RESUMO
Major depressive disorder (MDD) is a global health burden characterized by persistent low mood, deprivation of pleasure, recurrent thoughts of death, and physical and cognitive deficits. The current understanding of the pathophysiology of MDD is lacking, resulting in few rapid and effective antidepressant therapies. Recent studies have pointed to the sigma-1 (σ-1) receptor as a potential rapid antidepressant target; σ-1 agonists have shown promise in a variety of preclinical depression models. Hypidone hydrochloride (YL-0919), an independently developed antidepressant by our institute with faster onset of action and low rate of side effects, has recently emerged as a highly selective σ-1 receptor agonist; however, its underlying astrocyte-specific mechanism is unknown. In this study, we investigated the effect of YL-0919 treatment on gene expression in the prefrontal cortex of depressive-like mice by single-cell RNA sequencing. Furthermore, we knocked down σ-1 receptors on astrocytes in the medial prefrontal cortex of mice to explore the effects of YL-0919 on depressive-like behavior and neuroinflammation in mice. Our results demonstrated that astrocyte-specific knockdown of σ-1 receptor resulted in depressive-like behavior in mice, which was reversed by YL-0919 administration. In addition, astrocytic σ-1 receptor deficiency led to activation of the NF-κB inflammatory pathway, and crosstalk between reactive astrocytes and activated microglia amplified neuroinflammation, exacerbating stress-induced neuronal apoptosis. Furthermore, the depressive-like behavior induced by astrocyte-specific knockdown of the σ-1 receptor was improved by a selective NF-κB inhibitor, JSH-23, in mice. Our study not only reaffirms the σ-1 receptor as a key target of the faster antidepressant effect of YL-0919, but also contributes to the development of astrocytic σ-1 receptor-based novel drugs.
Assuntos
Antidepressivos , Astrócitos , Transtorno Depressivo Maior , Camundongos Endogâmicos C57BL , NF-kappa B , Córtex Pré-Frontal , Receptores sigma , Receptor Sigma-1 , Receptores sigma/metabolismo , Receptores sigma/agonistas , Animais , Astrócitos/metabolismo , Astrócitos/efeitos dos fármacos , Camundongos , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Antidepressivos/farmacologia , NF-kappa B/metabolismo , Masculino , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/tratamento farmacológico , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/tratamento farmacológico , Modelos Animais de Doenças , Depressão/metabolismo , Depressão/tratamento farmacológicoRESUMO
The synthesis and pharmacological activity of a new series of thieno[2,3-d]pyrimidin-4(3H)-one derivatives as sigma-1 receptor (σ1R) ligands are reported. A hit from a high-throughput screening program was evolved into a highly potent and selective σ1R agonist (14qR) that contains a free NH group as positive ionizable moiety, not fulfilling the usual pharmacophoric features of the σ1R. The compound shows good physicochemical and ADMET characteristics, displays an agonist profile in the binding immunoglobulin protein/σ1R association assay, induces neuron viability in an in vitro model of ß-amyloid peptide intoxication, and presents positive results against recognition memory impairment induced by hippocampal injection of Aß peptide in rats after oral treatment, altogether making 14qR (WLB-87848) an interesting candidate for neuroprotection.
