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1.
Life Sci ; 235: 116837, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31493481

RESUMO

AIMS: This study aimed to evaluate the effects of the sigma-1 receptor (S1R) on atrial fibrillation (AF) susceptibility in rats. MAIN METHODS: Rats were randomly assigned into three groups for intraperitoneal treatment with saline (CTL group), BD1047 (an antagonist of the S1R, BD group) or BD1047 plus fluvoxamine (an agonist of the S1R, BD + F group) for 4 weeks. The heart rate variability (HRV) and atrial electrophysiological parameters were measured via the PowerLab system and analyzed by LabChart 8.0 software. Atrial histology was determined with Masson staining. The protein levels of connexin (Cx) 40, Cav1.2, S1R, eNOS, p-eNOS, and p-AKT were detected by western blot assays. KEY FINDINGS: Our results showed that BD1047 significantly shortened the atrial effective refractory period (ERP) and action potential duration (APD), increased AF inducibility and duration, augmented sympathetic activity, depressed parasympathetic activity, and reduced heart rate variability (HRV) compared with the CTL group. Masson staining also showed a significant increase in atrial fibrosis in the BD group. Furthermore, the expressions of S1R, Cx40, Cav1.2, p-eNOS, and p-AKT were dramatically reduced in the BD group compared with the CTL group (all P < 0.01). However, fluvoxamine administration mitigated most of the abovementioned alterations. SIGNIFICANCE: Our findings indicated that S1R inhibition contributed to atrial electrical remodeling, cardiac autonomic remodeling and atrial fibrosis, which could be attenuated by fluvoxamine, thus providing new insights into the relationship between the S1R and AF.


Assuntos
Fibrilação Atrial/fisiopatologia , Remodelamento Atrial/fisiologia , Receptores sigma/antagonistas & inibidores , Receptores sigma/fisiologia , Potenciais de Ação , Animais , Fibrilação Atrial/patologia , Canais de Cálcio Tipo L , Conexinas/metabolismo , Etilenodiaminas/farmacologia , Fluvoxamina/farmacologia , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/metabolismo , Átrios do Coração/patologia , Frequência Cardíaca/efeitos dos fármacos , Masculino , Óxido Nítrico Sintase Tipo III/metabolismo , Proteína Oncogênica v-akt/metabolismo , Ratos , Receptores sigma/agonistas , Receptores sigma/metabolismo
2.
Prog Retin Eye Res ; 67: 130-149, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30075336

RESUMO

Retinal degenerative diseases are major causes of untreatable blindness worldwide and efficacious treatments for these diseases are sorely needed. A novel target for treatment of retinal disease is the transmembrane protein Sigma 1 Receptor (Sig1R). This enigmatic protein is an evolutionary isolate with no known homology to any other protein. Sig1R was originally thought to be an opioid receptor. That notion has been dispelled and more recent pharmacological and molecular studies suggest that it is a pluripotent modulator with a number of biological functions, many of which are relevant to retinal disease. This review provides an overview of the discovery of Sig1R and early pharmacologic studies that led to the cloning of the Sig1R gene and eventual elucidation of its crystal structure. Studies of Sig1R in the eye were not reported until the late 1990s, but since that time there has been increasing interest in the potential role of Sig1R as a target for retinal disease. Studies have focused on elucidating the mechanism(s) of Sig1R function in retina including calcium regulation, modulation of oxidative stress, ion channel regulation and molecular chaperone activity. Mechanistic studies have been performed in isolated retinal cells, such as Müller glial cells, microglial cells, optic nerve head astrocytes and retinal ganglion cells as well as in the intact retina. Several compelling studies have provided evidence of powerful in vivo neuroprotective effects against ganglion cell loss as well as photoreceptor cell loss. Also described are studies that have examined retinal structure/function in various models of retinal disease in which Sig1R is absent and reveal that these phenotypes are accelerated compared to retinas of animals that express Sig1R. The collective evidence from analysis of studies over the past 20 years is that Sig1R plays a key role in modulating retinal cellular stress and that it holds great promise as a target in retinal neurodegenerative disease.


Assuntos
Terapia de Alvo Molecular/métodos , Fármacos Neuroprotetores/uso terapêutico , Receptores sigma/fisiologia , Degeneração Retiniana , Animais , Humanos , Canais Iônicos/fisiologia , Chaperonas Moleculares/fisiologia , Neuroproteção/fisiologia , Estresse Oxidativo/fisiologia , Degeneração Retiniana/tratamento farmacológico , Degeneração Retiniana/metabolismo
3.
Exp Eye Res ; 167: 25-30, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29031856

