Allosteric Modulation of Sigma‐1 Receptors Elicits Rapid Antidepressant Activity

Wang, Yun; Guo, Lin; Jiang, Hua-Feng; Zheng, Longtai; Zhang, Ao; Zhen, Xuechu

doi:10.1111/cns.12502

Cited by 42 publications

(47 citation statements)

References 49 publications

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“…(Dalwadi et al, 2017 ). In support, we recently found that SKF83959, a recent identified Sig-1R allosteric modulator (Guo et al, 2013 ), elicited rapidly antidepressant effects via stimulating BDNF production (Wang et al, 2016 ).…”

Section: Sigma-1 Receptors and Astrocytesmentioning

confidence: 53%

Sigma-1 Receptor-Modulated Neuroinflammation in Neurological Diseases

Jia

Cheng

Wang

et al. 2018

Front. Cell. Neurosci.

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A large body of evidence indicates that sigma-1 receptors (Sig-1R) are important drug targets for a number of neuropsychiatric disorders. Sig-1Rs are enriched in central nervous system (CNS). In addition to neurons, both cerebral microglia and astrocytes express Sig-1Rs. Activation of Sig-1Rs is known to elicit potent neuroprotective effects and promote neuronal survival via multiple mechanisms, including promoting mitochondrial functions, decreasing oxidative stress and regulating neuroimmnological functions. In this review article, we focus on the emerging role of Sig-1Rs in regulating neuroinflammation and discuss the recent advances on the Sig-1R-modulating neuroinflammation in the pathophysiology and therapy of neurodegenerative disorders.

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Section: Sigma-1 Receptors and Astrocytesmentioning

confidence: 53%

Sigma-1 Receptor-Modulated Neuroinflammation in Neurological Diseases

Jia

Cheng

Wang

et al. 2018

Front. Cell. Neurosci.

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“…It is noted that, unlike in the case of AMPA component EPSC, D 1 ‐like receptor antagonist only partially attenuated the cocaine‐mediated inhibition on NMDA‐EPSC indicating other mechanism may also be involved (D'Ascenzo, Podda, & Grassi, ; van Waarde et al, ). For instance, cocaine is known to regulate sigma‐1 receptor function, we recent reported that sigma‐1 receptor is involved in GSK3β pathway activation (Wang et al, ), how sigma‐1 receptor is involved in the cocaine‐mediated inhibition on AMPA‐EPSCs is currently under investigation.…”

Section: Discussionmentioning

confidence: 99%

GSK‐3β inhibitors reverse cocaine‐induced synaptic transmission dysfunction in the nucleus accumbens

Zhao

Chen

Ren

et al. 2016

Synapse

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Nucleus accumbens receives glutamatergic projection from the prefrontal cortex (PFC) and dopaminergic input from the Ventral tegmental area (VTA). Recent studies have suggested a critical role for serine/threonine kinase glycogen synthase kinase 3β (GSK3β) in cocaine-induced hyperactivity; however, the effect of GSK3β on the modulation of glutamatergic and dopaminergic afferents is unclear. In this study, we found that the GSK3 inhibitors, LiCl (100 mg/kg, i.p.) or SB216763 (2.5 mg/kg, i.p.), blocked the cocaine-induced hyperlocomotor activity in rats. By employing single-unit recordings in vivo, we found that pretreatment with either SB216763 or LiCl for 15 min reversed the cocaine-inhibited firing frequency of medium spiny neuron (MSN) in the nucleus accumbens (NAc). Preperfusion of SB216763 (5 μM) ameliorated the inhibitory effect of cocaine on both the α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) (up to 99 ± 6.8% inhibition) and N-methyl-D-aspartic acid receptor (NMDAR)-mediate EPSC (up to 73 ± 9.7% inhibition) in the NAc in brain slices. The effect of cocaine on AMPA and NMDA receptor-mediate excitatory postsynaptic current (EPSC) were mimicked by the D1 -like receptor agonist SKF 38393 and blocked by the D1 -like receptor antagonist SCH 23390, whereas D2 -like receptor agonist or antagonist failed to mimic or to block the action of cocaine. Preperfusion of SB216763 for 5 min also ameliorated the inhibitory effect of SKF38393 on both AMPA and NMDA receptor-mediated components of EPSC, indicate the effect of SB216763 on cocaine was via the D1 -like receptor. Moreover, cocaine inhibited the presynaptic release of glutamate in the NAc, and SB216763 reversed this effect. In conclusion, D1 receptor-GSK3β pathway, which mediates glutamatergic transmission in the NAc core through a presynaptic mechanism, plays an important role in acute cocaine-induced hyperlocomotion.