Assuntos
Fármacos Neuroprotetores , Receptores sigma , Receptor Sigma-1 , Animais , Receptores sigma/agonistas , Receptores sigma/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Ratos , Humanos , Masculino , Relação Estrutura-Atividade , Peptídeos beta-Amiloides/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Pirimidinas/farmacologia , Pirimidinas/síntese química , Pirimidinas/química , Transtornos da Memória/tratamento farmacológico , Sobrevivência Celular/efeitos dos fármacos , Pirimidinonas/farmacologia , Pirimidinonas/síntese química , Pirimidinonas/química , Ratos Wistar , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismoRESUMO
Spinal Cord Injury (SCI) is a debilitating disease associated with a significant economic burden owing to its high level of disability; however, current treatment options have only limited efficacy. Past research has shown that iron-dependent programmed cell death, also known as ferroptosis, plays a critical role in the pathogenesis of SCI. The sigma-1 receptor (Sig-1R) is widely distributed in the central nervous system, and has been implicated in the pathophysiology of several neurological and psychiatric disorders. Several in vivo and ex vivo studies have shown that Sig-1R activation exerts unique neuroprotective effects. However, the underlying mechanisms remain unclear. To date, no study has yet demonstrated the association between Sig-1R activation and ferroptosis in patients with SCI. However, the present study found that Sig-1R activation effectively promoted the recovery of motor function in mice after spinal cord injury, attenuated neuronal apoptosis, reduced the production of pro-inflammatory cytokines and iron accumulation, and inhibited ferroptosis in spinal cord tissues following SCI in mice. Ferroptosis and IRE1α were significantly upregulated after spinal cord injury, while sigma-1 receptor agonists were able to facilitate this result through the elimination of inositol-requiring enzyme-1 alpha (IRE1α)-mediated neuronal ferroptosis. Therefore, sigma-1 receptor activation could attenuate ferroptosis after SCI by reducing IRE1α and improving functional recovery after SCI, potentially representing a new therapeutic strategy for treating SCI.
Assuntos
Ferroptose , Camundongos Endogâmicos C57BL , Neurônios , Proteínas Serina-Treonina Quinases , Receptores sigma , Receptor Sigma-1 , Traumatismos da Medula Espinal , Traumatismos da Medula Espinal/metabolismo , Animais , Receptores sigma/metabolismo , Receptores sigma/agonistas , Ferroptose/fisiologia , Ferroptose/efeitos dos fármacos , Camundongos , Proteínas Serina-Treonina Quinases/metabolismo , Neurônios/metabolismo , Endorribonucleases/metabolismo , Masculino , Recuperação de Função Fisiológica/fisiologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Apoptose/fisiologia , Apoptose/efeitos dos fármacos , Medula Espinal/metabolismoRESUMO
BACKGROUND: Aberrant neuronal Sigma-1 receptor (Sig-1r)-mediated endoplasmic reticulum (ER)- mitochondria signaling plays a key role in the neuronal cytopathology of Alzheimer's disease (AD). The natural psychedelic N, N-dimethyltryptamine (DMT) is a Sig-1r agonist that may have the anti-AD potential through protecting neuronal ER-mitochondrial interplay. METHODS: 3×TG-AD transgenic mice were administered with chronic DMT (2 mg/kg) for 3 weeks and then performed water maze test. The Aß accumulation in the mice brain were determined. The Sig-1r level upon DMT treatment was tested. The effect of DMT on the ER-mitochondrial contacts site and multiple mitochondria-associated membrane (MAM)-associated proteins were examined. The effect of DMT on calcium transport between ER and mitochondria and the mitochondrial function were also evaluated. RESULTS: chronic DMT (2 mg/kg) markedly alleviated cognitive impairment of 3×TG-AD mice. In parallel, it largely diminished Aß accumulation in the hippocampus and prefrontal cortex. DMT restored the decreased Sig-1r levels of 3×TG-AD transgenic mice. The hallucinogen reinstated the expression of multiple MAM-associated proteins in the brain of 3×TG-AD mice. DMT also prevented physical contact and calcium dynamic between the two organelles in in vitro and in vivo pathological circumstances. DMT modulated oxidative phosphorylation (OXPHOS) and ATP synthase in the in vitro model of AD. CONCLUSION: The anti-AD effects of DMT are associated with its protection of neuronal ER-mitochondria crosstalk via the activation of Sig-1r. DMT has the potential to serve as a novel preventive and therapeutic agent against AD.