RESUMO

Glaucoma is an incurable optic neuropathy characterized by dysfunction and death of retinal ganglion cells (RGCs). Brain derived neurotrophic factor (BDNF) is an essential neurotrophin that supports RGC function and survival. Despite BDNF's importance, our knowledge of molecular mechanisms that modulate BDNF processing and secretion is incomplete. Sigma-1 receptor (S1R) is associated with increased BDNF in hippocampus and with BDNF secretion by brain-derived astrocytes and neuronal cell lines. Much less is known about the relationship between S1R and BDNF in the visual system. Here, we examine how S1R activation and deletion alter expression of mature BDNF (mBDNF) and proBDNF in retina and cultured optic nerve head (ONH) astrocytes. For S1R activation, the S1R agonist (+)-pentazocine (PTZ, 0.5 mg/kg) was administered by intraperitoneal injection to C57BL/6J mice, 3 times per week, for 5 weeks. Expression of proBDNF and mBDNF was also examined in S1R knockout and age-matched C57BL/6J mice. In vitro, cultured ONH astrocytes were treated with 3 µM PTZ for 24 h followed by collection of media and ONH astrocyte lysates. Results showed that treatment with (+)-PTZ increased mBDNF protein in both retina and hippocampus. In contrast, S1R deletion was associated with retinal mBDNF deficits. In ONH astrocytes S1R agonist (+)-PTZ significantly increased levels of secreted BDNF and proBDNF in cell lysates. These findings support a role for S1R in the modulation of BDNF levels within the retina and optic nerve head. Treatment with S1R agonists might provide benefit in diseases such as glaucoma by increasing BDNF levels from endogenous sources.


Assuntos
Astrócitos/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Receptores sigma/fisiologia , Retina/metabolismo , Analgésicos Opioides/farmacologia , Animais , Western Blotting , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Glaucoma/metabolismo , Injeções Intraperitoneais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Disco Óptico/citologia , Pentazocina/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores sigma/agonistas
4.
Br J Pharmacol ; 175(3): 558-572, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29172248

RESUMO

BACKGROUND AND PURPOSE: Although we have recently demonstrated that spinal astrocyte gap junctions mediate the development of mirror-image pain (MIP), it is still unclear which astrocyte-derived factor is responsible for the development of MIP and how its production is controlled. In the present study, we focused on the role of ipsilateral versus contralateral D-serine in the development of MIP and investigated the possible involvement of σ1 receptors and gap junctions in astrocyte D-serine production. EXPERIMENTAL APPROACH: Following carrageenan injection, mechanical allodynia was tested at various time points to examine the effect of individual drugs. Immunohistochemistry and Western blot analyses were performed to clarify the expression levels of spinal D-serine, serine racemase, σ1 receptors and connexin 43. KEY RESULTS: The expression of ipsilateral D-serine was up-regulated during the early phase of inflammation, while contralateral D-serine increased during the later phase of inflammation. The pharmacological inhibition of D-serine during the early phase blocked the development of both ipsilateral and contralateral mechanical allodynia. However, the inhibition of D-serine during the later phase of inflammation blocked contralateral, but not ipsilateral mechanical allodynia. Furthermore, the inhibition of σ1 receptors during the earlier phase of inflammation inhibited the increase in ipsilateral D-serine. Conversely, the blockade of astrocyte gap junctions suppressed the up-regulation of contralateral D-serine during the later phase of inflammation. CONCLUSION AND IMPLICATIONS: Spinal astrocyte D-serine plays an important role in the development of mirror-image pain. Furthermore, σ1 receptors and astrocyte gap junction signalling mediate ipsilateral and contralateral D-serine production respectively.


Assuntos
Astrócitos/fisiologia , Carragenina/toxicidade , Junções Comunicantes/fisiologia , Dor/tratamento farmacológico , Receptores sigma/fisiologia , Serina/administração & dosagem , Animais , Astrócitos/efeitos dos fármacos , Relação Dose-Resposta a Droga , Junções Comunicantes/efeitos dos fármacos , Injeções Espinhais , Masculino , Dor/induzido quimicamente , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Ratos , Ratos Sprague-Dawley , Medula Espinal/efeitos dos fármacos , Medula Espinal/fisiologia
5.
Invest Ophthalmol Vis Sci ; 58(11): 4545-4558, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28877319

RESUMO

Purpose: Sigma 1 Receptor (Sig1R) is a novel therapeutic target in neurodegenerative diseases, including retinal disease. Sig1R-/- mice have late-onset retinal degeneration with ganglion cell loss that worsens under stress. Whether Sig1R plays a role in maintaining other retinal neurons is unknown, but was investigated here using rd10 mice, a model of severe photoreceptor degeneration. Methods: Wild-type, rd10, and rd10/Sig1R-/- mice were subjected to ERG and spectral-domain optical coherence tomography (SD-OCT) to assess visual function/structure in situ. Retinas imaged microscopically were subjected to morphometric analysis, immunodetection of cones, and analysis of gliosis. Oxidative and endoplasmic reticulum (ER) stress was evaluated at mRNA/protein levels. Results: Photopic ERG responses were reduced significantly in rd10/Sig1R-/- versus rd10 mice at P28 (31 ± 6 vs. 56 ± 7 µV), indicating accelerated cone loss when Sig1R was absent. At P28, SD-OCT revealed reduced retinal thickness in rd10/Sig1R-/- mice (60% of WT) versus rd10 (80% of WT). Morphometric analysis disclosed profound photoreceptor nuclei loss in rd10/Sig1R-/- versus rd10 mice. rd10/Sig1R-/- mice had 35% and 60% fewer photoreceptors, respectively, at P28 and P35, than rd10. Peanut agglutinin cone labeling decreased significantly; gliosis increased significantly in rd10/Sig1R-/- versus rd10 mice. At P21, NRF2 levels increased in rd10/Sig1R-/- mice versus rd10 and downstream antioxidants increased indicating oxidative stress. At P28, ER stress genes/proteins, especially XBP1, a potent transcriptional activator of the unfolded protein response and CHOP, a proapoptotic transcription factor, increased significantly in rd10/Sig1R-/- mice versus rd10. Conclusions: Photoreceptor cell degeneration accelerates and cone function diminishes much earlier in rd10/Sig1R-/- than rd10 mice emphasizing the importance of Sig1R as a modulator of retinal cell survival.


