1-(3-4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine-dihydrochloride and Disease-Models--Animal

Sigma (sigma) receptors, first defined as a subclass of opioid receptors, later confounded with the high affinity phencyclidine (PCP) binding sites, now are regarded as unique binding sites, distinct from opiate and PCP receptors, and related to higher brain function. The investigation of functional significance of sigma receptors in the brain has been hampered for many years by relative lack of specific tool drugs and by the unavailability of their coherent classification into postulated agonists and antagonists. However, a potential involvement of sigma receptors in psychotic disorders was first suggested soon after their discovery. The sigma receptors are classified into two subtypes, sigma (1) and sigma (2) receptors, of which the first was recently cloned from rodent and human tissues while the second has not yet been fully characterized. Although the precise mechanism of the functional response of these receptors is still uncertain, it is accepted that sigma receptors can modulate a number of central neurotransmitter systems, including noradrenergic, glutamatergic and dopaminergic ones. The sigma receptors have been postulated to be involved in numerous pharmacological and physiological functions, including motor disorders, psychotic disorders, neuroprotective mechanisms. In the last years, a number of compounds with a high affinity and selectivity for sigma binding sites have been discovered and investigated for their therapeutic potential. In this review, we try to summarize the behavioral effects of sigma receptor ligands that have been described, and their activity in animal models related to some brain disorders, especially schizophrenia and affective disorders.

Topics: Amnesia; Animals; Antidepressive Agents; Cinnamates; Cocaine-Related Disorders; Cyclopropanes; Disease Models, Animal; Drug Interactions; Humans; Hypericum; Ligands; Nootropic Agents; Piperazines; Plant Extracts; Psychopharmacology; Psychotic Disorders; Quinolones; Receptors, sigma; Steroids

Both traditional and novel sigma (sigma)-receptor agonists have been reported to possess anti-amnesic effects in rodents. In particular, the anti-amnesic effects induced by the novel sigma1-receptor agonists, such as (+)-pentazocine, SA4503 and PRE-084, were shown in beta amyloid-peptide-induced, basal forebrain (BF)-lesioned and carbon monoxide (CO)-induced amnesia models and senescence-accelerated mouse (SAM). In addition, these sigma1-receptor agonists have good profiles for the central acetylcholine and dopamine systems. Moreover, they also have neuroprotective and anti-depressive effects. These evidence suggested that the sigma1-receptor agonists may be promising compounds for the treatment of dementing disorders such as Alzheimer's disease, senile dementia and vascular dementia. However, the sigma-receptor family is still considered to be enigmatic molecular targets. More molecular cloning and biochemical studies on the sigma-receptor family are needed.

Topics: Acetylcholine; Amnesia; Animals; Disease Models, Animal; Dopamine; Ligands; Mice; Morpholines; Pentazocine; Phenazocine; Piperazines; Receptors, sigma; Sigma-1 Receptor

Sigma 1 receptor is a novel therapeutic target for retinal disease. Its activation, using a high-affinity, high-specificity ligand (+)-pentazocine ((+)-PTZ), rescues photoreceptor cells in the rd10 mouse model of RP. Here, we asked whether the robust retinal neuroprotective properties of (+)-PTZ are generalizable to SA4503 and PRE084, two other high-affinity sigma 1 receptor ligands.. We treated 661W cells with SA4503 or PRE084. Cell viability, oxidative stress, and expression of Nrf2 and NRF2-regulated antioxidant genes (Nqo1, Cat, and Sod1) were assessed. Rd10 mice were administered SA4503 (1 mg/kg), PRE084 (0.5 mg/kg), or (+)-PTZ (0.5 mg/kg). Visual acuity, retinal architecture, and retinal electrophysiologic function were measured in vivo and retinal structure was assessed histologically.. Similar to (+)-PTZ, SA4503 and PRE084 improved cell viability, attenuated oxidative stress, and increased Nrf2, Nqo1 and Cat expression. Although treatment of rd10 mice with (+)-PTZ improved visual acuity, increased outer retinal thickness, and improved photopic a- and b-wave responses compared with nontreated rd10 mice, treatment with SA4503 or PRE084 did not. The number of photoreceptor nuclei/100 µm retinal length in SA4503- and PRE084-treated rd10 mice (approximately 11/100) did not differ significantly from nontreated rd10 mice, whereas (+)-PTZ-treated mice had significantly more nuclei (approximately 22/100 µm).. Cell survival and gene regulation experiments yielded similar outcomes when SA4503, PRE084, or (+)-PTZ were conducted in vitro, however neither SA4503 or PRE084 afforded in vivo protection in the severe rd10 retinopathy model comparable to (+)-PTZ. Despite all three compounds demonstrating the potential to activate sigma 1 receptor, the retinal neuroprotective properties of the three ligands differ significantly.