Assuntos
Doença de Alzheimer , Retículo Endoplasmático , Alucinógenos , Camundongos Transgênicos , Mitocôndrias , N,N-Dimetiltriptamina , Receptores sigma , Receptor Sigma-1 , Animais , Receptores sigma/metabolismo , Receptores sigma/agonistas , Doença de Alzheimer/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Camundongos , Alucinógenos/farmacologia , N,N-Dimetiltriptamina/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , MasculinoRESUMO
Cardiovascular and renal diseases are among the leading causes of death worldwide, and regardless of current efforts, there is a demanding need for therapeutic alternatives to reduce their progression to advanced stages. The stress caused by diseases leads to the activation of protective mechanisms in the cell, including chaperone proteins. The Sigma-1 receptor (Sig-1R) is a ligand-operated chaperone protein that modulates signal transduction during cellular stress processes. Sig-1R interacts with various ligands and proteins to elicit distinct cellular responses, thus, making it a potential target for pharmacological modulation. Furthermore, Sig-1R ligands activate signaling pathways that promote cardioprotection, ameliorate ischemic injury, and drive myofibroblast activation and fibrosis. The role of Sig-1R in diseases has also made it a point of interest in developing clinical trials for pain, neurodegeneration, ischemic stroke, depression in patients with heart failure, and COVID-19. Sig-1R ligands in preclinical models have significantly beneficial effects associated with improved cardiac function, ventricular remodeling, hypertrophy reduction, and, in the kidney, reduced ischemic damage. These basic discoveries could inform clinical trials for heart failure (HF), myocardial hypertrophy, acute kidney injury (AKI), and chronic kidney disease (CKD). Here, we review Sig-1R signaling pathways and the evidence of Sig-1R modulation in preclinical cardiac and renal injury models to support the potential therapeutic use of Sig-1R agonists and antagonists in these diseases.
Assuntos
Doenças Cardiovasculares , Nefropatias , Receptores sigma , Humanos , Cardiomegalia , COVID-19/complicações , Insuficiência Cardíaca/complicações , Ligantes , Receptores sigma/agonistas , Receptores sigma/antagonistas & inibidores , Receptores sigma/genética , Receptores sigma/metabolismo , Transdução de Sinais/fisiologia , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Nefropatias/complicações , Nefropatias/genética , Nefropatias/metabolismo , Receptor Sigma-1RESUMO
To develop safer and potent analgesics, we designed, synthesized, and evaluated a new series of benzylaminofentanyl derivates as bifunctional µ opioid receptor (MOR) and σ1 receptor (σ1R) ligands. Compound 68 (Tao-191) showed desirable MOR agonism (Ki = 6.5 nΜ; EC50 = 48.5 nΜ, Emax = 66.3%) and σ1R antagonism (Ki = 35.7 nM) in vitro, and exerted powerful analgesic effects in the abdominal constriction test (ED50 = 0.32 mg/kg, in mice), formalin-induced pain test (phase II, ED50 = 2.26 mg/kg, in rats), and paclitaxel-induced neuropathic pain model (ED50 = 0.30 mg/kg, in mice). The contributions of MOR and σ1R to its antinociceptive effect were verified by combined administration with the MOR antagonist naloxone and the σ1R agonist PRE-084, respectively. At equianalgesic doses, compound 68 induced fewer MOR-related side effects-including physical and psychological dependence, respiratory depression, constipation, and acute hyperlocomotion-than fentanyl. The results provide a rationale for further exploration of the action and safety of dual MOR/σ1R ligands as a promising avenue for the development of potent and safe analgesics.