Assuntos
Apoptose , Modelos Animais de Doenças , Receptores sigma/fisiologia , Células Fotorreceptoras Retinianas Cones/patologia , Células Fotorreceptoras Retinianas Bastonetes/patologia , Retinite Pigmentosa/patologia , Animais , Eletrorretinografia , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estresse Oxidativo , Retina/fisiologia , Tomografia de Coerência Óptica
6.
Neurobiol Aging ; 59: 171-183, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28870519

RESUMO

Sigma-1 receptor (σ1R) is expressed in dopaminergic neurons of substantia nigra. Here, we show that σ1R knockout (σ1R-/-) mice, at age 6-12 months, appeared with age-related loss of dopaminergic neurons and decline of motor coordination. Levels of α-synuclein (αSyn) oligomers and fibrillar αSyn in substantia nigra of σ1R-/- mice were age-dependently increased without the changes in αSyn monomers. The phosphorylation of αSyn monomers or oligomers in dopaminergic neurons was enhanced in σ1R-/- mice. Levels of phosphorylated eIF2a and C/EBP homologous protein expression were elevated in σ1R-/- mice with decline of proteasome activity. Inhibition of endoplasmic reticulum stress by salubrinal recovered the αSyn phosphorylation and proteasome activity and prevented early oligomerization of αSyn in σ1R-/- mice. Rifampicin reduced the late increase of αSyn oligomers in σ1R-/- mice. Rifampicin or salubrinal could reduce the loss of dopaminergic neurons in σ1R-/- mice and improved their motor coordination. The results indicate that the σ1R deficiency through enhanced aggregation and phosphorylation of αSyn causes the loss of dopaminergic neurons leading to the decline of motor coordination.


Assuntos
Envelhecimento/genética , Envelhecimento/patologia , Neurônios Dopaminérgicos/patologia , Técnicas de Inativação de Genes , Transtornos Motores/genética , Agregação Patológica de Proteínas/genética , Receptores sigma/genética , Substância Negra/metabolismo , Substância Negra/patologia , alfa-Sinucleína/metabolismo , Animais , Cinamatos/farmacologia , Neurônios Dopaminérgicos/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Masculino , Camundongos Knockout , Transtornos Motores/fisiopatologia , Fosforilação/genética , Desempenho Psicomotor , Receptores sigma/deficiência , Receptores sigma/metabolismo , Receptores sigma/fisiologia , Rifampina/farmacologia , Tioureia/análogos & derivados , Tioureia/farmacologia
7.
J Neurochem ; 143(2): 171-182, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28815595

RESUMO

Adrenal chromaffin cells (ACCs) are the neuroendocrine arm of the sympathetic nervous system and key mediators of the physiological stress response. Acetylcholine (ACh) released from preganglionic splanchnic nerves activates nicotinic acetylcholine receptors (nAChRs) on chromaffin cells causing membrane depolarization, opening voltage-gated Ca2+ channels (VGCC), and exocytosis of catecholamines and neuropeptides. The serotonin transporter is expressed in ACCs and interacts with 5-HT1A receptors to control secretion. In addition to blocking the serotonin transporter, some selective serotonin reuptake inhibitors (SSRIs) are also agonists at sigma-1 receptors which function as intracellular chaperone proteins and can translocate to the plasma membrane to modulate ion channels. Therefore, we investigated whether SSRIs and other sigma-1 receptor ligands can modulate stimulus-secretion coupling in ACCs. Escitalopram and fluvoxamine (100 nM to 1 µM) reversibly inhibited nAChR currents. The sigma-1 receptor antagonists NE-100 and BD-1047 also blocked nAChR currents (≈ 50% block at 100 nM) as did PRE-084, a sigma-1 receptor agonist. Block of nAChR currents by fluvoxamine and NE-100 was not additive suggesting a common site of action. VGCC currents were unaffected by the drugs. Neither the increase in cytosolic [Ca2+ ] nor the resulting catecholamine secretion evoked by direct membrane depolarization to bypass nAChRs was altered by fluvoxamine or NE-100. However, both Ca2+ entry and catecholamine secretion evoked by the cholinergic agonist carbachol were significantly reduced by fluvoxamine or NE-100. Together, our data suggest that sigma-1 receptors do not acutely regulate catecholamine secretion. Rather, SSRIs and other sigma-1 receptor ligands inhibit secretion evoked by cholinergic stimulation because of direct block of Ca2+ entry via nAChRs.


