2020 Feb 21
Department of Neurology, Wayne State University School of Medicine, Detroit
Sigma-1 Receptor Agonists as Potential Protective Therapies in Multiple Sclerosis
https://pubmed.ncbi.nlm.nih.gov/32179326/
Abstract
The sigma-1 receptor (σ-1R) is an endoplasmic reticulum (ER) chaperone upregulated during ER stress, and regulates calcium homeostasis. Agonists of σ-1R are neuroprotective. ANAVEX2-73, a new σ-1R agonist, is undergoing several clinical trials. We show that ANAVEX2-73 protects oligodendroglia (OL) and oligodendroglial precursors (OPC) from apoptosis, excitotoxicity, reactive oxygen species (ROS) and quinolinic acid (QA), associated with inflammation. ANAVEX2-73 stimulates OPC proliferation, but does not alter early maturation to OL. We previously reported that dextromethorphan (DM), another σ-1R agonist with a different structure, had similar effects. We now show that both DM and ANAVEX2-73 protect neurons from the four cytotoxic agents.
https://www.anavex.com/
ANAVEX2-73
ANAVEX2-73
https://www.eboro.cz
Re: ANAVEX2-73
Graphical abstract:
Re: ANAVEX2-73
Petr75 wrote: ↑Sat Mar 28, 2020 11:10 pm 2020 Feb 21
Department of Neurology, Wayne State University School of Medicine, Detroit
Sigma-1 Receptor Agonists as Potential Protective Therapies in Multiple Sclerosis
https://pubmed.ncbi.nlm.nih.gov/32179326/
It may be some time before we see this available for MS. Anavex's drug pipeline doesn't even mention MS.
https://www.anavex.com/therapeutic-candidates
Re: ANAVEX2-73
Anavex Life Sciences Receives TGA Special Access Scheme Approval for ANAVEX®2-73 (blarcamesine) for Alzheimer’s Disease Patients
https://www.cnn.com/business/newsfeeds/ ... 91967.html
NEW YORK, Aug. 05, 2020 (GLOBE NEWSWIRE) -- Anavex Life Sciences Corp. (“Anavex” or the “Company”) (Nasdaq: AVXL), a clinical-stage biopharmaceutical company developing differentiated therapeutics for the treatment of neurodegenerative and neurodevelopmental disorders including Alzheimer’s disease, Parkinson’s disease, Rett syndrome and other central nervous system (CNS) diseases, today announced that patients from the ANAVEX®2-73-003 phase 2a Alzheimer’s disease trial will continue treatment with ANAVEX®2-73 (blarcamesine) via the Australian Government Department of Health - Therapeutic Goods Administration (TGA) compassionate use Special Access Scheme following completion of over 5-years daily dosing of ANAVEX®2-73 (blarcamesine) and recommendation by their physicians.
The TGA approved the Special Access Scheme Category B applications based on the safety profile of ANAVEX®2-73 (blarcamesine), as well as clinical evidence that ANAVEX®2-73 (blarcamesine) may benefit patients. Anavex will facilitate continued access to ANAVEX®2-73 (blarcamesine) through the Special Access Scheme at the physicians’ request.
“We are honored to support medical professionals and their patients seeking treatment for Alzheimer’s disease and who have very few medical options,” commented Christopher U Missling, PhD, President and Chief Executive Officer of Anavex. “The Phase 2a clinical ANAVEX®2-73-002/-003 studies are exploring the long-term effect of daily treatment with ANAVEX®2-73 (blarcamesine) over 5 years, however it is pleasing that physicians have requested extended treatment of their patients with ANAVEX®2-73 (blarcamesine) beyond these 5 years.”