Assuntos
Analgésicos , Neuralgia , Receptores Opioides mu , Receptores sigma , Analgésicos/farmacologia , Animais , Ligantes , Camundongos , Naloxona/farmacologia , Ratos , Receptores Opioides mu/agonistas , Receptores Opioides mu/antagonistas & inibidores , Receptores sigma/agonistas , Receptores sigma/antagonistas & inibidores , Receptor Sigma-1RESUMO
BACKGROUND: Angiogenesis plays a critical role on post-infarction heart failure (PIHF), the presence of which facilitates additional blood supply to maintain the survival of residual cardiomyocytes. The sigma-1 receptor (S1R) has been substantiated to stimulate angiogenesis, with the effect on a model of PIHF remaining unknown. AIMS: This study aims to investigate the effects of S1R on PIHF and the underlying mechanisms involved. METHODS: Rats were implemented left anterior descending artery ligation followed by rearing for 6 weeks to induce a phenotype of heart failure. Daily intraperitoneal injection of S1R agonist or antagonist for 5 weeks was applied from 2nd week after surgery. The effects exerted by S1R were detected by echocardiography, hemodynamic testing, western blot, Sirius red dyeing, ELISA, immunohistochemistry and fluorescence. We also cultured HUVECs to verify the mechanisms in vitro. RESULTS: Stimulation of S1R significantly ameliorated the cardiac function resulted from PIHF, in addition to the observation of reduced fibrosis in the peri-infarct region and the apoptosis of residual cardiomyocytes, which were associated with augmentation of microvascular density in peri-infarct region through activation of the JAK2/STAT3 pathway. We also indicated that suppression of JAK2/STAT3 pathway by specific inhibitor in vitro reversed the pro-angiogenic effects of S1R on HUVECs, which further confirmed that angiogenesis, responsible for PIHF amelioration, by S1R stimulation was in a JAK2/STAT3 pathway-dependent manner. CONCLUSION: S1R stimulation improved PIHF-induced cardiac dysfunction and ventricular remodeling through promoting angiogenesis by activating the JAK2/STAT3 pathway.
Assuntos
Insuficiência Cardíaca , Receptores sigma , Animais , Infarto , Ratos , Receptores sigma/agonistas , Receptores sigma/metabolismo , Roedores/metabolismo , Fator de Transcrição STAT3/metabolismo , Receptor Sigma-1RESUMO
Though a great many of studies on the development of antidepressants for the therapy of major depression disorder (MDD) and the development of antidepressants have been carried out, there still lacks an efficient approach in clinical practice. The involvement of Sigma-1 receptor in the pathological process of MDD has been verified. In this review, recent research focusing on the role of Sigma-1 receptor in the etiology of MDD were summarized. Preclinical studies and clinical trials have found that stress induce the variation of Sigma-1 receptor in the blood, brain and heart. Dysfunction and absence of Sigma-1 receptor result in depressive-like behaviors in rodent animals. Agonists of Sigma-1 receptor show not only antidepressant-like activities but also therapeutical effects in complications of depression. The mechanisms underlying antidepressant-like effects of Sigma-1 receptor may include suppressing neuroinflammation, regulating neurotransmitters, ameliorating brain-derived neurotrophic factor and N-Methyl-D-Aspartate receptor, and alleviating the endoplasmic reticulum stress and mitochondria damage during stress. Therefore, Sigma-1 receptor represents a potential target for antidepressants development.
Assuntos
Transtorno Depressivo Maior , Receptores sigma , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Receptores de N-Metil-D-Aspartato , Receptores sigma/agonistas , Receptor Sigma-1RESUMO
Sigma-1 receptor (S1R) is an important endoplasmic reticulum chaperone with various functions in health and disease. The purpose of the current work was to elucidate the involvement of S1R in cancer energy metabolism under its basal, activated, and inactivated states. For this, two cancer cell lines that differentially express S1R were treated with S1R agonist, (+)-SKF10047, and antagonist, BD1047. The effects of the agonist and antagonist on cancer energy metabolism were studied using single-cell fluorescence microscopy analysis of real-time ion and metabolite fluxes. Our experiments revealed that S1R activation by agonist increases mitochondrial bioenergetics of cancer cells while decreasing their reliance on aerobic glycolysis. S1R antagonist did not have a major impact on mitochondrial bioenergetics of tested cell lines but increased aerobic glycolysis of S1R expressing cancer cell line. Our findings suggest that S1R plays an important role in cancer energy metabolism and that S1R ligands can serve as tools to modulate it.