Assuntos
Medula Suprarrenal/metabolismo , Catecolaminas/metabolismo , Células Cromafins/metabolismo , Antagonistas Nicotínicos/farmacologia , Receptores Nicotínicos/fisiologia , Receptores sigma/fisiologia , Medula Suprarrenal/citologia , Medula Suprarrenal/efeitos dos fármacos , Animais , Anisóis/farmacologia , Catecolaminas/antagonistas & inibidores , Bovinos , Células Cultivadas , Células Cromafins/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Propilaminas/farmacologia , Receptores sigma/agonistas
8.
Anesth Analg ; 125(2): 662-669, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28682953

RESUMO

BACKGROUND: The endoplasmic reticulum chaperone protein Sigma-1 receptor (Sig-1 R) and mitogen-activated protein kinases (MAPKs) are involved in the mechanism of pain. Acupoint stimulation exerts an exact antihyperalgesic effect in inflammatory pain. However, whether Sig-1 R and MAPKs are associated with the acupoint stimulation-induced analgesic effects is not clear. This study investigated the analgesic effect of acupoint catgut embedding (ACE) and the inhibition of Sig-1 R and MAPKs in ACE analgesia. METHODS: Rats were prepared with intrathecal catheter implantation. ACE was applied to bilateral "Kunlun" (BL60), "Zusanli" (ST36), and "Sanyinjiao" (SP6) acupoints in the rat model of inflammatory pain (complete Freund's adjuvant [CFA] intraplantar injection). Then, Sig-1R agonist PRE084 or saline was intrathecally given daily. The paw withdrawal thresholds and paw edema were measured before CFA injection and at 1, 3, and 5 day after CFA injection. Western bolt was used to evaluate the protein expression of spinal Sig-1R, p38MAPK, and extracellular signal-regulated kinase (ERK), and immunohistochemistry of Sig-1R was detected at 1, 3, and 5 days after CFA injection. RESULTS: ACE exhibited specific analgesic effects. ACE increased paw withdrawal thresholds and markedly decreased CFA-induced paw edema at 1, 3, and 5 days. ACE downregulated the protein expression of Sig-1R, which was increased significantly at 1, 3, and 5 days after CFA injection. ACE decreased the expression of p38 MAPK and ERK at 1 and 3 days but not at 5 days. However, an injection of Sig-1R agonist PRE084 markedly reversed these alterations, except ERK expression. CONCLUSIONS: The present study demonstrated that ACE exhibited antihyperalgesic effects via the inhibition of the Sig-1R that modulated p38 MAPK, but not ERK, expression in the CFA-induced inflammatory pain model in rats.


Assuntos
Pontos de Acupuntura , Analgésicos/uso terapêutico , Inflamação/tratamento farmacológico , Manejo da Dor/métodos , Limiar da Dor/efeitos dos fármacos , Receptores sigma/fisiologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Terapia por Acupuntura , Animais , Categute , Edema/tratamento farmacológico , Eletroacupuntura , Adjuvante de Freund , Hiperalgesia/tratamento farmacológico , Inflamação/induzido quimicamente , Injeções Espinhais , Masculino , Dor/tratamento farmacológico , Fosforilação , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
9.
Pharmacol Biochem Behav ; 150-151: 198-206, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27851908

RESUMO

This study examined the effect of the N-phenylpropyl-N'-substituted piperazine ligands SA4503 (3.4-dimethoxyphenethyl), YZ-067 (4-methoxyphenethyl), YZ-185 (3-methoxyphenethyl) and Nahas-3h (4-methoxybenzyl) on methamphetamine-induced hyperactivity in mice. In a previous study in rats, SA4503 increased methamphetamine-induced hyperactivity at a lower ligand dose and enhanced it at a higher dose. The other ligands have not been investigated in this assay. Presently, mice were administered sigma ligands, and specific [125I]E-IA-DM-PE-PIPZE and [125I]RTI-121 binding was measured to determine σ1 sigma receptor and dopamine transporter occupancy, respectively. Mice were also administered sigma ligands followed by methamphetamine, and locomotor activity was measured. Each of the ligands occupied σ1 sigma receptors (ED50=0.2-0.6µmol/kg) with similar potency, but none occupied the transporter (ED50>10µmol/kg). At the highest dose tested (31.6µmol/kg) all four sigma ligands significantly attenuated methamphetamine-induced hyperactivity. Interestingly, SA4503, YZ-067 and Nahas-3h, but not YZ-185, enhanced methamphetamine-induced hyperactivity at lower ligand doses (1-3.16µmol/kg). These results suggest that these ligands function as stimulant agonists at lower doses and as antagonists at higher does, with subtle changes in the substitution pattern at the 3- and 4-positions of the phenethyl group contributing to the nature of the interactions. Overall, these data indicate a complex role for σ1 sigma receptor ligands in methamphetamine's behavioral effects.


