Sigma-1 Agonists Offer Combination Approach to Dementia Symptoms
Research from the past decade suggests that sigma-1 receptors and their encoding gene, SIGMAR1, together act as a therapeutic target for patients with dementia.
In Alzheimer disease and dementias, patients are often affected by a number of symptoms due to their dementia. There are a number of therapies in development for the treatment and managment of the symptoms of dementia, including several therapies affecting the sigma-1 receptor.
Eduardo Benarroch, MD
Research over the last few years has shown that acting on the SIGMAR1 pathway could hold therapeutic promise in the treatment of symptoms associated with dementia, as well as a number of other conditions. Sigma receptors are unique intracellular proteins that are expressed ubiquitously. They are, however, most prominent in neurons and glial cells, where they act as chaperone proteins in the endoplasmic reticulum (ER).1,2 Two subtypes are known: sigma-1 and sigma-2. Through binding with a number of ligands, sigma-1 receptors modulate various cellular processes involved in neurodegeneration. Specifically, research from the past decade suggests that sigma-1 receptors and their encoding gene, SIGMAR1, together act as a therapeutic target for patients with dementia. Unlike the majority of existing pharmacological interventions, sigma-1 agonists could address underlying disease pathology to improve symptoms.
Available Therapies
Although no sigma-1 receptor—selective medications are currently approved by the FDA, several currently marketed agents and other substances interact with sigma-1 receptors in a nonselective manner, such as fluvoxamine, donepezil, haloperidol, and pentazocine.3 Most therapeutic agents that act on sigma-1 are selective agonists that cause sigma-1 translocation from the ER to: (a) the plasma membrane, where they interact with ion channels or receptors, or (b) the nuclear envelope, where they regulate gene transcription.3 Through these avenues, sigma-1 receptors modulate calcium and glutamate levels; alter functions of the ER, mitochondria, and glial cells; and reduce production of reactive species.2 Therefore, sigma-1 agonists are able to reduce inflammation, oxidative stress, apoptosis, and glial cell activity. Because these factors incite underlying neurologic damage that causes dementia symptoms in a number of conditions, the therapeutic potential of sigma-r agonists could be broad.
Eduardo E. Benarroch, MD, a professor of neurology at Mayo Clinic, described the current understanding in a recent publication in the journal, Neurology.
“Evidence from experimental models indicates that [sigma-1 receptors] are involved in the pathobiology of several neurodegenerative disorders associated with impaired proteostasis, mitochondrial dysfunction, and altered RNA metabolism,” he wrote.3
Investigators have evaluated sigma-1 receptor agonists in various disease models, including diabetes, retinal degeneration, Huntington disease, Parkinson disease, amyotrophic lateral sclerosis (ALS), Alzheimer disease, stroke, and frontotemporal lobar degeneration and motor neuron disease.2,4-8 Some of these topics are more relevant to the present discussion of dementia symptoms. For instance, patients with Alzheimer disease lose just over a quarter (26%) of the sigma-1 receptors in the hippocampal CA1 region, which correlates with damage to pyramidal neurons.9 In an Alzheimer cell line, sigma-1 agonist fabomotizole decreased caspase-3 and Bax levels while limiting microglial activation, thereby reducing inflammation and apoptosis of cultured neurons.10 With such effects, sigma-1 agonists could save neurons and slow disease progression, thereby limiting associated dementia symptoms.
In another example, in vitro models of ischemia show that sigma-1—preferring and mixed sigma receptor agonists limit intracellular calcium levels while reducing glutamate release.11,12 Animal models of stroke show that these effects could have a clinical impact, as demonstrated by improved short-term neuronal survival and reduced infarct volume.12,13 Continued administration, starting 2 days after a model of stroke in rats, was associated with neuronal regrowth and improved functional recovery.14 If translatable to humans, sigma-1 agonists could improve or limit vascular dementia following stroke.