The Special Access Scheme: Most therapeutic goods are required to undergo an evaluation for quality, safety, and efficacy, and be included on the Australian Register of Therapeutic Goods (ARTG) before they can be supplied in Australia. In recognition that there are circumstances where patients need access to therapeutic goods that are not listed on the ARTG, the TGA facilitates a Special Access Scheme (SAS) for physicians seeking to use medicines that have not yet been approved in Australia. The SAS refers to arrangements, which provide for the supply of an unapproved therapeutic good for individual patients. Applications under the SAS are made to the TGA by their treating doctor, and approval to treat the patient takes into account the safety of the drug as well as supporting evidence that the drug may benefit the patients, along with the failure of any current therapies.1
1 https://www.tga.gov.au/form/special-access-scheme
About ANAVEX®2-73 (blarcamesine): ANAVEX®2-73 (blarcamesine) activates the Sigma-1 receptor (S1R) protein, which serves as a molecular chaperone and functional modulator involved in restoring homeostasis. S1R activation has demonstrated ability to reduce key pathophysiological signs of Alzheimer’s disease: beta amyloid, hyperphosphorylated tau, and increased inflammation. In the Phase 2a 57-week Alzheimer’s disease (AD) ANAVEX®2-73-002 (ClinicalTrials.gov NCT02244541) study, ANAVEX®2-73 (blarcamesine) has shown dose dependent improvement in exploratory endpoints of cognition (MMSE) and function (ADCS-ADL). Its open-label extension study ANAVEX®2-73-003 (ClinicalTrials.gov NCT02756858) for an additional 208 weeks included full genomic analysis of patients with Alzheimer’s disease treated with ANAVEX®2-73 (blarcamesine). A 48-week Phase 2b/3 study ANAVEX®2-73-AD-004 (ClinicalTrials.gov NCT03790709) of ANAVEX®2-73 (blarcamesine) in 450 patients with early Alzheimer’s disease is ongoing and currently over 60% enrolled.
About Anavex Life Sciences Corp.: Anavex Life Sciences Corp. (Nasdaq: AVXL) is a publicly traded biopharmaceutical company dedicated to the development of differentiated therapeutics for the treatment of neurodegenerative and neurodevelopmental disorders including Alzheimer’s disease, Parkinson’s disease, Rett syndrome and other central nervous system (CNS) diseases, pain and various types of cancer. Anavex’s lead drug candidate, ANAVEX®2-73 (blarcamesine), recently completed a successful Phase 2a clinical trial for Alzheimer’s disease. ANAVEX®2-73 (blarcamesine) is an orally available drug candidate that restores cellular homeostasis by targeting sigma-1 and muscarinic receptors. Preclinical studies demonstrated its potential to halt and/or reverse the course of Alzheimer’s disease. ANAVEX®2-73 (blarcamesine) also exhibited anticonvulsant, anti-amnesic, neuroprotective and anti-depressant properties in animal models, indicating its potential to treat additional CNS disorders, including epilepsy. The Michael J. Fox Foundation for Parkinson’s Research previously awarded Anavex a research grant, which fully funded a preclinical study to develop ANAVEX®2-73 (blarcamesine) for the treatment of Parkinson’s disease. ANAVEX®3-71, which targets sigma-1 and muscarinic receptors, is a promising clinical drug candidate demonstrating disease-modifying activity against the major hallmarks of Alzheimer’s disease in transgenic (3xTg-AD) mice, including cognitive deficits, amyloid and tau pathologies. In preclinical trials, ANAVEX®3-71 has shown beneficial effects on mitochondrial dysfunction and neuroinflammation.
https://www.cnn.com/business/newsfeeds/ ... 91967.html
NEW YORK, Aug. 05, 2020 (GLOBE NEWSWIRE) -- Anavex Life Sciences Corp. (“Anavex” or the “Company”) (Nasdaq: AVXL), a clinical-stage biopharmaceutical company developing differentiated therapeutics for the treatment of neurodegenerative and neurodevelopmental disorders including Alzheimer’s disease, Parkinson’s disease, Rett syndrome and other central nervous system (CNS) diseases, today announced that patients from the ANAVEX®2-73-003 phase 2a Alzheimer’s disease trial will continue treatment with ANAVEX®2-73 (blarcamesine) via the Australian Government Department of Health - Therapeutic Goods Administration (TGA) compassionate use Special Access Scheme following completion of over 5-years daily dosing of ANAVEX®2-73 (blarcamesine) and recommendation by their physicians.
The TGA approved the Special Access Scheme Category B applications based on the safety profile of ANAVEX®2-73 (blarcamesine), as well as clinical evidence that ANAVEX®2-73 (blarcamesine) may benefit patients. Anavex will facilitate continued access to ANAVEX®2-73 (blarcamesine) through the Special Access Scheme at the physicians’ request.
“We are honored to support medical professionals and their patients seeking treatment for Alzheimer’s disease and who have very few medical options,” commented Christopher U Missling, PhD, President and Chief Executive Officer of Anavex. “The Phase 2a clinical ANAVEX®2-73-002/-003 studies are exploring the long-term effect of daily treatment with ANAVEX®2-73 (blarcamesine) over 5 years, however it is pleasing that physicians have requested extended treatment of their patients with ANAVEX®2-73 (blarcamesine) beyond these 5 years.”