Assuntos
Hipercinese/induzido quimicamente , Metanfetamina/farmacologia , Piperazinas/farmacologia , Receptores sigma/efeitos dos fármacos , Animais , Cocaína/análogos & derivados , Cocaína/metabolismo , Masculino , Camundongos , Receptores sigma/agonistas , Receptores sigma/fisiologia , Relação Estrutura-Atividade
10.
Pharmacol Biochem Behav ; 148: 136-44, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27397487

RESUMO

Several receptor mediated pathways have been shown to modulate the murine head twitch response (HTR). However, the role of sigma receptors in the murine (±)-2,5-dimethoxy-4-iodoamphetamine (DOI)-induced HTR has not been previously investigated. We examined the ability of LS-1-137, a novel sigma-1 vs. sigma-2 receptor selective phenylacetamide, to modulate the DOI-induced HTR in DBA/2J mice. We also assessed the in vivo efficacy of reference sigma-1 receptor antagonists and agonists PRE-084 and PPCC. The effect of the sigma-2 receptor selective antagonist RHM-1-86 was also examined. Rotarod analysis was performed to monitor motor coordination after LS-1-137 administration. Radioligand binding techniques were used to determine the affinity of LS-1-137 at 5-HT2A and 5-HT2C receptors. LS-1-137 and the sigma-1 receptor antagonists haloperidol and BD 1047 were able to attenuate a DOI-induced HTR, indicating that LS-1-137 was acting in vivo as a sigma-1 receptor antagonist. LS-1-137 did not compromise rotarod performance within a dose range capable of attenuating the effects of DOI. Radioligand binding studies indicate that LS-1-137 exhibits low affinity binding at both 5-HT2A and 5-HT2C receptors. Based upon the results from these and our previous studies, LS-1-137 is a neuroprotective agent that attenuates the murine DOI-induced HTR independent of activity at 5-HT2 receptor subtypes, D2-like dopamine receptors, sigma-2 receptors and NMDA receptors. LS-1-137 appears to act as a sigma-1 receptor antagonist to inhibit the DOI-induced HTR. Therefore, the DOI-induced HTR can be used to assess the in vivo efficacy of sigma-1 receptor selective compounds.


Assuntos
Acetanilidas/farmacologia , Anfetaminas/farmacologia , Movimentos da Cabeça/efeitos dos fármacos , Piperidinas/farmacologia , Receptores sigma/fisiologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos DBA , Morfolinas/farmacologia , Receptor 5-HT2A de Serotonina/fisiologia , Receptor 5-HT2C de Serotonina/fisiologia , Receptores sigma/antagonistas & inibidores
11.
Biochim Biophys Acta ; 1866(2): 339-349, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27452206

RESUMO

Progesterone receptor membrane component 1 (PGRMC1) is a multi-functional protein with a heme-binding moiety related to that of cytochrome b5, which is a putative progesterone receptor. The recently solved PGRMC1 structure revealed that heme-binding involves coordination by a tyrosinate ion at Y113, and induces dimerization which is stabilized by hydrophobic stacking of heme on adjacent monomers. Dimerization is required for association with cytochrome P450 (cyP450) enzymes, which mediates chemoresistance to doxorubicin and may be responsible for PGRMC1's anti-apoptotic activity. Here we review the multiple attested involvement of PGRMC1 in diverse functions, including regulation of cytochrome P450, steroidogenesis, vesicle trafficking, progesterone signaling and mitotic spindle and cell cycle regulation. Its wide range of biological functions is attested to particularly by its emerging association with cancer and progesterone-responsive female reproductive tissues. PGRMC1 exhibits all the hallmarks of a higher order nexus signal integration hub protein. It appears capable of acting as a detector that integrates information from kinase/phosphatase pathways with heme and CO levels and probably redox status.


Assuntos
Proteínas de Membrana/fisiologia , Neoplasias/metabolismo , Receptores de Progesterona/fisiologia , Ciclo Celular , Proliferação de Células , Humanos , Proteínas de Membrana/química , Neoplasias/patologia , Multimerização Proteica , Receptores de Progesterona/química , Receptores sigma/fisiologia
12.
Eur J Pain ; 20(4): 594-606, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26358747