Unfortunately, this may be a very big “if.” In the first human trial of a sigma-1 agonist, patients with ischemic stroke were given selective sigma-1 agonist cutamesine (SA4503), but this did not lead to significant improvements in functional recovery compared with placebo.15 As such, some experts maintain a skeptical outlook that sigma-1 agonists will be a silver bullet for various causes of dementia.
“Despite affecting multiple mechanisms in neurons, [sigma-1 receptor] activation as a stand-alone treatment may not be sufficient, given the multidimensional nature of pathogenic mechanisms in neurodegenerative disorders,” Benarroch wrote.3
In a recent review of sigma-1 receptors in neurodegenerative diseases, Linda Nguyen, MD, PhD, of the University of California, San Diego, echoed Benarroch’s caution, citing a lack evidence.
“Further work is needed to characterize the potential for using sigma-1 receptor ligands to slow the progression of neurodegeneration and/or reverse an existing pathology,” she wrote. “Clarifying the cellular mechanisms and molecular targets of sigma-1 receptors in the [central nervous system] will also be critical to understanding the physiological roles and pathological alterations of sigma-1 receptors.”2
In the Pipeline
Numerous sigma-1 agonists, as selective monotherapy or in combination with other agents, have been studied in preclinical models, with some in or approaching clinical trials for conditions involving dementia.2,3 Five prominent agents are described below, with brief summaries and outlooks:
ANAVEX2-73: The leading sigma-1 agonist under development is ANAVEX2-73, an amino-tetrahydrofuran derivative and mixed muscarinic/sigma-1 receptor agonist.16 At present, 3 active clinical trials involve ANAVEX2-73: one for Parkinson disease with dementia and 2 for Alzheimer disease.17 Another clinical trial for Rett syndrome is planned, announced in October 2018 by manufacturer Anavex Life Sciences.
The most advanced data for ANAVEX2-73 come from a completed phase 2a trial involving patients with Alzheimer disease.18,19 The study involved 32 patients with mild to moderate disease, with baseline Mini-Mental State Examination (MMSE) scores between 16 and 28. The initial 5 weeks of the study involved crossover from oral to intravenous administration, followed by a year of oral therapy. Primary endpoints focused on safety, dose, and tolerability, while secondary endpoints evaluated efficacy measured by MMSE, Alzheimer’s Disease Cooperative Study-Activities of Daily Living inventory, and electroencephalography (EEG)/event-related potentials (ERPs). After 1 year, multivariable analysis showed a strong relationship between high doses (30 mg and 50 mg) and improved responses compared with patients who received low doses (3 mg and 5 mg) and had poor responses. The agent was very well tolerated, with no serious or clinically significant adverse effects.
The extended period of this trial has been ongoing for 3 years. The most recent findings echoed earlier reports, namely that the high-dose group continued to show significantly better responses in functional and cognitive endpoints than patients treated with low doses. The investigators also highlighted 2 genomic biomarkers that continued to be significantly associated with responses: SIGMAR1 and COMT. The former suggests that sigma-1 activation is a critical component of patient responses. In a press release issued by Anavex, Harald Hampel, MD, PhD, professor at the Sorbonne in Paris reflected on the biomarker findings: “These results further confirm the impact of actionable genetic variants that were previously identified through a full, unbiased genomic analysis of ANAVEX2-73 in Alzheimer’s disease, raising optimism for the future of biomarker-guided precision medicine to effectively combat this devastating disease.”
