Gut microbiota-derived short-chain fatty acids ameliorate methamphetamine-induced depression- and anxiety-like behaviors in a Sigmar-1 receptor-dependent manner

Methamphetamine (Meth) abuse can cause serious mental disorders, including anxiety and depression. The gut microbiota is a crucial contributor to maintaining host mental health. Here, we aim to investigate if microbiota participate in Meth-induced mental disorders, and the potential mechanisms involved. Here, 15 mg/kg Meth resulted in anxiety- and depression-like behaviors of mice successfully and suppressed the Sigma-1 receptor (SIGMAR1)/BDNF/TRKB pathway in the hippocampus. Meanwhile, Meth impaired gut homeostasis by arousing the Toll-like receptor 4 (TLR4)-related colonic inflammation, disturbing the gut microbiome and reducing the microbiota-derived short-chain fatty acids (SCFAs). Moreover, fecal microbiota from Meth-administrated mice mediated the colonic inflammation and reproduced anxiety- and depression-like behaviors in recipients. Further, SCFAs supplementation optimized Meth-induced microbial dysbiosis, ameliorated colonic inflammation, and repressed anxiety- and depression-like behaviors. Finally, Sigmar1 knockout (Sigmar1-/-) repressed the BDNF/TRKB pathway and produced similar behavioral phenotypes with Meth exposure, and eliminated the anti-anxiety and -depression effects of SCFAs. The activation of SIGMAR1 with fluvoxamine attenuated Meth-induced anxiety- and depression-like behaviors. Our findings indicated that gut microbiota-derived SCFAs could optimize gut homeostasis, and ameliorate Meth-induced mental disorders in a SIGMAR1-dependent manner. This study confirms the crucial role of microbiota in Meth-related mental disorders and provides a potential preemptive therapy.

PRE-084 ameliorated learning and memory impairment in T1DM via regulating neuronal MAM / 西安交通大学学报(医学版)

【Objective】 Diabetic mice could show learning and memory dysfunction, and we aimed to investigate the effect of Sigma-1 receptor agonist, PRE-084, on neurons and cognitive impairment in mice with type 1 diabetes (T1DM). 【Methods】 Twenty mice with T1DM induced by streptozocin, aged 8-10 weeks, and 20 control mice (CON) were randomly divided into four groups (CON+Vehicle, CON+PRE-084, T1DM+Vehicle and T1DM+PRE-084). Mouse primary neurons were cultured in high glucose medium with PRE-084 and control solvent, respectively. The body weight, food and water intake, and fasting blood glucose level of mice in each group were detected and recorded. The learning and memory abilities of mice were detected by new object recognition experiment. The mitochondria-associated endoplasmic reticulum membrane (MAM) structure of neurons in hippocampal CA1 area of mice was detected by transmission electron microscope. And the expression levels of ATP and reactive oxygen species (ROS) in hippocampus of mice were detected by biochemical kit. Cell viability and ROS level of primary neurons were detected by CCK8 and cellular ROS kit. 【Results】 PRE-084 reduced the increase of body weight, food and water intake, and blood glucose caused by diabetes. PRE-084 significantly ameliorated the learning and memory impairment of the mice with T1DM, improved the changes of MAM structure in neurons of hippocampal CA1 area of diabetic mice, increased the level of ATP in hippocampus of diabetic mice, and decreased the increase of ROS expression in diabetic hippocampus and neurons under high glucose conditions. 【Conclusion】 Sigma-1 receptor agonist, PRE-084, could improve learning and memory impairment in the mice with T1DM, which might be related to the structural changes of MAM, the increase of ATP production, and the decrease of ROS production in hippocampal neurons.

Bispecific sigma-1 receptor antagonism and mu-opioid receptor partial agonism: WLB-73502, an analgesic with improved efficacy and safety profile compared to strong opioids

Opioids are the most effective painkillers, but their benefit-risk balance often hinder their therapeutic use. WLB-73502 is a dual, bispecific compound that binds sigma-1 (S1R) and mu-opioid (MOR) receptors. WLB-73502 is an antagonist at the S1R. It behaved as a partial MOR agonist at the G-protein pathway and produced no/unsignificant β-arrestin-2 recruitment, thus demonstrating low intrinsic efficacy on MOR at both signalling pathways. Despite its partial MOR agonism, WLB-73502 exerted full antinociceptive efficacy, with potency superior to morphine and similar to oxycodone against nociceptive, inflammatory and osteoarthritis pain, and superior to both morphine and oxycodone against neuropathic pain. WLB-73502 crosses the blood-brain barrier and binds brain S1R and MOR to an extent consistent with its antinociceptive effect. Contrary to morphine and oxycodone, tolerance to its antinociceptive effect did not develop after repeated 4-week administration. Also, contrary to opioid comparators, WLB-73502 did not inhibit gastrointestinal transit or respiratory function in rats at doses inducing full efficacy, and it was devoid of proemetic effect (retching and vomiting) in ferrets at potentially effective doses. WLB-73502 benefits from its bivalent S1R antagonist and partial MOR agonist nature to provide an improved antinociceptive and safety profile respect to strong opioid therapy.