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“…It has been reported that one feature seen in the Sig-1R knockout mice is depressive behaviors (Sabino, Cottone, Parylak, Steardo, & Zorrilla, 2009). Our previous study and other researches show that activation of Sig-1R by agonists displays more rapid and robust antidepressant-like action compare to clinical antidepressants (Fukunaga & Moriguchi, 2017;Moriguchi et al, 2015;Wang et al, 2016). In addition, many of clinical antidepressants possess an agonistic activity for the Sig-1R with nM Ki value (Albayrak & Hashimoto, 2017).…”

mentioning

confidence: 88%

“…The chronic unpredictable mild stress (CUMS) procedure, forced swimming test (FST), tail suspension test (TST), open field test (OFT), and sucrose preference test (SPT) was performed as previously described (Wang et al, 2016;. After different treatments, the tissues were collected for western blotting, Golgi staining, or immunofluorescence staining as previously described (Liu et al, 2018;Zhang et al, 2018).…”

Section: Behavioral Tests Western Blotting and Morphological Analmentioning

confidence: 99%

Activation of astrocytic sigma‐1 receptor exerts antidepressant‐like effect via facilitating CD38‐driven mitochondria transfer

Wang

Gao

et al. 2020

Glia

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Despite sigma‐1 receptor (Sig‐1R) is a promising therapeutic target in depression, little is known regarding the cellular mechanisms underlying its antidepressant responses. Here, we demonstrated that astrocyte can be a direct cellular target of Sig‐1R exerting antidepressant‐like effect. In multiple behavioral models including forced swimming test (FST), tail suspension test (TST), open field test (OFT), and chronic unpredictable mild stress (CUMS), inhibition of astrocyte function blocked pharmacological Sig‐1R activation‐induced antidepressant‐like effect, while specific activation of astrocytc Sig‐1R by adeno‐associated virus (AAV) was sufficient to produce antidepressant‐like effect. In depression‐related cellular tests, Sig‐1R agonist or lentivirus‐stimulated astrocyte conditioned medium (ACM) promoted neuronal neurite outgrowth, dendritic branch, and survival. Mechanismly, stimulation of Sig‐1R enhanced the expression of CD38 via activation of extracellular regulated protein kinases 1/2 (ERK1/2), resulting in facilitating mitochondrial transfer from astrocyte. Furthermore, blockage of CD38‐driven astrocyte transferring mitochondria in vivo and in vitro reversed the antidepressant‐like effect of pharmacological Sig‐1R activation. Thus, this study sheds light on the cellular mechanism of Sig‐1R activation producing antidepressant‐like effect. These data present the first evidence that enhancement of Sig‐1R action on astrocytes entirely exerts antidepressant‐like effect, indicating that specific activation of astrocytic Sig‐1R may provide a new approach for antidepressant drug development.

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Allosteric Modulation of Sigma‐1 Receptors Elicits Rapid Antidepressant Activity

Abstract: SOMCL-668, a novel allosteric modulator of sigma-1 receptors, elicits a potent and rapid acting antidepressant effect. The present data provide the first evidence that allosteric modulation of sigma-1 receptors may represent a new approach for antidepressant drug discovery.

Cited by 42 publications

References 49 publications

Sigma-1 Receptor-Modulated Neuroinflammation in Neurological Diseases

Sigma-1 Receptor-Modulated Neuroinflammation in Neurological Diseases

GSK‐3β inhibitors reverse cocaine‐induced synaptic transmission dysfunction in the nucleus accumbens

Activation of astrocytic sigma‐1 receptor exerts antidepressant‐like effect via facilitating CD38‐driven mitochondria transfer

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