Targeting ligand-operated chaperone sigma-1 receptors in the treatment of neuropsychiatric disorders

Abstract

Introduction Current conventional therapeutic drugs for the treatment of psychiatric or neurodegenerative disorders have certain limitations of use. Psychotherapeutic drugs such as typical and atypical antipsychotics, tricyclic antidepressants, and selective monoamine reuptake inhibitors, aim to normalize the hyper- or hypo-neurotransmission of monoaminergic systems. Despite their great contribution to the outcomes of psychiatric patients, these agents often exert severe side effects and require chronic treatments to promote amelioration of symptoms. Furthermore, drugs available for the treatment of neurodegenerative disorders are severely limited. Areas covered This review discusses recent evidence that has shed light on sigma-1 receptor ligands, which may serve as a new class of antidepressants or neuroprotective agents. Sigma-1 receptors are novel ligand-operated molecular chaperones regulating a variety of signal transduction, ER stress, cellular redox, cellular survival, and synaptogenesis. Selective sigma-1 receptor ligands exert rapid antidepressant-like, anxiolytic, antinociceptive and robust neuroprotective actions in preclinical studies. The review also looks at recent studies which suggest that reactive oxygen species might play a crucial role as signal integrators at the downstream of Sig-1Rs Expert opinion The significant advances in sigma receptor research in the last decade have begun to elucidate the intracellular signal cascades upstream and downstream of sigma-1 receptors. The novel ligand-operated properties of the sigma-1 receptor chaperone may enable a variety of interventions by which stress-related cellular systems are pharmacologically controlled.

The effects of sigma (σ1) receptor‐selective ligands on muscarinic receptor antagonist‐induced cognitive deficits in mice

“…The σ1 receptor has also been postulated to act as a molecular chaperone that regulates cellular survival and synaptogenesis (Hayashi and Su, 2007;Tsai et al, 2009;Fujimoto et al, 2012). Ligands selective for σ1 receptors have been reported to exert antidepressant-like, anxiolytic and analgesic actions in preclinical studies (Hayashi et al, 2011). In addition, σ1 receptor occupation has been linked to neurorestorative effects and has been suggested as a novel therapeutic target for the treatment of cognition deficit (Maurice et al, 1994;Urani et al, 1998;Maurice, 2002;Espallergues et al, 2007;Antonini et al, 2011;van Waarde et al, 2011;Kourrich et al, 2012).…”

Phase II Trial of the Sigma-1 Receptor Agonist Cutamesine (SA4503) for Recovery Enhancement After Acute Ischemic Stroke

“…8 Specific activation of the Sig-1R thus affects multiple physiological pathways, and these mechanisms offer a rationale for the functional recovery and cognitive effects of Sig-1R agonists observed in models of central nervous system injury and functional impairment. 9 Cutamesine (1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl) piperazine dihydrochloride, SA4503), 10 an orally available, central nervous system active, selective agonist of the Sig-1R, enhanced functional recovery after experimental stroke in rats when treatment commenced 48 hours after stroke and continued for 1 month, without affecting infarct size. 3 Treatment with cutamesine in vivo increased the levels of the synaptic proteins neurabin and neurexin in the peri-infarct area, whereas in vitro the compound stimulated neurite outgrowth in primary cortical neuronal cultures.…”

Genesis of ER stress in Huntington’s Disease

“…Sigma-1R has been implicated in a large variety of cellular processes, such as cellular redox, neurotransmitter release, inflammation, cellular differentiation, neuronal survival and synaptogenesis. It seems to act as a molecular chaperone, though the characteristics of Sigma-1R interactions in each pathway are still unclear [126,127].…”

“…Activation of Sigma-1R was also shown to decrease expression levels of Bax and caspase 3, which are associated with ER stress-mediated apoptosis, and hence aids cell survival in cells affected by amyloid beta [129]. Sigma-1R activation also provides significant protection against oxidative damage by reducing ER stress [123,124,126,130]. It was recently suggested that through its interaction with Rac1-GTPase at the MAMs, Sigma1R induces mild oxidative stress, preventing apoptosis [131].…”