Research advances in neuroprotective role of sigma-1 receptor in retina / 中华实验眼科杂志

Retinal degenerative diseases are a major contributor to visual impairment worldwide, and research related to retinal degenerative diseases is increasingly becoming a hot topic.The sigma-1 receptor is a 223-amino-acid endoplasmic reticulum transmembrane protein, and its gene sequence is highly conserved throughout mammals.Sigma-1 receptors are widely distributed in various tissues and organs.Numerous studies have proved the protective role of sigma-1 receptors in retinal pathological processes, including anti-oxidative stress, anti-inflammatory response, and anti-apoptosis.In addition, sigma-1 receptors have potential therapeutic roles in retinal diseases, especially diabetic retinopathy, retinitis pigmentosa and glaucomatous neuropathy.In this paper, the molecular mechanisms of sigma-1 receptor-mediated retinal neuroprotection and its application in the treatment of retinal diseases were reviewed.

Regulation of the Sigma-1 Receptor on Chronic Pain and Its Neuromechanism / 中国生物化学与分子生物学报

Sigma-1 receptor (Sig-1R) is a ligand-regulated chaperone protein widely expressed in multiple regions of the nervous system. It mediates intracellular effects of several types of ion channels and G protein coupled receptors (GPCRs) by binding them, and regulates intracellular Ca

Inhibiting effect of retinal Sigma-1 receptor antagonist on the form deprivation myopia in guinea pigs and its mechanism / 中华实验眼科杂志

Objective:To investigate the role and mechanism of retinal Sigma-1 receptor antagonist N, N-diethyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethanaminehydrochloride (NE-100) in the formation of form deprivation myopia (FDM) in guinea pigs.Methods:Eighty-five 21-day-old guinea pigs were selected, and 36 of them were randomly divided into normal control group, occluded 14-day group and occluded 11-day group, with 12 in each group.The right eyes of guinea pigs in the occluded 14-day group were covered with translucent eye shield for consecutive 14 days, and guinea pigs in the occluded 11-day group were treated in the same way for consecutive 11 days plus 3 days without cover, and guinea pigs in the normal control group were not covered.The other 49 guinea pigs were randomly divided into FDM group ( n=10), FDM+ NE-100 6 μg group ( n=12), FDM+ NE-100 60 μg group ( n=10), FDM+ NE-100 600 μg group ( n=9), and FDM+ saline group ( n=8). The right eyes in each group received 100 μl peribulbar injection of NE-100 6 μg, 60 μg and 600 μg or saline once a day according to grouping.Ocular refraction and axial dimensions were measured using eccentric infrared photorefractor and A-scan ultrasonography, respectively.Corneal curvature was measured with keratometer.Immunohistochemical staining and Western blot were used to detect the expression levels of Sigma-1 receptor protein, and retinal dopamine content was evaluated by high-performance liquid chromatography with electrochemical detection.This study was approved by an Ethics Committee of the Department of Laboratory Animal Science of Central South University (No.2020sydw0084). The use and care of experimental animals followed the Regulations for the Administration of Affairs Concerning Experimental Animals in China. Results:There were statistical significant differences in diopter and axial length among the normal control group, occluded 14-day group and occluded 11-day group ( F=147.81, 160.10; both at P<0.01). Compared with the normal control group, the relative myopia was the deepest and the axial length was the longest in the occluded 14-day group, then the occluded 11-day group, showing significant differences between them (all at P<0.05). In the normal control group, Sigma-1 protein was mainly expressed in retinal ganglion cells (RGCs), photoreceptor inner segment and the inner nuclear layer.In the occluded 14-day group, Sigma-1 protein staining was enhanced in RGCs and photoreceptor inner segment.Sigma-1 staining positive cells in the inner nuclear layer were increased significantly and were also seen in the inner and outer plexiform layers, especially in Müller cells, in which the expression levels of Sigma-1 receptor protein were significantly increased.Compared with the occluded 14-day group, the Sigma-1 receptor protein expression levels in the retina of the occluded 11-day group was significantly decreased ( P<0.01). The diopters of guinea pigs in the FDM+ NE-100 6 μg, 60 μg and 600 μg groups were lower than those in the FDM group, and the diopters of FDM+ NE-100 60 μg and 600 μg guinea pigs were lower than those in the FDM+ NE-100 6 μg group, and the differences were statistically significant (all at P<0.05). The dopamine content in the retina of the FDM+ NE-100 60 μg group was (0.74±0.09) ng/mg, which was significantly higher than (0.57±0.10) ng/mg in the FDM group, with a significant difference between them ( t=15.18, P<0.01). Conclusions:Sigma-1 receptor antagonist inhibits FDM formation, which may be associated with the elevation of dopamine content in retina.