RESUMO

BACKGROUND: The role of peripheral sigma-1 receptors (Sig-1Rs) in normal nociception and in pathologically induced pain conditions has not been thoroughly investigated. Since there is mounting evidence that Sig-1Rs modulate ischaemia-induced pathological conditions, we investigated the role of Sig-1Rs in ischaemia-induced mechanical allodynia (MA) and addressed their possible interaction with acid-sensing ion channels (ASICs) and P2X receptors at the ischaemic site. METHODS: We used a rodent model of hindlimb thrombus-induced ischaemic pain (TIIP) to investigate their role. Western blot was performed to observe changes in Sig-1R expression in peripheral nervous tissues. MA was measured after intraplantar (i.pl.) injections of antagonists for the Sig-1, ASIC and P2X receptors in TIIP rats or agonists of each receptor in naïve rats. RESULTS: Sig-1R expression significantly increased in skin, sciatic nerve and dorsal root ganglia at 3 days post-TIIP surgery. I.pl. injections of the Sig-1R antagonist, BD-1047 on post-operative days 0-3 significantly attenuated the development of MA during the induction phase, but had no effect on MA when given during the maintenance phase (days 3-6 post-surgery). BD-1047 synergistically increased amiloride (an ASICs blocker)- and TNP-ATP (a P2X antagonist)-induced analgesic effects in TIIP rats. In naïve rats, i.pl. injection of Sig-1R agonist PRE-084 alone did not produce MA; but it did induce MA when co-administered with either an acidic pH solution or a sub-effective dose of αßmeATP. CONCLUSION: Peripheral Sig-1Rs contribute to the induction of ischaemia-induced MA via facilitation of ASICs and P2X receptors. Thus, peripheral Sig-1Rs represent a novel therapeutic target for the treatment of ischaemic pain.


Assuntos
Canais Iônicos Sensíveis a Ácido/fisiologia , Hiperalgesia/metabolismo , Isquemia/complicações , Dor/metabolismo , Receptores Purinérgicos P2X/fisiologia , Receptores sigma/fisiologia , Trifosfato de Adenosina/análogos & derivados , Animais , Etilenodiaminas , Membro Posterior/irrigação sanguínea , Hiperalgesia/etiologia , Isquemia/metabolismo , Masculino , Morfolinas , Dor/etiologia , Ratos , Ratos Sprague-Dawley
13.
J Pharmacol Exp Ther ; 356(2): 232-43, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26574517

RESUMO

Sigma-2 receptors are attractive antineoplastic targets due to their ability to induce apoptosis and their upregulation in rapidly proliferating cancer cells compared with healthy tissue. However, this role is inconsistent with overexpression in cancer, which is typically associated with upregulation of prosurvival factors. Here, we report a novel metabolic regulatory function for sigma-2 receptors. CM764 [6-acetyl-3-(4-(4-(2-amino-4-fluorophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H)-one] binds with Ki values of 86.6 ± 2.8 and 3.5 ± 0.9 nM at the sigma-1 and sigma-2 receptors, respectively. CM764 increased reduction of MTT [3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide] in human SK-N-SH neuroblastoma compared with untreated cells, an effect not due to proliferation. This effect was attenuated by five different sigma antagonists, including CM572 [3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)-6-isothiocyanatobenzo[d]oxazol-2(3H)-one], which has no significant affinity for sigma-1 receptors. This effect was also observed in MG-63 osteosarcoma and HEK293T cells, indicating that this function is not exclusive to neuroblastoma or to cancer cells. CM764 produced an immediate, robust, and transient increase in cytosolic calcium, consistent with sigma-2 receptor activation. Additionally, we observed an increase in the total NAD(+)/NADH level and the ATP level in CM764-treated SK-N-SH cells compared with untreated cells. After only 4 hours of treatment, basal levels of reactive oxygen species were reduced by 90% in cells treated with CM764 over untreated cells, and HIF1α and VEGF levels were increased after 3-24 hours of treatment. These data indicate that sigma-2 receptors may play a role in induction of glycolysis, representing a possible prosurvival function for the sigma-2 receptor that is consistent with its upregulation in cancer cells compared with healthy tissue.


Assuntos
Benzoxazóis/química , Benzoxazóis/metabolismo , Glicólise/fisiologia , Neuroblastoma/metabolismo , Piperazinas/química , Piperazinas/metabolismo , Receptores sigma/antagonistas & inibidores , Receptores sigma/fisiologia , Animais , Benzoxazóis/farmacologia , Linhagem Celular Tumoral , Glicólise/efeitos dos fármacos , Células HEK293 , Humanos , Piperazinas/farmacologia , Ratos
14.
Biochem J ; 473(1): 1-5, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-26467159

RESUMO

Sigma-1 receptor (Sig-1R) is an intracellular chaperone protein with many ligands, located at the endoplasmic reticulum (ER). Binding of cocaine to Sig-1R has previously been found to modulate endothelial functions. In the present study, we show that cocaine dramatically inhibits store-operated Ca(2+) entry (SOCE), a Ca(2+) influx mechanism promoted by depletion of intracellular Ca(2+) stores, in rat brain microvascular endothelial cells (RBMVEC). Using either Sig-1R shRNA or pharmacological inhibition with the unrelated Sig-1R antagonists BD-1063 and NE-100, we show that cocaine-induced SOCE inhibition is dependent on Sig-1R. In addition to revealing new insight into fundamental mechanisms of cocaine-induced changes in endothelial function, these studies indicate an unprecedented role for Sig-1R as a SOCE inhibitor.