The Special Access Scheme: Most therapeutic goods are required to undergo an evaluation for quality, safety, and efficacy, and be included on the Australian Register of Therapeutic Goods (ARTG) before they can be supplied in Australia. In recognition that there are circumstances where patients need access to therapeutic goods that are not listed on the ARTG, the TGA facilitates a Special Access Scheme (SAS) for physicians seeking to use medicines that have not yet been approved in Australia. The SAS refers to arrangements, which provide for the supply of an unapproved therapeutic good for individual patients. Applications under the SAS are made to the TGA by their treating doctor, and approval to treat the patient takes into account the safety of the drug as well as supporting evidence that the drug may benefit the patients, along with the failure of any current therapies.1
1 https://www.tga.gov.au/form/special-access-scheme
About ANAVEX®2-73 (blarcamesine): ANAVEX®2-73 (blarcamesine) activates the Sigma-1 receptor (S1R) protein, which serves as a molecular chaperone and functional modulator involved in restoring homeostasis. S1R activation has demonstrated ability to reduce key pathophysiological signs of Alzheimer’s disease: beta amyloid, hyperphosphorylated tau, and increased inflammation. In the Phase 2a 57-week Alzheimer’s disease (AD) ANAVEX®2-73-002 (ClinicalTrials.gov NCT02244541) study, ANAVEX®2-73 (blarcamesine) has shown dose dependent improvement in exploratory endpoints of cognition (MMSE) and function (ADCS-ADL). Its open-label extension study ANAVEX®2-73-003 (ClinicalTrials.gov NCT02756858) for an additional 208 weeks included full genomic analysis of patients with Alzheimer’s disease treated with ANAVEX®2-73 (blarcamesine). A 48-week Phase 2b/3 study ANAVEX®2-73-AD-004 (ClinicalTrials.gov NCT03790709) of ANAVEX®2-73 (blarcamesine) in 450 patients with early Alzheimer’s disease is ongoing and currently over 60% enrolled.
About Anavex Life Sciences Corp.: Anavex Life Sciences Corp. (Nasdaq: AVXL) is a publicly traded biopharmaceutical company dedicated to the development of differentiated therapeutics for the treatment of neurodegenerative and neurodevelopmental disorders including Alzheimer’s disease, Parkinson’s disease, Rett syndrome and other central nervous system (CNS) diseases, pain and various types of cancer. Anavex’s lead drug candidate, ANAVEX®2-73 (blarcamesine), recently completed a successful Phase 2a clinical trial for Alzheimer’s disease. ANAVEX®2-73 (blarcamesine) is an orally available drug candidate that restores cellular homeostasis by targeting sigma-1 and muscarinic receptors. Preclinical studies demonstrated its potential to halt and/or reverse the course of Alzheimer’s disease. ANAVEX®2-73 (blarcamesine) also exhibited anticonvulsant, anti-amnesic, neuroprotective and anti-depressant properties in animal models, indicating its potential to treat additional CNS disorders, including epilepsy. The Michael J. Fox Foundation for Parkinson’s Research previously awarded Anavex a research grant, which fully funded a preclinical study to develop ANAVEX®2-73 (blarcamesine) for the treatment of Parkinson’s disease. ANAVEX®3-71, which targets sigma-1 and muscarinic receptors, is a promising clinical drug candidate demonstrating disease-modifying activity against the major hallmarks of Alzheimer’s disease in transgenic (3xTg-AD) mice, including cognitive deficits, amyloid and tau pathologies. In preclinical trials, ANAVEX®3-71 has shown beneficial effects on mitochondrial dysfunction and neuroinflammation.
Re: ANAVEX2-73
Thanks. Interesting.
Re: ANAVEX2-73
Anavex Life Sciences Announces Commitment for Financial Investment by Shake It Up Foundation for Parkinson’s Research for Clinical Trial of ANAVEX®2-73 (Blarcamesine) in Patients with Parkinson’s Disease
https://www.cnn.com/business/newsfeeds/ ... 99000.html
NEW YORK, Aug. 19, 2020 (GLOBE NEWSWIRE) -- Anavex Life Sciences Corp. (“Anavex” or the “Company”) (Nasdaq: AVXL), a clinical-stage biopharmaceutical company developing differentiated therapeutics for the treatment of neurodegenerative and neurodevelopmental diseases including Alzheimer’s disease, Parkinson’s disease, Rett syndrome and other central nervous system (CNS) diseases, today announced that the Shake It Up Foundation for Parkinson’s Research and its international partners has committed to invest into Anavex up to 50% of the costs of a disease modifying clinical study to develop ANAVEX®2-73 (blarcamesine) for the disease modifying treatment of Parkinson’s disease.