Assuntos
Neoplasias , Receptores sigma , Retículo Endoplasmático/metabolismo , Metabolismo Energético , Ligantes , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Receptores sigma/agonistas , Receptores sigma/metabolismo , Receptor Sigma-1Assuntos
Encefalopatias , Síndrome do Cromossomo X Frágil , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Proteína do X Frágil da Deficiência Intelectual , Síndrome do Cromossomo X Frágil/genética , Furanos , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores sigma/agonistas , Transdução de Sinais , Receptor Sigma-1RESUMO
Peripheral nerve injuries lead to the loss of motor, sensory and autonomic functions in the territories supplied by the injured nerve. Currently, nerve injuries are managed by surgical repair procedures, and there are no effective drugs in the clinic for improving the capacity of axonal regeneration. Sigma-1 receptor (Sig-1R) is an endoplasmic reticulum chaperon protein involved in many functions, including neuroprotection and neuroplasticity. A few previous studies using Sig-1R ligands reported results that suggest this receptor as a putative target to enhance regeneration. The aim of this study was to evaluate the possible effects of Sig-1R ligands on axonal regeneration in a sciatic nerve section and repair model in mice. To this end, mice were treated either with the Sig-1R agonist PRE-084 or the antagonist BD1063, and a Sig-1R knock-out (KO) mice group was also studied. The electrophysiological and histological data showed that treatment with Sig-1R ligands, or the lack of this protein, did not markedly modify the process of axonal regeneration and target reinnervation after sciatic nerve injury. Nevertheless, the nociceptive tests provided results indicating a role of Sig-1R in sensory perception after nerve injury, and immunohistochemical labeling indicated a regulatory role in inflammatory cell infiltration in the injured nerve.
Assuntos
Traumatismos dos Nervos Periféricos , Receptores sigma , Animais , Ligantes , Camundongos , Camundongos Knockout , Regeneração Nervosa , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Receptores sigma/agonistas , Receptor Sigma-1RESUMO
The Wolfram syndrome is a rare autosomal recessive disease affecting many organs with life-threatening consequences; currently, no treatment is available. The disease is caused by mutations in the WSF1 gene, coding for the protein wolframin, an endoplasmic reticulum (ER) transmembrane protein involved in contacts between ER and mitochondria termed as mitochondria-associated ER membranes (MAMs). Inherited mutations usually reduce the protein's stability, altering its homeostasis and ultimately reducing ER to mitochondria calcium ion transfer, leading to mitochondrial dysfunction and cell death. In this study, we found that activation of the sigma-1 receptor (S1R), an ER-resident protein involved in calcium ion transfer, could counteract the functional alterations of MAMs due to wolframin deficiency. The S1R agonist PRE-084 restored calcium ion transfer and mitochondrial respiration in vitro, corrected the associated increased autophagy and mitophagy, and was able to alleviate the behavioral symptoms observed in zebrafish and mouse models of the disease. Our findings provide a potential therapeutic strategy for treating Wolfram syndrome by efficiently boosting MAM function using the ligand-operated S1R chaperone. Moreover, such strategy might also be relevant for other degenerative and mitochondrial diseases involving MAM dysfunction.