Assuntos
Cálcio/metabolismo , Cocaína/farmacologia , Células Endoteliais/metabolismo , Microvasos/metabolismo , Receptores sigma/fisiologia , Animais , Canais de Cálcio/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Sinalização do Cálcio/fisiologia , Células Cultivadas , Células Endoteliais/efeitos dos fármacos , Microvasos/efeitos dos fármacos , Ratos , Receptores sigma/agonistas
15.
Free Radic Biol Med ; 86: 25-36, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25920363

RESUMO

Oxidative stress figures prominently in retinal diseases, including diabetic retinopathy, and glaucoma. Ligands for σ1R, a unique transmembrane protein localized to the endoplasmic reticulum, mitochondria, and nuclear and plasma membranes, have profound retinal neuroprotective properties in vitro and in vivo. Studies to determine the mechanism of σ1R-mediated retinal neuroprotection have focused mainly on neurons. Little is known about the effects of σ1R on Müller cell function, yet these radial glial cells are essential for homeostatic support of the retina. Here we investigated whether σ1R mediates the oxidative stress response of Müller cells using wild-type (WT) and σ1R-knockout (σ1RKO) mice. We observed increased endogenous reactive oxygen species (ROS) levels in σ1RKO Müller cells compared to WT, which was accompanied by decreased expression of Sod1, catalase, Nqo1, Hmox1, Gstm6, and Gpx1. The protein levels of SOD1, CAT, NQO1, and GPX1 were also significantly decreased. The genes encoding these antioxidants contain an antioxidant response element (ARE), which under stress is activated by NRF2, a transcription factor that typically resides in the cytoplasm bound by KEAP1. In the σ1RKO Müller cells Nrf2 expression was decreased significantly at the gene (and protein) level, whereas Keap1 gene (and protein) levels were markedly increased. NRF2-ARE binding affinity was decreased markedly in σ1RKO Müller cells. We investigated system xc(-), the cystine-glutamate exchanger important for synthesis of glutathione (GSH), and observed decreased function in σ1RKO Müller cells compared to WT as well as decreased GSH and GSH/GSSG ratios. This was accompanied by decreased gene and protein levels of xCT, the unique component of system xc(-). We conclude that Müller glial cells lacking σ1R manifest elevated ROS, perturbation of antioxidant balance, suppression of NRF2 signaling, and impaired function of system xc(-). The data suggest that the oxidative stress-mediating function of retinal Müller glial cells may be compromised in the absence of σ1R. The neuroprotective role of σ1R may be linked directly to the oxidative stress-mediating properties of supportive glial cells.


Assuntos
Sistema y+ de Transporte de Aminoácidos/metabolismo , Células Ependimogliais/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Receptores sigma/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Elementos de Resposta Antioxidante , Células Cultivadas , Proteínas do Citoesqueleto/metabolismo , Feminino , Glutationa/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Cultura Primária de Células , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Ativação Transcricional
16.
Inflamm Res ; 64(6): 377-81, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25902777

RESUMO

INTRODUCTION: The sigma-1 receptor (Sig-1R) is a unique ligand-regulated molecular chaperone that interacts with several protein targets such as G protein-coupled receptors and ion channels to modulate their activity. Sig-1R is located in areas of the central and peripheral nervous system that are key to pain control. Previous preclinical studies have suggested a potential therapeutic use of Sig-1R antagonists for the management of neuropathic pain. DISCUSSION: Recent studies using pharmacological and genetic tools have explored the role of Sig-1R in inflammatory pain conditions. Mice lacking the Sig-1R have shown different patterns of phenotypic responses to inflammatory injury. Systemic or peripheral administration of several Sig-1R antagonists, including the selective Sig-1R antagonist S1RA, inhibited both mechanical and thermal hypersensitivity in several preclinical models of inflammatory pain. These recent studies are summarized in the present commentary. CONCLUSION: Central and peripheral pharmacological blockade of Sig-1R could be an effective option to treat inflammatory pain.


Assuntos
Inflamação/fisiopatologia , Dor/fisiopatologia , Receptores sigma , Animais , Humanos , Inflamação/complicações , Camundongos , Dor/etiologia , Receptores sigma/antagonistas & inibidores , Receptores sigma/genética , Receptores sigma/fisiologia
17.
Behav Brain Res ; 287: 315-22, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25848705