“Shake It Up is proud and excited to support research like this that may create opportunities for breakthroughs that could be a game-changer for people with Parkinson’s,” said Clyde Campbell, Founder and CEO of the Shake It Up Foundation. “The potential of a disease modifying treatment for Parkinson’s disease could be a very promising next step in further human testing of ANAVEX®2-73 (blarcamesine), in which the therapy goes through a rigorous process to determine whether it is safe, tolerable and efficacious.”
“We see this collaboration as an important step in our global effort to expedite the development of ANAVEX®2-73 (blarcamesine) and to evaluate ANAVEX®2-73 (blarcamesine) for Parkinson’s disease as a potential disease modifying agent. Shake It Up Foundation shares our commitment to move rapidly to address the unmet need for treatments for Parkinson’s disease, and brings deep experience and an extensive network within the Parkinson’s community,” said Christopher U Missling, PhD, President and Chief Executive Officer of Anavex.
The planned clinical study will use a convenient, once-daily oral ANAVEX®2-73 (blarcamesine) formulation to confirm the previously established potential disease modifying features of ANAVEX®2-73 (blarcamesine) in an animal model of Parkinson’s disease. Safety and efficacy will be investigated in an appropriately powered placebo-controlled clinical study of Parkinson’s disease patients over at least 48-weeks including ANAVEX®2-73-specific precision medicine biomarkers. All patients who participate in the study will be eligible to receive ANAVEX®2-73 (blarcamesine) under a voluntary open label extension protocol.
https://www.cnn.com/business/newsfeeds/ ... 99000.html
NEW YORK, Aug. 19, 2020 (GLOBE NEWSWIRE) -- Anavex Life Sciences Corp. (“Anavex” or the “Company”) (Nasdaq: AVXL), a clinical-stage biopharmaceutical company developing differentiated therapeutics for the treatment of neurodegenerative and neurodevelopmental diseases including Alzheimer’s disease, Parkinson’s disease, Rett syndrome and other central nervous system (CNS) diseases, today announced that the Shake It Up Foundation for Parkinson’s Research and its international partners has committed to invest into Anavex up to 50% of the costs of a disease modifying clinical study to develop ANAVEX®2-73 (blarcamesine) for the disease modifying treatment of Parkinson’s disease.
“Shake It Up is proud and excited to support research like this that may create opportunities for breakthroughs that could be a game-changer for people with Parkinson’s,” said Clyde Campbell, Founder and CEO of the Shake It Up Foundation. “The potential of a disease modifying treatment for Parkinson’s disease could be a very promising next step in further human testing of ANAVEX®2-73 (blarcamesine), in which the therapy goes through a rigorous process to determine whether it is safe, tolerable and efficacious.”
“We see this collaboration as an important step in our global effort to expedite the development of ANAVEX®2-73 (blarcamesine) and to evaluate ANAVEX®2-73 (blarcamesine) for Parkinson’s disease as a potential disease modifying agent. Shake It Up Foundation shares our commitment to move rapidly to address the unmet need for treatments for Parkinson’s disease, and brings deep experience and an extensive network within the Parkinson’s community,” said Christopher U Missling, PhD, President and Chief Executive Officer of Anavex.
The planned clinical study will use a convenient, once-daily oral ANAVEX®2-73 (blarcamesine) formulation to confirm the previously established potential disease modifying features of ANAVEX®2-73 (blarcamesine) in an animal model of Parkinson’s disease. Safety and efficacy will be investigated in an appropriately powered placebo-controlled clinical study of Parkinson’s disease patients over at least 48-weeks including ANAVEX®2-73-specific precision medicine biomarkers. All patients who participate in the study will be eligible to receive ANAVEX®2-73 (blarcamesine) under a voluntary open label extension protocol.
Re: ANAVEX2-73
From...
A precision medicine framework using artificial intelligence for the identification and confirmation of genomic biomarkers of response to an Alzheimer's disease therapy: Analysis of the blarcamesine (ANAVEX2-73) Phase 2a clinical study
Alzheimers Dement (N Y). 2020 Apr 19;6(1):e12013.