Assuntos
Receptores sigma , Síndrome de Wolfram , Animais , Cálcio/metabolismo , Feminino , Humanos , Masculino , Camundongos , Receptores sigma/agonistas , Peixe-Zebra/metabolismo , Receptor Sigma-1RESUMO
Fenfluramine (N-ethyl-α-methl-3-(trifluoromethyl)phenethylamine) is an anti-seizure medication (ASM) particularly effective in patients with Dravet syndrome, a severe treatment-resistant epileptic encephalopathy. Fenfluramine acts not only as neuronal serotonin (5-HT) releaser but also as a positive modulator of the sigma-1 receptor (S1R). We here examined the modulatory activity of Fenfluramine on the S1R-mediated anti-amnesic response in mice using combination analyses. Fenfluramine and Norfenfluramine, racemate and isomers, were combined with either the S1R agonist (PRE-084) or the S1R-acting neuro(active)steroids, pregnenolone sulfate (PREGS), Dehydroepiandrosterone sulfate (DHEAS), or progesterone. We report that Fenfluramine racemate or (+)-Fenfluramine, in the 0.1-1â¯mg/kg dose range, attenuated the dizocilpine-induced learning deficits in spontaneous alternation and passive avoidance, and showed low-dose synergies in combination with PRE-084. These effects were blocked by the S1R antagonist NE-100. Dehydroepiandrosterone sulfate or PREGS attenuated dizocilpine-induced learning deficits in the 5-20â¯mg/kg dose range. Co-treatments at low dose between steroids and Fenfluramine or (+)-Fenfluramine were synergistic. Progesterone blocked Fenfluramine effect. Finally, Fenfluramine and (+)-Fenfluramine effects were prevented by the 5-HT1A receptor antagonist WAY-100635 or 5-HT2A antagonist RS-127445, but not by the 5-HT1B/1D antagonist GR 127935 or the 5-HT2C antagonist SB 242084, confirming a 5-HT1A and 5-HT2A receptor involvement in the drug effect on memory. We therefore confirmed the positive modulation of Fenfluramine racemate or dextroisomer on S1R and showed that, in physiological conditions, the drug potentiated the low dose effects of neuro(active)steroids, endogenous S1R modulators. The latter are potent modulators of the excitatory/inhibitory balance in the brain, and their levels must be considered in the antiepileptic action of Fenfluramine.
Assuntos
Fenfluramina , Receptores sigma , Animais , Relação Dose-Resposta a Droga , Fenfluramina/farmacologia , Fenfluramina/uso terapêutico , Humanos , Aprendizagem , Camundongos , Receptores sigma/agonistas , Esteroides/farmacologia , Receptor Sigma-1RESUMO
Sigma-2 receptor/TMEM97 is overexpressed in many tumours, and sigma-2 receptor ligands are under investigation for cancer therapy. We intended to evaluate the effect of PB28 on renal cancer in proliferation, migration and invasion in vitro and in vivo. Invasive renal cancer cell lines treated with PB28 (or sigma-2 receptor antagonist 1) were subjected to cell proliferation, migration and invasion assays. The therapeutic effect of PB28 was performed on nude mice. Western blot for proteins in the PI3K-AKT-mTOR signalling pathway was conducted. A CCK-8 assay was used to examine the effect of the combination of PB28 and cisplatin on renal cancer cells. Significant inhibitory effects were observed on proliferation, migration and invasion of 786-O and ACHN cells after culturing with PB28. But, the outcomes of sigma-2 receptor antagonist 1 presented the opposite tendency. PB28 significantly inhibited the proliferative and invasive ability of OS-RC-2 cells in vivo. Treatment resulted in decreased phosphorylation of constituents of the PI3K-AKT-mTOR pathway. The combination of PB28 and cisplatin showed enhanced efficacy in the inhibition of renal cancer cell proliferation. Taken together, PB28 inhibited the tumorigenic behaviours of renal cancer cells by regulating the PI3K-AKT-mTOR signalling pathway and was expected to be a sensitizer of cisplatin.