Topics: Animals; Catalase; Cell Line; Cell Survival; Disease Models, Animal; Electroretinography; Gene Expression Regulation; Ligands; Mice; Mice, Inbred C57BL; Morpholines; NAD(P)H Dehydrogenase (Quinone); Nootropic Agents; Oxidative Stress; Pentazocine; Piperazines; Receptors, sigma; Retina; Retinal Cone Photoreceptor Cells; Retinitis Pigmentosa; Sigma-1 Receptor; Superoxide Dismutase-1; Visual Acuity

Global cerebral ischemic/reperfusion (I/R) injury after cardiac arrest (CA) is a major cause of mortality and morbidity in survivors of resuscitation. We utilized a rat model of asphyxia CA to explore the functional effects and mechanisms of Sigma-1 receptor (Sig-1R) activation in cerebral protection using the Sig-1R agonist cutamesine (SA-4503).. After resuscitation, the surviving rats were randomly divided into three groups (n = 18 each): the cardiopulmonary resuscitation (CPR) group (0.9% saline at 1 mL/kg); the SA4503 low-dose group (1 mg/kg SA4503); and the SA4503 high-dose group (2.5 mg/kg SA4503). The neurological deficit scores were recorded, and the cerebral cortex was harvested for western blotting. Mitochondrial transmembrane potential, adenosine triphosphate (ATP) concentrations, calcium homeostasis, and mitochondrial ultrastructure were also studied.. The SA4503 treatment groups exhibited improved neurological outcomes compared with the CPR group. The protein levels of caspase-3 and the endoplasmic reticulum stress markers C/EBP homologous protein and caspase-12 were lower in the SA4503 treatment groups compared with the CPR group. SA4503 treatment also normalized mitochondrial membrane potential, tissue ATP concentrations, intracellular Ca overload, and upregulated Sig-1R protein level compared with the CPR group. The SA4503 high dose treatment showed significant cerebral protective effects compared with the SA4503 low dose treatment. The therapeutic effect of SA4503 was dose-dependent.. CA downregulated Sig-1R protein expression. Activating Sig-1R using SA4503 protected against global cerebral I/R injury in a rat model of asphyxia CA by alleviating endoplasmic reticulum stress and mitochondrial dysfunction and eventually inhibiting neuronal apoptosis.

Topics: Animals; Apoptosis; Asphyxia; Brain; Disease Models, Animal; Endoplasmic Reticulum Stress; Heart Arrest; Male; Neurons; Piperazines; Rats; Rats, Sprague-Dawley; Receptors, sigma; Reperfusion Injury; Resuscitation; Sigma-1 Receptor

α-thalassemia X-linked intellectual disability (ATR-X) syndrome is caused by mutations in

Topics: alpha-Thalassemia; Animals; Brain-Derived Neurotrophic Factor; Cells, Cultured; Cognitive Dysfunction; Disease Models, Animal; Ligands; Male; Mental Retardation, X-Linked; Mice, Inbred C57BL; Neuroprotective Agents; Piperazines; Receptors, sigma; Sigma-1 Receptor

Aberrations in intracellular calcium (Ca

Topics: Amyotrophic Lateral Sclerosis; Animals; Calcium; Calcium Signaling; Cells, Cultured; Disease Models, Animal; Humans; Male; Mice, Inbred C57BL; Mice, Transgenic; Motor Neurons; Piperazines; Receptors, AMPA; Receptors, sigma; Sigma-1 Receptor; Spinal Cord; Superoxide Dismutase-1