Free full text.
Figure 2: Linear mixed effect (LME) models of change in Mini‐Mental State Examination (MMSE) and Alzheimer's Disease Co‐operative Study‐Activities of Daily Living scale (ADCS‐ADL) since baseline over 148 weeks. To analyze the effect of high concentration on outcome over time, significant fixed effect terms linked to concentration were kept in the model. This has the effect of “correcting” for all other parameters except concentration. Because part of the response signal is not explained by the model (random error), this “residual” was added to the adjusted response values. For each time point, the model generates an adjusted predicted outcome for each patient. This adjusted outcome includes the residual mentioned above. For each time point, a mean and standard deviation of the adjusted outcome were calculated for the 21 patients and represented as solid points and error bars linked by dotted lines. A, LME‐adjusted slopes for the high concentration (green) cohort versus low and medium concentration patient cohort (magenta) with time (in weeks) against adjusted change in MMSE. Average adjusted values with residuals at the population level were plotted at each time point (dotted line). B, LME‐adjusted slopes for the high concentration (green) cohort versus low and medium concentration patient cohort (magenta) with time (in weeks) against adjusted change in ADCS‐ADL. Average adjusted values with residuals at the population level were plotted at each time point (dotted line)
A precision medicine framework using artificial intelligence for the identification and confirmation of genomic biomarkers of response to an Alzheimer's disease therapy: Analysis of the blarcamesine (ANAVEX2-73) Phase 2a clinical study
Alzheimers Dement (N Y). 2020 Apr 19;6(1):e12013.
Free full text.
Figure 2: Linear mixed effect (LME) models of change in Mini‐Mental State Examination (MMSE) and Alzheimer's Disease Co‐operative Study‐Activities of Daily Living scale (ADCS‐ADL) since baseline over 148 weeks. To analyze the effect of high concentration on outcome over time, significant fixed effect terms linked to concentration were kept in the model. This has the effect of “correcting” for all other parameters except concentration. Because part of the response signal is not explained by the model (random error), this “residual” was added to the adjusted response values. For each time point, the model generates an adjusted predicted outcome for each patient. This adjusted outcome includes the residual mentioned above. For each time point, a mean and standard deviation of the adjusted outcome were calculated for the 21 patients and represented as solid points and error bars linked by dotted lines. A, LME‐adjusted slopes for the high concentration (green) cohort versus low and medium concentration patient cohort (magenta) with time (in weeks) against adjusted change in MMSE. Average adjusted values with residuals at the population level were plotted at each time point (dotted line). B, LME‐adjusted slopes for the high concentration (green) cohort versus low and medium concentration patient cohort (magenta) with time (in weeks) against adjusted change in ADCS‐ADL. Average adjusted values with residuals at the population level were plotted at each time point (dotted line)
Re: ANAVEX2-73
The involvement of the sigma-1 receptor in neurodegeneration and neurorestoration
J Pharmacol Sci. 2015 Jan;127(1):30-5.
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.
Free full text.
J Pharmacol Sci. 2015 Jan;127(1):30-5.
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.
Free full text.
Re: ANAVEX2-73
Well, this is interesting. It seems that the sigma-1 receptor is over expressed in several cancers and is utilized to bypass apoptotic signals allowing the cells to survive and proliferate. What we don't know yet is if taking a sigma-1 agonist alters one's risk for cancer.
The Sigma-1 Receptor: When Adaptive Regulation of Cell Electrical Activity Contributes to Stimulant Addiction and Cancer
Front Neurosci. 2019; 13: 1186.
The sigma-1 receptor (σ1R) is an endoplasmic reticulum (ER)-resident chaperone protein that acts like an inter-organelle signaling modulator. Among its several functions such as ER lipid metabolisms/transports and indirect regulation of genes transcription, one of its most intriguing feature is the ability to regulate the function and trafficking of a variety of functional proteins. To date, and directly relevant to the present review, σ1R has been found to regulate both voltage-gated ion channels (VGICs) belonging to distinct superfamilies (i.e., sodium, Na+; potassium, K+; and calcium, Ca2+ channels) and non-voltage-gated ion channels. This regulatory function endows σ1R with a powerful capability to fine tune cells’ electrical activity and calcium homeostasis—a regulatory power that appears to favor cell survival in pathological contexts such as stroke or neurodegenerative diseases. In this review, we present the current state of knowledge on σ1R’s role in the regulation of cellular electrical activity, and how this seemingly adaptive function can shift cell homeostasis and contribute to the development of very distinct chronic pathologies such as psychostimulant abuse and tumor cell growth in cancers.