In August 2018, the first patient was enrolled in an ongoing phase 2b/3 trail for ANAVEX2-73 (NCT03790709).17,20
Fluvoxamine: Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) with sigma-1 agonist activity. It is currently used for a variety of disorders, including obsessive-compulsive disorder, depression, and anxiety, but it may be repurposed for dementia.2
One of the first studies using fluvoxamine for neuroprotection, Sato et al showed that fluvoxamine in the acute setting for stroke in rats led to improved sensorimotor scores, measured by limb placing tests.21 Several years later, Omi et al showed that neuroprotective effects might translate to Alzheimer disease in a study that involved cell lines, a stroke model in mice, and knockdown of ATF4 expression. Results showed that fluvoxamine enhanced cellular resistance to ER stress and lessened tau phosphorylation, with this latter finding being the highlight, suggesting possibilities for the treatment of Alzheimer disease.22
Most recently, the results of a 2018 study by Kim et al suggested that fluvoxamine could inhibit Alzheimer disease progression and associated dementia.23 Fluvoxamine reduced Aβ production in a cell line that consistently expresses AβPP. This action was dose-dependent, with a drug concentration of 10 μM dropping Aβ levels 2-fold. Further analysis showed that fluvoxamine impacted AβPP processing via sigma-1 receptor activation. A mouse model of Alzheimer disease supported these findings, showing that mice treated with fluvoxamine had better novel object recognition.
Although case reports and randomized trials involving fluvoxamine support beneficial impacts on behavioral and psychological symptoms of Alzheimer disease, these effects could be due to SSRI activity, instead of, or in addition to, sigma-1 receptor activity.24,25 Further studies are needed to clarify the benefits of fluvoxamine in Alzheimer disease, particularly as a method of preventing plaques and tangles. Currently, no such studies are planned, nor are any listed for other forms of dementia.
“[T]he repurposing or development of sigma-1 receptor active drugs, selective or not, and usage of selective sigma-1 ligands as an adjunct treatment require further investigation as viable therapeutic approaches for treating neurodegenerative diseases,” Nguyen noted.
Citalopram: Like fluvoxamine, citalopram is an SSRI with an affinity for sigma-1 receptors, although this affinity is milder (citalopram Ki = 292 nM vs fluvoxamine Ki = 36 nM).26 Studies involving citalopram hold promise for Alzheimer disease, despite suffering the same lack of clarity found in fluvoxamine studies; specifically, whether therapeutic effects are due to sigma-1 activity or SSRI activity.
Nevertheless, efficacy results have been notable. Findings from a 2011 study by Cirrito et al showed that a mouse model of Alzheimer disease developed 50% less plaques with chronic citalopram therapy.27 A similar stud by Sheline et al, conducted in 2014, supported these findings, with results showing that citalopram decreased new plaque formation in a mouse model of Alzheimer disease by 78%.28 In healthy volunteers, citalopram reduced Aβ concentrations in cerebrospinal fluid by 38% compared with placebo.
As with fluvoxamine, the above findings for citalopram are promising for Alzheimer disease; however, more studies are needed. At present, 1 clinical trial is recruiting to test escitalopram (Lexapro; the (S)-stereoisomer of citalopram) for improvement of cognitive impairment and prevention of cognitive decline in patients with Alzheimer disease (NCT03274817).17
Cutamesine (SA4503): Described earlier in this article, cutame-sine (SA4503) is a sigma-1 receptor agonist that was tested in 60 patients who had a stroke.15 The medication was given at doses of 1 mg/d, 3 mg/d, or placebo for 28 days. Although a higher proportion of patients who received cutamesine completed the 10-meter timed walk test and had improved National Institutes of Health Stroke Scale scores, functional recovery was not significantly different between treatment arms. No other human trials are planned or ongoing.
Dextromethorphan: Dextromethorphan is a noncompetitive NMDA antagonist and nonselective sigma-1 agonist.29 In a study involving a model of Parkinson disease in rats, dextromethorphan suppressed levodopa-induced dyskinesia, while other NMDA antagonists did not, suggesting that sigma-1 activity mediated this therapeutic effect. In humans, dextromethorphan has been tested as monotherapy for dementia, more often in the form of AVP-923, which is a combination of dextromethorphan and quinidine, the latter of which extends the effect of dextromethorphan.
