ANAVEX®2-73 (blarcamesine), a Sigma-1 receptor agonist, ameliorates neurologic impairments in a mouse model of Rett syndrome
Abstract
Rett syndrome (RTT) is a severe neurodevelopmental disorder that is associated in most cases with mutations in the transcriptional regulator MECP2. At present, there are no effective treatments for the disorder. Despite recent advances in RTT genetics and neurobiology, most drug development programs have focused on compounds targeting the IGF-1 pathway and no pivotal trial has been completed as yet. Thus, testing novel drugs that can ameliorate RTT's clinical manifestations is a high priority. ANAVEX2-73 (blarcamesine) is a Sigma-1 receptor agonist and muscarinic receptor modulator with a strong safety record and preliminary evidence of efficacy in patients with Alzheimer's disease. Its role in calcium homeostasis and mitochondrial function, cellular functions that underlie pathological processes and compensatory mechanisms in RTT, makes blarcamesine an intriguing drug candidate for this disorder. Mice deficient in MeCP2 have a range of physiological and neurological abnormalities that mimic the human syndrome. We tested blarcamesine in female heterozygous mice carrying one null allele of Mecp2 (HET) using a two-tier approach, with age-appropriate tests. Administration of the drug to younger and older adult mice resulted in improvement in multiple motor, sensory, and autonomic phenotypes of relevance to RTT. The latter included motor coordination and balance, acoustic and visual responses, hindlimb clasping, and apnea in expiration. In line with previous animal and human studies, blarcamesine also showed a good safety profile in this mouse model of RTT. Clinical studies in RTT with blarcamesine are ongoing.
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Kaufman et al. reported significant benefits in the Rett syndrome mouse model with a rescue of behavior and BDNF levels, and this led to patient studies in Rett syndrome that have demonstrated efficacy in a controlled trial.
“In addition, Kaufman et al. [145] also reported significant benefits in the Rett syndrome mouse model with a rescue of behavior and BDNF levels and this work lead to patient studies in Rett syndrome that have demonstrated efficacy in a controlled trial (Anavex Life Sciences press release 2021).”
From An Update on Psychopharmacological Treatment of Autism Spectrum Disorder (2022) · cites this paper as [145]
The therapeutic purpose of Blarcamesine is its potential to correct metabolic and synaptic abnormalities, as the sigma 1 receptor restores cellular homeostasis and synaptic plasticity when activated by targeting mitochondrial dysfunction and associated OS, protein misfolding, proteostasis, autophagy, and neuroinflammation.
“The therapeutic purpose of the treatment with this compound is its potential to correct a number of metabolic and synaptic abnormalities, as this receptor has been shown to restore cellular homeostasis and synaptic plasticity when activated by targeting mitochondrial dysfunction and associated OS, protein misfolding, proteostasis, and associated autophagy, and neuroinflammation [164].”
From Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery (2021) · cites this paper as [164]
Blarcamesine (ANAVEX2-73) is an agonist of the sigma 1 receptor.
“Blarcamesine or ANAVEX2-73 (NTC03790709) is a chemical compound known as an agonist of the sigma 1 receptor [164].”
From Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery (2021) · cites this paper as [164]
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- Authors
- Kaufmann, W. E., Sprouse, J., Rebowe, N., Hanania, T., Klamer, D., & Missling, C. U.
- Affiliations
- Emory University (US)
- Anavex Life Sciences Corp. (United States) (US)
- Psychogenics (United States) (US)
- Corresponding author
- Kaufmann, Walter E.
- Venue
- Pharmacology Biochemistry and Behavior
- Publisher
- Elsevier BV
- Published
- 2019-12
- Volume
- 187
- Pages
- 172796
- ISSN
- 0091-3057 (ISSN-L)
- OpenAlex
- W2989333414
- Cited by
- 54
- References
- 61
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 10 · 2023: 8 · 2022: 9 · 2021: 9 · 2020: 2
- FWCI
- 3.01
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Pharmacology Biochemistry and Behavior (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Rettsyndrome.org foundation Scout Program
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pharmacological Receptor Mechanisms and Effects
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- Rett syndrome, sigma-1 receptor agonist, MeCP2, neurodevelopmental disorders, motor coordination, sensory responses, autonomic dysfunction, drug safety, mitochondrial function, calcium homeostasis
- MeSH terms
- Sigma-1 Receptor, Animals, Apnea, Body Weight, Disease Models, Animal, Female, Furans, Mice, Inbred C57BL, Mice, Transgenic, Motor Skills, Reflex, Startle, Visual Acuity, Rett Syndrome, Treatment Outcome, Receptors, sigma, Neuroprotective Agents, Rotarod Performance Test, Mice, Methyl-CpG-Binding Protein 2
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