo neuroprotective effects against ganglion cell loss as well as photoreceptor cell loss. Also described are studies that have examined retinal structure/function in various models of retinal disease in which Sig1R is absent and reveal that these phenotypes are accelerated compared to retinas of animals that express Sig1R. The collective evidence from analysis of studies over the past 20 years is that Sig1R plays a key role in modulating retinal cellular stress and that it holds great promise as a target in retinal neurodegenerative disease.

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“…One factor which stands out in its increasingly recognized importance to neurodegenerative processes is Sigma1 receptor (Sig1R) [ 53 – 58 ]. It is a pluripotent modulator with a number of biological functions, many of which are relevant to retinal disease, including involvement in calcium regulation, modulation of oxidative stress, ion channel regulation, and molecular chaperone activity.…”

Section: Drn Pathophysiologymentioning

confidence: 99%

Recent Developments in Diabetic Retinal Neurodegeneration: A Literature Review

Pillar

Moisseiev

Sokolovska

et al. 2020

Journal of Diabetes Research

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Neurodegeneration plays a significant role in the complex pathology of diabetic retinopathy. Evidence suggests the onset of neurodegeneration occurs early on in the disease, and so a greater understanding of the process is essential for prompt detection and targeted therapies. Neurodegeneration is a common pathway of assorted processes, including activation of inflammatory pathways, reduction of neuroprotective factors, DNA damage, and apoptosis. Oxidative stress and formation of advanced glycation end products amplify these processes and are elevated in the setting of hyperglycemia, hyperlipidemia, and glucose variability. These key pathophysiologic mechanisms are discussed, as well as diagnostic modalities and novel therapeutic avenues, with an emphasis on recent discoveries. The aim of this article is to highlight the crucial role of neurodegeneration in diabetic retinopathy and to review the molecular basis for this neuronal dysfunction, its diagnostic features, and the progress currently made in relevant therapeutic interventions.

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Relationship between Sigma-1 receptor and BDNF in the visual system

Cited by 24 publications

References 53 publications

Pridopidine Induces Functional Neurorestoration Via the Sigma-1 Receptor in a Mouse Model of Parkinson's Disease

Pridopidine Induces Functional Neurorestoration Via the Sigma-1 Receptor in a Mouse Model of Parkinson's Disease

Sigma 1 receptor: A novel therapeutic target in retinal disease

Recent Developments in Diabetic Retinal Neurodegeneration: A Literature Review

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