Cardiovascular diseases are risk factors for depression in humans. We recently proposed that σ1 receptor (σ1R) stimulation rescued cardiac hypertrophy and heart failure induced by transverse aortic constriction (TAC) in mice. Importantly, σ1R stimulation reportedly ameliorates depression-like behaviors in rodents. Thus, we hypothesized that impaired σ1R activity in brain triggers depression-like behaviors in animals with cardiovascular disease. Indeed, here we found that cardiac hypertrophy and heart failure induced by TAC were associated with depression-like behaviors concomitant with downregulation of σ1R expression in brain 6 weeks after surgery. σ1R levels significantly decreased in astrocytes in both the hippocampal CA1 region and dentate gyrus. Oral administration of the specific σ1R agonist SA4503 (0.3-1.0mg/kg) significantly improved TAC-induced depression-like behaviors concomitant with rescued astrocytic σ1R expression in CA1 and the dentate gyrus. Plasma corticosterone levels significantly increased 6 weeks after TAC, and chronic treatment of mice with corticosterone for 3 weeks elicited depression-like behaviors concomitant with reduced astrocytic σ1R expression in hippocampus. Furthermore, the glucocorticoid receptor antagonist mifepristone antagonized depressive-like behaviors and ameliorated decreased hippocampal σ1R expression in TAC mice. We conclude that elevated corticosterone levels trigger hippocampal σ1R downregulation and that σ1R stimulation with SA4503 is an attractive therapy to improve not only cardiac dysfunction but depression-like behaviors associated with heart failure.

Topics: Adenosine Triphosphate; Administration, Oral; Animals; Aorta; Behavior, Animal; Cardiomegaly; Corticosterone; Dentate Gyrus; Depression; Disease Models, Animal; Down-Regulation; Echocardiography; Heart Failure; Hippocampus; Male; Mice; Mice, Inbred ICR; Mifepristone; Piperazines; Receptors, sigma

The sigma-1 receptor, which is expressed throughout the brain, provides physiological benefits that include higher brain function. The sigma-1 receptor functions as a chaperone in the endoplasmic reticulum and may control cell death and regeneration within the central nervous system. Cutamesine (1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl) piperazine dihydrochloride) is a ligand selective for this receptor and may mediate neuroprotective effects in the context of neurodegenerative disease. We therefore assessed whether cutamesine protects the inner ear from noise-induced or aging-associated hearing loss. Immunohistochemistry and Western blotting revealed that the sigma-1 receptor is present in adult cochlea. We treated mice with 0, 3, or 30 mg/kg cutamesine from 10 days before noise exposure until the end of the study. All subjects were exposed to a 120-dB, 4-kHz octave-band noise for 2 hr. We assessed auditory thresholds by measuring the auditory-evoked brainstem responses at 4, 8, and 16 kHz, prior to and 1 week, 1 month, or 3 months following noise exposure. For the aging study, measurements were made before treatment was initiated and after 3 or 9 months of cutamesine treatment. Damage to fibrocytes within the cochlear spiral limbus was assessed by quantitative histology. Cutamesine significantly reduced threshold shifts and cell death within the spiral limbus in response to intense noise. These effects were not dose or time dependent. Conversely, cutamesine did not prevent aging-associated hearing loss. These results suggest that cutamesine reduces noise-induced hearing loss and cochlear damage during the acute phase that follows exposure to an intense noise.

Topics: Acoustic Stimulation; Acoustics; Age Factors; Animals; Animals, Newborn; Cochlea; Disease Models, Animal; Evoked Potentials, Auditory, Brain Stem; Follow-Up Studies; Gene Expression Regulation; Hearing Loss, Noise-Induced; Male; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Organ of Corti; Piperazines; Receptors, sigma; Sodium-Potassium-Exchanging ATPase

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease. Recently, it has been reported that a mutation in the sigma-1 receptor causes juvenile ALS. Therefore, the function of the sigma-1 receptor may be important in the pathology of ALS. In the present study, we investigated the effect of SA4503, a sigma-1 receptor agonist, against in in vitro and in vivo ALS models. We first investigated whether SA4503, a sigma-1 receptor agonist, prevented superoxide dismutase 1 (SOD1(G93A))- and serum free-induced cell death of mice motor neuron cells (NSC34) in in vitro model of an ALS. At concentrations of 1-10μM, SA4503 reduced SOD1(G93A)-induced cell death in a concentration-dependent manner, and BD1047, a sigma-1 receptor antagonist, inhibited the protective effect of SA4503. Next, we investigated whether SA4503 affected the phosphorylation levels of Akt (Ser 473) and extracellular signal-regulated kinase (ERK) 1/2 and the expression of the sigma-1 receptor. SA4503 promoted the phosphorylation of Akt (Ser 473) and ERK1/2 in a time-dependent manner, but SA4503 did not affect the expression of the sigma-1 receptor. These results suggest that the protective effect of SA4503 might be involved in promoting the phosphorylation of Akt and ERK1/2. We then investigated whether SA4503 suppressed the progression of ALS in an SOD1(G93A) ALS mouse model. SA4503 did not affect the onset time of ALS. However, it significantly extended the survival time in the SOD1(G93A) mice compared with a vehicle-treated group. These findings indicate that SA4503 is effective in suppressing motor neuron degeneration and symptom progression in ALS.