Assuntos
Proteínas de Membrana/agonistas , Fosfatidilinositol 3-Quinases/metabolismo , Piperazinas/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores sigma/agonistas , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Animais , Carcinoma de Células Renais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Camundongos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Optic neuropathies such as glaucoma are characterized by retinal ganglion cell (RGC) degeneration and death. The sigma-1 receptor (S1R) is an attractive target for treating optic neuropathies as it is highly expressed in RGCs, and its absence causes retinal degeneration. Activation of the S1R exerts neuroprotective effects in models of retinal degeneration. Pridopidine is a highly selective and potent S1R agonist in clinical development. We show that pridopidine exerts neuroprotection of retinal ganglion cells in two different rat models of glaucoma. Pridopidine strongly binds melanin, which is highly expressed in the retina. This feature of pridopidine has implications to its ocular distribution, bioavailability, and effective dose. Mitochondria dysfunction is a key contributor to retinal ganglion cell degeneration. Pridopidine rescues mitochondrial function via activation of the S1R, providing support for the potential mechanism driving its neuroprotective effect in retinal ganglion cells.
Assuntos
Glaucoma/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Piperidinas/farmacologia , Receptores sigma/agonistas , Células Ganglionares da Retina/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Glaucoma/metabolismo , Glaucoma/patologia , Mitocôndrias/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Piperidinas/administração & dosagem , Ratos , Espécies Reativas de Oxigênio/metabolismo , Células Ganglionares da Retina/metabolismo , Receptor Sigma-1RESUMO
Exposure to stress plays a detrimental role in the pathogenesis of hypertension via neuroinflammation pathways. Microglial neuroinflammation in the rostral ventrolateral medulla (RVLM) exacerbates stress-induced hypertension (SIH) by increasing sympathetic hyperactivity. Mitochondria of microglia are the regulators of innate immune response. Sigma-1R (σ-1R) localizes to the mitochondria-associated membranes (MAMs) and regulates endoplasmic reticulum (ER) and mitochondria communication, in part through its chaperone activity. The present study aims to investigate the protective role of σ-1R on microglial-mediated neuroinflammation. Stress-induced hypertension (SIH) was induced in rats using electric foot shocks and intermittent noise. Arterial blood pressure (ABP), heart rate (HR), and renal sympathetic nerve activity (RSNA) were measured to evaluate the sympathetic nervous system (SNS) activities. SKF10047 (100 µM), an agonist of σ-1R, was administrated to rats, then σ-1R localization and MAM alterations were detected by immuno-electron microscopy. Mitochondrial calcium homeostasis was examined in primary microglia and/or BV-2 microglia cells. The effect of SKF10047 treatment on the mitochondrial respiratory function of cultured microglia was measured using a Seahorse Extracellular Flux Analyzer. Confocal microscopic images were performed to indicate mitochondrial dynamics. Stress reduces σ-1R's localization at the MAMs, leading to decreased ER-mitochondria contact and IP3R-GRP75-VDAC calcium transport complexes expression in the RVLM of rats. SKF10047 promotes the length and coverage of MAMs in the prorenin-treated microglia. Prorenin treatment increases mitoROS levels, and inhibits Ca2+ signalling between the two organelles, therefore negatively affects ATP production in BV2 cells, and these effects are reversed by SKF10047 treatment. We found mitochondrial hyperfusion and microglial M1 polarization in prorenin-treated microglia. SKF10047 suppresses microglial M1 polarization and RVLM neuroinflammation, subsequently ameliorates sympathetic hyperactivity in stress-induced hypertensive rats. Sigma-1 receptor activation suppresses microglia M1 polarization and neuroinflammation via regulating endoplasmic reticulum-mitochondria contact and mitochondrial functions in stress-induced hypertension rats.