In 2010, the FDA approved this combination for the treatment of pseudobulbar affect in patients with ALS or multiple sclerosis (MS) (Nuedexta; Avanir Pharmaceuticals Inc.).30 More recently, the results of a phase 2a trial by Cummings et al, involving 220 patients with Alzheimer disease, showed that AVP-923 provided significant clinical improvements in agitation.31 Falls were more common in the group receiving AVP-923 (8.6% vs 3.9%), but the investigators pointed to a higher fall rate in the AVP-923 group before treatment began (20.4% vs 12.8%). Although AVP-923 is not specifically approved for patients with Parkinson disease or dementia, many clinicians are already writing AVP-923 prescriptions for these conditions; findings from a 2019 study showed that AVP-923 is more commonly prescribed for such patients (57%), instead of patients with ALS (6.8%) or MS (8.4%), as approved by the FDA.32
Conclusions
Numerous existing agents have been interacting with sigma-1 receptors for years, but now this particular pathway is gaining traction as an actionable target in several neurodegenerative diseases that cause dementia symptoms. At the forefront, ANAVEX2-73 is a mixed muscarinic/sigma-1 receptor agonist that is starting phase 3 trials, after demonstrating clinical benefit in patients with Alzheimer disease. AVP-293, a combination of dextromethorphan and quinidine (Nuedexta), is a noncompetitive NMDA antagonist/sigma-1 agonist presently approved for pseudobulbar affect, and clinicians are already prescribing this agent for patients with dementia, based on a small but growing body of evidence.
Other combinations of SSRI/sigma-1 agonists, such as fluvoxamine and citalopram, have also demonstrated benefit, with a form of the latter agent now recruiting for a clinical trial involving patients with dementia. The only pure sigma-1 agonist described above, cutamesine, fell short for functional recovery in patients with stroke. Taken as a whole, the research landscape suggest that sigma-1 agonists alone are unlikely to take center stage, but they will likely play supporting roles.
“[Sigma-1 receptors] may constitute a potential target for adjunctive therapy in association with other approaches,” Dr. Benarroch concluded. “Agonists of [sigma-1 receptors] may have a favorable safety profile reflecting a selective modulatory action during pathologic conditions while sparing normal physiologic activity.”
REFERENCES
1. Jabs E, Kniffin C. 601978: sigma nonopioid intracellular receptor 1; SIGMAR1. Online Mendelian Inheritance in Man Database. omim.org/entry/601978#title. Published August 3, 2015. Accessed February 25, 2019.
2. Nguyen L, Lucke-Wold BP, Mookerjee SA, et al. Role of sigma-1 receptors in neurodegenerative diseases. J Pharmacol Sci. 2015;127(1):17-29. doi: 10.1016/j.jphs.2014.12.005.
3. Benarroch EE. Sigma-1 receptor and amyotrophic lateral sclerosis. Neurology. 2018;91(16):743- 747. doi: 10.1212/WNL.0000000000006347
4. Smith SB, Duplantier J, Dun Y, et al. In vivo protection against retinal neurodegeneration by sigma receptor 1 ligand (+)-pentazocine. Investig Opthalmology Vis Sci. 2008;49(9):4154. doi: 10.1167/iovs.08-1824.
5. Ha Y, Dun Y, Thangaraju M, et al. Sigma receptor 1 modulates endoplasmic reticulum stress in retinal neurons. Investig Opthalmology Vis Sci. 2011;52(1):527-540. doi: 10.1167/iovs.
6. Hyrskyluoto A, Pulli I, Törnqvist K, Huu Ho T, Korhonen L, Lindholm D. Sigma-1 receptor agonist PRE084 is protective against mutant huntingtin-induced cell degeneration: involve- ment of calpastatin and the NF-κB pathway. Cell Death Dis. 2013;4(5):e646-e646. doi: 10.1038/ cddis.2013.170.
7. Fukunaga K, Shinoda Y, Tagashira H. The role of SIGMAR1 gene mutation and mitochon- drial dysfunction in amyotrophic lateral sclerosis. J Pharmacol Sci. 2015;127(1):36-41.doi: 10.1016/j.jphs.2014.