Topics: Amyotrophic Lateral Sclerosis; Animals; Cell Line; Disease Models, Animal; Female; Humans; Mice; Mice, Transgenic; Motor Neurons; Neural Inhibition; Piperazines; Receptors, sigma; Sigma-1 Receptor

Dextromethorphan (DM) has been shown to protect against endotoxic shock in mice. Heatstroke resembles sepsis in many respects. The objective of this study was to examine the heat-induced acute lung inflammation and injury in rats with or without DM, and for comparison with those of the rats with MK-801 (an N-methyl-D-aspartate receptor antagonist), SA4503 (a sigma-1 receptor agonist), or fluoxetine (a serotonin reuptake inhibitor). Heatstroke was induced by exposing the anesthetized rats to heat stress (43°C for 68 min). At 68 minutes after start of heat stress, animals treated with vehicle medium, DM (10-30 mg/kg of body weight, intramuscular), MK-801 (1 mg/kg of body weight, intraperitoneal), SA4503 (1 mg/kg of body weight, intraperitoneal), or fluoxetine (5 mg/kg of body weight, intraperitoneal) were allowed to recover at room temperature (26°C). As compared with vehicle-treated heatstroke rats (25-31 min; n = 8), DM (30 mg/kg)-treated heatstroke rats and MK-801 (1 mg/kg)-treated heatstroke rats had significantly greater survival time (193-209 min [n = 7] and 121-133 min [n = 8], respectively). However, the survival times for the SA4503-treated heatstroke rats (28-34 min; n = 8) or the fluoxetine-treated heatstroke rats (20-26 min; n = 8) were not significantly different from the vehicle-treated heatstroke rats. DM treatment significantly: (1) reduced acute lung injury, including edema, neutrophils infiltration, and hemorrhage scores; (2) decreased acute pleurisy; and (3) decreased bronchoalveolar fluid levels of the proinflammatory cytokines, and ischemia and oxidative damage markers during heatstroke. Our results indicate that DM therapy may improve outcomes of heatstroke in rats by antagonizing the N-methyl-D-aspartate receptors.

Topics: Acute Lung Injury; Animals; Biomarkers; Bronchoalveolar Lavage Fluid; Dextromethorphan; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Fluoxetine; Heat Stroke; Hemodynamics; Inflammation Mediators; Lung; Male; Piperazines; Pneumonia; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Receptors, sigma; Selective Serotonin Reuptake Inhibitors; Time Factors

Stroke leads to brain damage with subsequent slow and incomplete recovery of lost brain functions. Enriched housing of stroke-injured rats provides multi-modal sensorimotor stimulation, which improves recovery, although the specific mechanisms involved have not been identified. In rats housed in an enriched environment for two weeks after permanent middle cerebral artery occlusion, we found increased sigma-1 receptor expression in peri-infarct areas. Treatment of rats subjected to permanent or transient middle cerebral artery occlusion with 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride, an agonist of the sigma-1 receptor, starting two days after injury, enhanced the recovery of lost sensorimotor function without decreasing infarct size. The sigma-1 receptor was found in the galactocerebroside enriched membrane microdomains of reactive astrocytes and in neurons. Sigma-1 receptor activation increased the levels of the synaptic protein neurabin and neurexin in membrane rafts in the peri-infarct area, while sigma-1 receptor silencing prevented sigma-1 receptor-mediated neurite outgrowth in primary cortical neuronal cultures. In astrocytic cultures, oxygen and glucose deprivation induced sigma-1 receptor expression and actin dependent membrane raft formation, the latter blocked by sigma-1 receptor small interfering RNA silencing and pharmacological inhibition. We conclude that sigma-1 receptor activation stimulates recovery after stroke by enhancing cellular transport of biomolecules required for brain repair, thereby stimulating brain plasticity. Pharmacological targeting of the sigma-1 receptor provides new opportunities for stroke treatment beyond the therapeutic window of neuroprotection.