Cyproheptadine Regulates Pyramidal Neuron Excitability in Mouse Medial Prefrontal Cortex / 神经科学通报·英文版

Cyproheptadine (CPH), a first-generation antihistamine, enhances the delayed rectifier outward K current (I) in mouse cortical neurons through a sigma-1 receptor-mediated protein kinase A pathway. In this study, we aimed to determine the effects of CPH on neuronal excitability in current-clamped pyramidal neurons in mouse medial prefrontal cortex slices. CPH (10 µmol/L) significantly reduced the current density required to generate action potentials (APs) and increased the instantaneous frequency evoked by a depolarizing current. CPH also depolarized the resting membrane potential (RMP), decreased the delay time to elicit an AP, and reduced the spike threshold potential. This effect of CPH was mimicked by a sigma-1 receptor agonist and eliminated by an antagonist. Application of tetraethylammonium (TEA) to block I channels hyperpolarized the RMP and reduced the instantaneous frequency of APs. TEA eliminated the effects of CPH on AP frequency and delay time, but had no effect on spike threshold or RMP. The current-voltage relationship showed that CPH increased the membrane depolarization in response to positive current pulses and hyperpolarization in response to negative current pulses, suggesting that other types of membrane ion channels might also be affected by CPH. These results suggest that CPH increases the excitability of medial prefrontal cortex neurons by regulating TEA-sensitive I channels as well as other TEA-insensitive K channels, probably I and inward-rectifier Kir channels. This effect of CPH may explain its apparent clinical efficacy as an antidepressant and antipsychotic.

Sigma-1 Receptor Stimulation with PRE-084 Ameliorates Myocardial Ischemia-Reperfusion Injury in Rats / 中华医学杂志(英文版)

<p><b>Background</b>The sigma receptors are a relatively novel receptor group with respect to knowledge of their effect on health. Although the sigma-1 receptor agonist PRE-084 exhibits a cardioprotective effect in some studies, the benefits in cases of myocardial ischemia/reperfusion (I/R) are not clear. The aim of this study was to explore the mechanism of action and assess the effect of PRE-084 on myocardial I/R injury in rats.</p><p><b>Methods</b>In this study, rats were assigned randomly to three groups with computer (n = 14 for each group): a sham group, an I/R group, and a PRE-084 group. In the PRE-084 group, rats were administered PRE-084 1 h before operation. In the myocardial I/R model, the left anterior descending branch of rats was ligated and opened half an hour later. Cardiac function was assessed, and the apoptosis index was evaluated. The mechanisms of the cardioprotective effects of PRE-084 were explored.</p><p><b>Results</b>PRE-084 pretreatment preserved cardiac function and reduced myocardial apoptosis (F = 86.0, P < 0.01) with Western blotting analysis, showing significantly reduced expression of Bax (F = 75.7, P < 0.01) and cleaved-caspase 3 (F = 44.7, P < 0.01), along with increased expression of the Bcl-2 protein (P < 0.01) and phosphorylated protein kinase B (p-Akt) (P < 0.01) and phosphorylated-endothelial nitric oxide synthase (p-eNOS; P < 0.01).</p><p><b>Conclusion</b>PRE-084 preserved cardiac function and reduced myocardial apoptosis through the activation of Akt and eNOS.</p>

Experimental study on mouse acute toxicity and analgesic pharmacodynamics of new compound L11 / 中国药理学通报

Aim To observe the effect of new com-pound L11 on the affinity and function of sigma-1 re-ceptor,as well as the mouse acute toxicity and analge-sic effect, so as to provide the experimental basis for its pharmacodynamics and preliminary toxicity evalua-tion. Methods Using binding and function test of sig-ma-1 receptor in vitro, the acute toxicity and formalin model test of mice,as well as the rat chronic constric-tion injury(CCI) model test in vivo,the effects of L11 on the inhibitory rate and function of sigma-1 receptor, LD50,lifting/licking time of mice and mechanical pain threshold of rats were respectively measured to evaluate the analgesic effect and mechanism of L11. Results The inhibitory rate and Kiof L11 on the sigma-1 recep-tor were 103.07% and 4.81 nmol·L-1,respectively. The Kivalue was 8.10 nmol·L-1while adding pheny-toin (sigma-1 receptor allosteric modulator). The in-tragastric administration of L11 in mice was 1 680.03 mg·kg-1LD50,and the 95% confidence interval was (1 559.35 ~1 819.40) mg·kg-1. Compared with model group, the II phase lifting/licking time of mice was significantly reduced and the mechanical pain threshold of rat obviously increased by L11. Conclu-sions The new compound L11 has high affinity to sig-ma-1 receptor, which belongs to the antagonist of sig-ma-1 receptor;L11 is less toxic to intragastric adminis-tration and has obvious analgesic effect on the formalin model of mice and CCI model of rats, which may be relative with the sigma-1 receptor antagonism.