8. Luty AA, Kwok JBJ, Dobson-Stone C, et al. Sigma nonopioid intracellular receptor 1 mutations cause frontotemporal lobar degeneration-motor neuron disease. Ann Neurol. 2010;68(5):639- 649. doi: 10.1002/ana.22274.
9. Jansen KLR, Faull RLM, Storey P, Leslie RA. Loss of sigma binding sites in the CA1 area of the anterior hippocampus in Alzheimer’s disease correlates with CA1 pyramidal cell loss. Brain Res. 1993;623(2):299-302. doi: 10.1016/0006-8993(93)91441-T.
10. Behensky AA, Yasny IE, Shuster AM, Seredenin SB, Petrov A V., Cuevas J. Stimulation of sigma receptors with afobazole blocks activation of microglia and reduces toxicity caused by amyloid-β25-35. J Pharmacol Exp Ther. 2013;347(2):458-467. doi: 10.1124/jpet.113.208348.
11. Lobner D, Lipton P. σ-Ligands and non-competitive NMDA antagonists inhibit gluta- mate release during cerebral ischemia. Neurosci Lett. 1990;117(1-2):169-174. doi: 10.1016/0304-3940(90)90139-Z.
12. Katnik C, Guerrero WR, Pennypacker KR, Herrera Y, Cuevas J. Sigma-1 receptor activation prevents intracellular calcium dysregulation in cortical neurons during in vitro ischemia. J Pharmacol Exp Ther. 2006;319(3):1355-1365. doi: 10.1124/jpet.106.107557.
13. Ajmo Jr. C, Vernon D, Collier L, Pennypacker K, Cuevas J. Sigma receptor activation reduces infarct size at 24 hours after permanent middle cerebral artery occlusion in rats. Curr Neurovasc Res. 2006;3(2):89-98. doi: 10.2174/156720206776875849
14. Ruscher K, Shamloo M, Rickhag M, et al. The sigma-1 receptor enhances brain plas- ticity and functional recovery after experimental stroke. Brain. 2011;134(3):732-746. doi: 10.1093/brain/awq367.
15. Urfer R, Moebius HJ, Skoloudik D, et al. Phase II Trial of the Sigma-1 Receptor Agonist Cutamesine (SA4503) for Recovery Enhancement After Acute Ischemic Stroke. Stroke. 2014;45(11):3304-3310. doi: 10.1161/STROKEAHA.
16. Villard V, Espallergues J, Keller E, Vamvakides A, Maurice T. Anti-amnesic and neuropro- tective potentials of the mixed muscarinic receptor/sigma 1 (σ1) ligand ANAVEX2-73, a novel aminotetrahydrofuran derivative. J Psychopharmacol. 2011;25(8):1101-1117. doi: 10.1177/0269881110379286.
17. ANAVEX2-73 for Treatment of Early Alzheimer’s Disease. clinicaltrials.gov/ct2/show/ NCT03790709. Updated January 1, 2019. Accessed February 26, 2019.
18. Anavex Life Sciences Corp. Analysis of ANAVEX2-73 Phase 2a Data. Published October 2017. anavex.com/wp-content/uploads/ANAVEX2-73-PKPD-Phase-2a-2017.pdf. Accessed February 26, 2019.
19. Anavex Life Sciences presents new three-year, longitudinal clinical efficacy data for ANAVEX2-73 in Alzheimer’s disease at the 2018 Clinical Trials on Alzheimer’s Disease (CTAD) Meeting [press release]. New York, NY: Anavex Life Sciences; October 26, 2018. anavex.com/anavex-life-scienc- es-presents-new-three-year-longitudinal-clinical-efficacy-data-for-anavex2-73-in-alzheimers- disease-at-the-2018-clinical-trials-on-alzheimers-disease-ctad/. Accessed February 26, 2019.