Topics: Animals; Astrocytes; Brain; Caveolin 1; Cell Hypoxia; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Environment; Gene Expression Regulation; Glucose; Infarction, Middle Cerebral Artery; Male; Movement; Neurites; Neuronal Plasticity; Neurons; Nootropic Agents; Piperazines; Protein Transport; Psychomotor Performance; Rats; Rats, Inbred SHR; Receptors, sigma; Recovery of Function; RNA, Small Interfering; Sigma-1 Receptor; Statistics, Nonparametric; Transfection

Sigma receptors are implicated in memory and cognitive functions, drug addiction, depression and schizophrenia. In addition, sigma receptors are strongly overexpressed in many tumours. Although the natural ligands are still unknown, steroid hormones are potential candidates. Here, we examined changes in binding of the sigma-1 agonist (11)C-SA4503 in C6 glioma cells and in living rats after modification of endogenous steroid levels.. (11)C-SA4503 binding was assessed in C6 monolayers by gamma counting and in anaesthetized rats by microPET scanning. C6 cells were either repeatedly washed and incubated in steroid-free medium or exposed to five kinds of exogenous steroids (1 h or 5 min before tracer addition, respectively). Tumour-bearing male rats were repeatedly treated with pentobarbital (a condition known to result in reduction of endogenous steroid levels) or injected with progesterone.. Binding of (11)C-SA4503 to C6 cells was increased (approximately 50%) upon removal and decreased (approximately 60%) upon addition of steroid hormones (rank order of potency: progesterone > allopregnanolone = testosterone = androstanolone > dehydroepiandrosterone-3-sulphate, IC(50) progesterone 33 nM). Intraperitoneally administered progesterone reduced tumour uptake and tumour-to-muscle contrast (36%). Repeated treatment of animals with pentobarbital increased the PET standardized uptake value of (11)C-SA4503 in tumour (16%) and brain (27%), whereas the kinetics of blood pool radioactivity was unaffected.. The binding of (11)C-SA4503 is sensitive to steroid competition. Since not only increases but also decreases of steroid levels affect ligand binding, a considerable fraction of the sigma-1 receptor population in cultured tumour cells or tumour-bearing animals is normally occupied by endogenous steroids.

Topics: Animals; Binding, Competitive; Cell Line, Tumor; Disease Models, Animal; Hormones; Ligands; Neoplasms; Piperazines; Positron-Emission Tomography; Rats; Receptors, sigma; Steroids; Tissue Distribution

The selective sigma1 receptor agonist 1-(3,4-dimethoxyphenethyl)-4-(3-phenyl propyl)piperazine dihydrochloride (SA4503) was reported to reverse the amnesia induced by the muscarinic receptor antagonist scopolamine at sub-mg/kg doses. We examined its effect on the learning impairment induced in mice by the non-competitive NMDA receptor antagonist dizocilpine. Learning capacities were evaluated using spontaneous alternation in the Y-maze for spatial working memory, and step-down type passive avoidance. SA4503 (0.03-1 mg/kg s.c.) attenuated the dizocilpine (0.15 mg/kg i.p.)-induced memory deficits following a bell-shaped curve in both tests. These effects of SA4503 were blocked by haloperidol (0.05 mg/kg i.p.), implicating sigma1 receptors. SA4503 also reversed the alternation deficit induced by N(omega)-nitro-L-arginine methyl ester (L-NAME, 100 mg/kg i.p.) at the same dosage, indicating that it acted on working memory through the nitric oxide (NO)-mediated signalling pathway. Furthermore, progesterone (2 mg/kg s.c.) blocked the SA4503 effects in the dizocilpine- and L-NAME-amnesia models, in accordance with the purported neurosteroids/sigma1 receptors interaction. These results demonstrate a promising neurobehavioural profile of SA4503, a ligand equally efficient to reverse the deficit in the glutamatergic as well as in the cholinergic amnesia model. Pertinent informations on the potential mechanism of the anti-amnesic effects of sigma1 receptor ligands were also obtained.

Topics: Amnesia; Analysis of Variance; Animals; Avoidance Learning; Cognition; Disease Models, Animal; Dizocilpine Maleate; Dopamine Antagonists; Drug Interactions; Excitatory Amino Acid Antagonists; Haloperidol; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Maze Learning; Mice; NG-Nitroarginine Methyl Ester; Nitric Oxide; Piperazines; Progesterone; Receptors, N-Methyl-D-Aspartate; Receptors, sigma; Spatial Behavior