RESUMO

Sigma-1 receptor (Sig-1R) has been proposed as a novel therapeutic target for drug and alcohol addiction. We have shown previously that Sig-1R agonists facilitate the reinforcing effects of ethanol and induce binge-like drinking, while Sig-1R antagonists on the other hand block excessive drinking in genetic and environmental models of alcoholism, without affecting intake in outbred non-dependent rats. Even though significant progress has been made in understanding the function of Sig-1R in alcohol reinforcement, its role in the early and late stage of alcohol addiction remains unclear. Administration of the selective Sig-1R antagonist BD-1063 dramatically reduced the acquisition of alcohol drinking behavior as well as the preference for alcohol in genetically selected TSRI Sardinian alcohol preferring (Scr:sP) rats; the treatment had instead no effect on total fluid intake, food intake or body weight gain, proving selectivity of action. Furthermore, BD-1063 dose-dependently decreased alcohol-seeking behavior in rats trained under a second-order schedule of reinforcement, in which responding is maintained by contingent presentation of a conditioned reinforcer. Finally, an innate elevation in Sig-1R protein levels was found in the nucleus accumbens of alcohol-preferring Scr:sP rats, compared to outbred Wistar rats, alteration which was normalized by chronic, voluntary alcohol drinking. Taken together these findings demonstrate that Sig-1R blockade reduces the propensity to both acquire alcohol drinking and to seek alcohol, and point to the nucleus accumbens as a potential key region for the effects observed. Our data suggest that Sig-1R antagonists may have therapeutic potential in multiple stages of alcohol addiction.


Assuntos
Consumo de Bebidas Alcoólicas/fisiopatologia , Comportamento de Procura de Droga/fisiologia , Receptores sigma/fisiologia , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Animais , Núcleo Central da Amígdala/metabolismo , Comportamento de Procura de Droga/efeitos dos fármacos , Etanol , Masculino , Núcleo Accumbens/metabolismo , Piperazinas/administração & dosagem , Ratos , Ratos Wistar , Receptores sigma/antagonistas & inibidores , Receptores sigma/metabolismo
19.
J Pharmacol Sci ; 127(1): 6-9, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25704012

RESUMO

Endoplasmic reticulum (ER) protein sigma-1 receptor represents unique chaperone activity in the central nervous system, and it exerts a potent influence on a number of neurotransmitter systems. Several lines of evidence suggest that activation of sigma-1 receptor plays a role in the pathophysiology of neuropsychiatric diseases, as well as in the mechanisms of some therapeutic drugs and neurosteroids. Preclinical studies showed that some selective serotonin reuptake inhibitors (SSRIs; fluvoxamine, fluoxetine, excitalopram), donepezil, and ifenprodil act as sigma-1 receptor agonists. Furthermore, sigma-1 receptor agonists could improve the N-methyl-D-aspartate (NMDA) antagonist phencyclidine (PCP)-induced cognitive deficits in mice. A study using positron emission tomography have demonstrated that an oral administration of fluvoxamine or donepezil could bind to sigma-1 receptor in the healthy human brain, suggesting that sigma-1 receptor might be involved in the therapeutic mechanisms of these drugs. Moreover, case reports suggest that sigma-1 receptor agonists, including fluvoxamine, and ifenprodil, may be effective in the treatment of cognitive impairment in schizophrenia, delirium in elderly people, and flashbacks in post-traumatic stress disorder. In this review article, the author would like to discuss the clinical implication of sigma-1 receptor agonists, including endogenous neurosteroids, in the neuropsychiatric diseases.


Assuntos
Indanos/farmacologia , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/fisiopatologia , Piperidinas/farmacologia , Receptores sigma/agonistas , Receptores sigma/fisiologia , Animais , Donepezila , Humanos , Modelos Neurológicos , Neurotransmissores/farmacologia , Inibidores de Captação de Serotonina/farmacologia , Inibidores de Captação de Serotonina/uso terapêutico
20.
J Pharmacol Sci ; 127(1): 10-6, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25704013

RESUMO

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease affecting spinal cord motoneurons (MN) with an associative connection to Frontotemporal Lobar Dementia (FTLD). The endoplasmic reticulum (ER) bound Sigma-1 Receptor (S1R) chaperone protein localizes to specialized ER cisternae within 10 nm of the plasma membrane in spinal cord ventral horn cholinergic post synaptic C-terminals. Removal of the S1R gene in the Superoxide Dismutase-1 (SOD-1) mouse model of ALS exacerbated the neurodegenerative condition and resulted in a significantly reduced longevity when compared to the SOD-1/S1R wild type (WT) mouse. The proposed amelioration of the ALS phenotype by the S1R is likely due to a "brake" on excitation of the MN as evidenced by a reduction in action potential generation in the MN of the WT when compared to the S1R KO mouse MN. Although the precise signal transduction pathway(s) regulated by the S1R in the MN has/have not been elucidated at present, it is likely that direct or indirect functional interactions occur between the S1R in the ER cisternae with voltage gated potassium channels and/or with muscarinic M2 receptor signaling in the post synaptic plasma membrane. Possible mechanisms for regulation of MN excitability by S1R are discussed.


Assuntos
Esclerose Amiotrófica Lateral/fisiopatologia , Receptores sigma/fisiologia , Potenciais de Ação/fisiologia , Esclerose Amiotrófica Lateral/genética , Animais , Humanos , Camundongos Knockout , Neurônios Motores/fisiologia , Neurônios Motores/ultraestrutura , Receptores sigma/genética
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