Free full text.
The Sigma-1 Receptor: When Adaptive Regulation of Cell Electrical Activity Contributes to Stimulant Addiction and Cancer
Front Neurosci. 2019; 13: 1186.
The sigma-1 receptor (σ1R) is an endoplasmic reticulum (ER)-resident chaperone protein that acts like an inter-organelle signaling modulator. Among its several functions such as ER lipid metabolisms/transports and indirect regulation of genes transcription, one of its most intriguing feature is the ability to regulate the function and trafficking of a variety of functional proteins. To date, and directly relevant to the present review, σ1R has been found to regulate both voltage-gated ion channels (VGICs) belonging to distinct superfamilies (i.e., sodium, Na+; potassium, K+; and calcium, Ca2+ channels) and non-voltage-gated ion channels. This regulatory function endows σ1R with a powerful capability to fine tune cells’ electrical activity and calcium homeostasis—a regulatory power that appears to favor cell survival in pathological contexts such as stroke or neurodegenerative diseases. In this review, we present the current state of knowledge on σ1R’s role in the regulation of cellular electrical activity, and how this seemingly adaptive function can shift cell homeostasis and contribute to the development of very distinct chronic pathologies such as psychostimulant abuse and tumor cell growth in cancers.
Free full text.
Re: ANAVEX2-73
Sigma-1 Receptor Activation Induces Autophagy and Increases Proteostasis Capacity In Vitro and In Vivo
Cells. 2019 Mar 2;8(3):211.
Dysfunction of autophagy and disturbed protein homeostasis are linked to the pathogenesis of human neurodegenerative diseases and the modulation of autophagy as the protein clearance process has become one key pharmacological target. Due to the role of sigma-1 receptors (Sig-1R) in learning and memory, and the described pleiotropic neuroprotective effects in various experimental paradigms, Sig-1R activation is recognized as one potential approach for prevention and therapy of neurodegeneration and, interestingly, in amyotrophic lateral sclerosis associated with mutated Sig-1R, autophagy is disturbed. Here we analyzed the effects of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73), a muscarinic receptor ligand and Sig-1R agonist, on autophagy and proteostasis. We describe, at the molecular level, for the first time, that pharmacological Sig-1R activation a) enhances the autophagic flux in human cells and in Caenorhabditis elegans and b) increases proteostasis capacity, ultimately ameliorating paralysis caused by protein aggregation in C. elegans. ANAVEX2-73 is already in clinical investigation for the treatment of Alzheimer's disease, and the novel activities of this compound on autophagy and proteostasis described here may have consequences for the use and further development of the Sig-1R as a drug target in the future. Moreover, our study defines the Sig-1R as an upstream modulator of canonical autophagy, which may have further implications for various conditions with dysfunctional autophagy, besides neurodegeneration.
Free full text.
Cells. 2019 Mar 2;8(3):211.
Dysfunction of autophagy and disturbed protein homeostasis are linked to the pathogenesis of human neurodegenerative diseases and the modulation of autophagy as the protein clearance process has become one key pharmacological target. Due to the role of sigma-1 receptors (Sig-1R) in learning and memory, and the described pleiotropic neuroprotective effects in various experimental paradigms, Sig-1R activation is recognized as one potential approach for prevention and therapy of neurodegeneration and, interestingly, in amyotrophic lateral sclerosis associated with mutated Sig-1R, autophagy is disturbed. Here we analyzed the effects of tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73), a muscarinic receptor ligand and Sig-1R agonist, on autophagy and proteostasis. We describe, at the molecular level, for the first time, that pharmacological Sig-1R activation a) enhances the autophagic flux in human cells and in Caenorhabditis elegans and b) increases proteostasis capacity, ultimately ameliorating paralysis caused by protein aggregation in C. elegans. ANAVEX2-73 is already in clinical investigation for the treatment of Alzheimer's disease, and the novel activities of this compound on autophagy and proteostasis described here may have consequences for the use and further development of the Sig-1R as a drug target in the future. Moreover, our study defines the Sig-1R as an upstream modulator of canonical autophagy, which may have further implications for various conditions with dysfunctional autophagy, besides neurodegeneration.
Free full text.