Role of Sigma Receptor and Neurosteroids in Pain Sensation / 한양의대학술지

The sigma-1 receptor has recently been implicated in a myriad of cellular functions and biological processes. Previous studies have demonstrated that the spinal sigma-1 receptor plays a pro-nociceptive role in acute pain and that the direct activation of sigma-1 receptor enhances the nociceptive response to peripheral stimuli, which is closely associated with calcium-dependent second messenger cascades including protein kinase C (PKC). In addition, the activation of sigma-1 receptor increases PKC- and protein kinase alpha (PKA)-dependent phosphorylation of the N-Methyl- D-aspartate (NMDA) receptor in the spinal cord, which results in the potentiation of intrathecal NMDA-evoked spontaneous pain behavior. Moreover, the blockade of spinal sigma-1 receptor suppresses the development of neuropathic pain and blocks the increase of phosphorylation of extracellular signal-regulated kinase (ERK) as well as pNR1 in the spinal cord. Recently, it was also reported that spinal neurosteroids such as pregnenolone and dehydroepiandrosterone sulfate, which are recognized as endogenous ligands for sigma-1 receptor, could produce mechanical hypersensitivity via sigma-1 receptor-mediated increase of pNR1. Collectively, these findings demonstrate that the activation of spinal sigma-1 receptor or the increase of neurosteroids is closely associated with the acute pain sensation or the development of chronic pain, and imply that sigma-1 receptor can be a new potential target for the development of analgesics.

Sigma-1 Receptor Antagonist BD1047 Reduces Allodynia and Spinal ERK Phosphorylation Following Chronic Compression of Dorsal Root Ganglion in Rats

Many therapeutic roles have been proposed for sigma-1 receptor (Sig-1R), but the involvement of Sig-1R in neuropathic pain has currently not been well explored. The present study aimed to evaluate the anti-nociceptive effect of Sig-1R antagonist (BD1047) in a rat model of chronic compression of the dorsal root ganglion (CCD), which is a model of human foraminal stenosis and radicular pain. When stainless steel rods were inserted into the intervertebral foramen of lumbar vertebrae 4 and 5, the CCD developed reliable mechanical (from 3 day) and cold allodynia (from 1 day) as compared with the sham operation group. The spinal expressions of Sig-1R and phosphorylation of extracellular signal-regulated kinase (pERK) were significantly increased from day 3 to day 14 after CCD surgery, as is consistent with the manifestation of allodynia. The BD 1047 (10, 30, 100 mg/kg) administered on postoperative days 0~5 dose-dependently suppressed both the induction of allodynia and the elevation of the spinal pERK expression in a manner comparable with that of gabapentin (100 mg/kg). At 7 days post-CCD surgery, BD1047 (10, 30, 100 mg/kg) administration also produced anti-nociceptive effects on the mechanical and cold allodynia similar with those of gabapentin (100 mg/kg). Therefore, this data suggested that Sig-1R may play an important role in both the development and maintenance of CCD-induced neuropathy.

The Antinociceptive Effect of Sigma-1 Receptor Antagonist, BD1047, in a Capsaicin Induced Headache Model in Rats

Intracranial headaches, including migraines, are mediated by nociceptive activation of the trigeminal nucleus caudalis (TNC), but the precise mechanisms are poorly understood. We previously demonstrated that selective blockage of spinal sigma-1 receptors (Sig-1R) produces a prominent antinociceptive effect in several types of pain models. This study evaluates whether the Sig-1R antagonist (BD1047) has an antinociceptive effect on capsaicin (a potent C-fiber activator) induced headache models in rats. Intracisternal infusion of capsaicin evoked pain behavior (face grooming), which was significantly attenuated by BD1047 pretreatment. BD1047 consistently reduced capsaicin-induced Fos-like immunoreactivity (Fos-LI), a neuronal activator, in the TNC in a dose-dependent manner. Moreover, capsaicin-induced phosphorylation of N-methyl-D-aspartate receptor subunit 1 was reversed by BD1047 pretreatment in the TNC. These results indicate that the Sig-1R antagonist has an inhibitory effect on nociceptive activation of the TNC in the capsaicin-induced headache animal model.