Assuntos
Retículo Endoplasmático/metabolismo , Hipertensão/metabolismo , Microglia/metabolismo , Mitocôndrias/metabolismo , Receptores sigma/agonistas , Animais , Pressão Sanguínea/fisiologia , Cálcio/metabolismo , Polaridade Celular/efeitos dos fármacos , Eletrochoque/efeitos adversos , Retículo Endoplasmático/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Hipertensão/etiologia , Hipertensão/fisiopatologia , Mitocôndrias/efeitos dos fármacos , Fenazocina/análogos & derivados , Fenazocina/farmacologia , Ratos , Sistema Nervoso Simpático/metabolismo , Sistema Nervoso Simpático/fisiopatologia , Receptor Sigma-1RESUMO
Sigma1 Receptor (S1R) is involved in oxidative stress, since its activation is triggered by oxidative or endoplasmic reticulum stress. Since specific aquaporins (AQP), called peroxiporins, play a relevant role in controlling H2O2 permeability and ensure reactive oxygen species wasted during oxidative stress, we studied the effect of S1R modulators on AQP-dependent water and hydrogen peroxide permeability in the presence and in the absence of oxidative stress. Applying stopped-flow light scattering and fluorescent probe methods, water and hydrogen peroxide permeability in HeLa cells have been studied. Results evidenced that S1R agonists can restore water permeability in heat-stressed cells and the co-administration with a S1R antagonist totally counteracted the ability to restore the water permeability. Moreover, compounds were able to counteract the oxidative stress of HeLa cells specifically knocked down for S1R. Taken together these results support the hypothesis that the antioxidant mechanism is mediated by both S1R and AQP-mediated H2O2 permeability. The finding that small molecules can act on both S1R and AQP-mediated H2O2 permeability opens a new direction toward the identification of innovative drugs able to regulate cell survival during oxidative stress in pathologic conditions, such as cancer and degenerative diseases.
Assuntos
Aquaporinas/metabolismo , Peróxido de Hidrogênio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Receptores sigma/genética , Aquaporinas/genética , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Células HeLa , Humanos , Permeabilidade/efeitos dos fármacos , Peroxirredoxinas/genética , Peroxirredoxinas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores sigma/agonistas , Receptores sigma/metabolismo , Receptor Sigma-1RESUMO
Fragile X syndrome (FXS), a disorder of synaptic development and function, is the most prevalent genetic form of intellectual disability and autism spectrum disorder. FXS mouse models display clinically-relevant phenotypes, such as increased anxiety and hyperactivity. Despite their availability, so far advances in drug development have not yielded new treatments. Therefore, testing novel drugs that can ameliorate FXS' cognitive and behavioral impairments is imperative. ANAVEX2-73 (blarcamesine) is a sigma-1 receptor (S1R) agonist with a strong safety record and preliminary efficacy evidence in patients with Alzheimer's disease and Rett syndrome, other synaptic neurodegenerative and neurodevelopmental disorders. S1R's role in calcium homeostasis and mitochondrial function, cellular functions related to synaptic function, makes blarcamesine a potential drug candidate for FXS. Administration of blarcamesine in 2-month-old FXS and wild type mice for 2 weeks led to normalization in two key neurobehavioral phenotypes: open field test (hyperactivity) and contextual fear conditioning (associative learning). Furthermore, there was improvement in marble-burying (anxiety, perseverative behavior). It also restored levels of BDNF, a converging point of many synaptic regulators, in the hippocampus. Positron emission tomography (PET) and ex vivo autoradiographic studies, using the highly selective S1R PET ligand [18F]FTC-146, demonstrated the drug's dose-dependent receptor occupancy. Subsequent analyses also showed a wide but variable brain regional distribution of S1Rs, which was preserved in FXS mice. Altogether, these neurobehavioral, biochemical, and imaging data demonstrates doses that yield measurable receptor occupancy are effective for improving the synaptic and behavioral phenotype in FXS mice. The present findings support the viability of S1R as a therapeutic target in FXS, and the clinical potential of blarcamesine in FXS and other neurodevelopmental disorders.
Assuntos
Síndrome do Cromossomo X Frágil/tratamento farmacológico , Furanos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Receptores sigma/agonistas , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/genética , Furanos/farmacocinética , Furanos/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/farmacocinética , Fármacos Neuroprotetores/farmacologia , Fenótipo , Ligação Proteica , Receptores sigma/metabolismo , Receptor Sigma-1RESUMO
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