20. First patient enrolled in Anavex Life Sciences phase 2b/3 clinical trial of 19. ANAVEX2-73 for the treatment of early Alzheimer’s disease [press release]. New York, NY: Anavex Life Sciences; August 28, 2018. anavex.com/first-patient-enrolled-in-anavex-life-sciences-phase-2b-3-clinical- trial-of-anavex2-73-for-the-treatment-of-early-alzheimers-disease/. Accessed February 26, 2019.
21. Sato S, Kawamata T, Kobayashi T, Okada Y. Antidepressant fluvoxamine reduces cerebral infarct volume and ameliorates sensorimotor dysfunction in experimental stroke. Neuroreport. 2014;25(10):731-736. doi: 10.1097/WNR.0000000000000162.
22. Omi T, Kudo T, Tanimukai H, et al. Fluvoxamine attenuates tau phosphorylation through an upregulation of sigma-1 receptors (Sig-1Rs). Alzheimer’s Dement. 2013;9(4):P304. doi: 10.1016/j. jalz.2013.05.627.
23. Kim WS, Fu Y, Dobson-Stone C, et al. Effect of fluvoxamine on amyloid-β peptide generation and memory. J Alzheimer’s Dis. 2018;62(4):1777-1787. doi: 10.3233/JAD-171001.
24. Kurita M, Sato T, Nishino S, et al. Effects of fluvoxamine on behavioral and psychological symptoms of dementia in Alzheimer’s disease: a report of three cases. Fukushima J Med Sci. 2006;52(2):143-148. doi: 10.5387/fms.52.143.
25. Teranishi M, Kurita M, Nishino S, et al. Efficacy and tolerability of risperidone, yokukansan, and fluvoxamine for the treatment of behavioral and psychological symptoms of dementia. J Clin Psychopharmacol. 2013;33(5):600-607. doi: 10.1097/JCP.0b013e31829798d5.
26. Tsai S-YA, Pokrass MJ, Klauer NR, De Credico NE, Su T-P. Sigma-1 receptor chaperones in neurodegenerative and psychiatric disorders. Expert Opin Ther Targets. 2014;263(2):1-16. doi: 10.1517/14728222.2014.972939.
27. Cirrito JR, Disabato BM, Restivo JL, et al. Serotonin signaling is associated with lower amyloid levels and plaques in transgenic mice and humans. Proc Natl Acad Sci. 2011;108(36):14968- 14973. doi: 10.1073/pnas.1107411108.
28. Sheline YI, West T, Yarasheski K, et al. An antidepressant decreases CSF Aβ production in healthy individuals and in transgenic AD mice. Sci Transl Med. 2014;6(236):236re4. doi: 10.1126/ scitranslmed.3008169.
29. Paquette MA, Brudney EG, Putterman DB, Meshul CK, Johnson SW, Berger SP. Sigma ligands, but not N-methyl-D-aspartate antagonists, reduce levodopa-induced dyskinesias. Neuroreport. 2008;19(1):111-115. doi: 10.1097/WNR.0b013e3282f3b0d1.
30. Avanir Pharmaceuticals Inc. Nuedexa (dextromethorphan hydrobromide and quinidine sulfate) [FDA drug label]. accessdata.fda.gov/drugsatfda_docs/label/2010/021879s000lbl.pdf. Published October 2010. Accessed February 27, 2019.
31. Cummings J, Lyketsos CG, Tariot P, et al. Dextromethorphan/quinidine (AVP-923) efficacy and safety for treatment of agitation in persons with Alzheimer’s disease: Results from a phase 2 Study (NCT01584440). Am J Geriatr Psychiatry. 2015;23(3):S164-S165. doi: 10.1016/j. jagp.2014.12.171.
32. Fralick M, Sacks CA, Kesselheim AS. Assessment of use of combined dextromethorphan and quinidine in patients with dementia or Parkinson disease after US Food and Drug Administration approval for pseudobulbar affect. JAMA Intern Med. 2019;179(2):224. doi: 10.1001/jamainternmed.2018.6112.
