Fluvoxamine as a sigma-1 receptor agonist improved cognitive impairments in a patient with schizophrenia

Iyo, Masaomi; Shirayama, Yukihiko; Watanabe, Hiroyuki; Fujisaki, Mihisa; Miyatake, Ryosuke; Fukami, Goro; Shiina, Akihiro; Nakazato, Michiko; Shiraishi, Tetsuya; Ookami, Tsuyoshi; Hashimoto, Kenji

doi:10.1016/j.pnpbp.2008.01.005

Cited by 31 publications

(27 citation statements)

References 8 publications

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“…Because Sig-1Rs are implicated in memory and cognition (33,34), our findings also provide a mechanistic insight into the action of Sig-1Rs in neuroplasticity and cognition.…”

Section: Discussionmentioning

confidence: 75%

Sigma-1 receptors regulate hippocampal dendritic spine formation via a free radical-sensitive mechanism involving Rac1·GTP pathway

Tsai

Hayashi

Harvey

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

146

152

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Sigma-1 receptors (Sig-1Rs) are endoplasmic reticulum (ER)-resident proteins known to be involved in learning and memory. Dendritic spines in hippocampal neurons play important roles in neuroplasticity and learning and memory. This study tested the hypothesis that Sig-1Rs might regulate denritic spine formation in hippocampal neurons and examined potential mechanisms therein. In rat hippocampal primary neurons, the knockdown of Sig-1Rs by siRNAs causes a deficit in the formation of dendritic spines that is unrelated to ER Ca 2؉ signaling or apoptosis, but correlates with the mitochondrial permeability transition and cytochrome c release, followed by caspase-3 activation, Tiam1 cleavage, and a reduction in Rac1⅐GTP. Sig-1R-knockdown neurons contain higher levels of free radicals when compared to control neurons. The activation of superoxide dismutase or the application of the hydroxyl-free radical scavenger N-acetyl cysteine (NAC) to the Sig-1R-knockdown neurons rescues dendritic spines and mitochondria from the deficits caused by Sig-1R siRNA. Further, the caspase-3-resistant TIAM1 construct C1199DN, a stable guanine exchange factor able to constitutively activate Rac1 in the form of Rac1⅐GTP, also reverses the siRNA-induced dendritic spine deficits. In addition, constitutively active Rac1⅐GTP reverses this deficit. These results implicate Sig-1Rs as endogenous regulators of hippopcampal dendritic spine formation and suggest a free radicalsensitive ER-mitochondrion-Rac1⅐GTP pathway in the regulation of dendritic spine formation in the hippocampus. mitochondria ͉ ROS ͉ N-acetyl cyteine ͉ learning and memory ͉ caspase-3 D endritic spines in the CNS are important for many functions. Dendritic atrophy in the neocortical region is related to aging-induced amnesia, and its reversal improves memory retention (1). Similarly, the loss of dendritic spine-related synapses is currently a strong pathologic correlate of cognitive decline, and synaptic dysfunction is evident long before synapses and neurons are lost (2). On the other hand, exposure to drugs of abuse including cocaine, nicotine, or morphine produces persistent changes, usually in the form of increased dendritic spines and arborizations, in cells in brain regions involved in incentive motivation and reward (3). These persistent changes are thought to represent the neuronal reorganization that contributes to some of the persistent sequelae associated with drug use, including the establishment of motivational conditioning and learning (3).The morphology of dendritic spines and axons is determined by the dynamic cytoskeleton protein actin. Rho family small GTPases including Rho, Cdc42, and Rac1 regulate the dynamics of actin and are critical for neuronal polarization and morphogenesis (4-6). Rho proteins are regulated by guanine nucleotide exchange factors (GEFs). In early stages of neural morphogenesis, the activation of Cdc42 promotes the formation of filopodia, the long thin protrusions serving as primary precursors of axons and dendritic spines (7). However, Ra...

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“…Because Sig-1Rs are implicated in memory and cognition (33,34), our findings also provide a mechanistic insight into the action of Sig-1Rs in neuroplasticity and cognition.…”

Section: Discussionmentioning

confidence: 75%

Sigma-1 receptors regulate hippocampal dendritic spine formation via a free radical-sensitive mechanism involving Rac1·GTP pathway

Tsai

Hayashi

Harvey

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

146

152

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“…Interestingly, fluvoxamine but not paroxetine was also found to improve the lack of concentration, poor memory, slowness of mind, and poor executive function in a patient with schizophrenia [54]. The affinity of fluvoxamine for sigma-1 receptors is more than 50 times higher than that of paroxetine, although both compounds are potent selective serotonin reuptake inhibitors (SSRIs) [119].…”

Section: Improvement Of Cognitive Function In Humansmentioning

confidence: 99%

The cholinergic system, sigma-1 receptors and cognition

Waarde

Ramakrishnan

Rybczynska

et al. 2011

Behavioural Brain Research

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a b s t r a c tThis article provides an overview of present knowledge regarding the relationship between the cholinergic system and sigma-1 receptors, and discusses potential applications of sigma-1 receptor agonists in the treatment of memory deficits and cognitive disorders. Sigma-1 receptors, initially considered as a subtype of the opioid family, are unique ligand-regulated molecular chaperones in the endoplasmatic reticulum playing a modulatory role in intracellular calcium signaling and in the activity of several neurotransmitter systems, particularly the cholinergic and glutamatergic pathways. Several central nervous system (CNS) drugs show high to moderate affinities for sigma-1 receptors, including acetylcholinesterase inhibitors (donepezil), antipsychotics (haloperidol, rimcazole), selective serotonin reuptake inhibitors (fluvoxamine, sertraline) and monoamine oxidase inhibitors (clorgyline). These compounds can influence cognitive functions both via their primary targets and by activating sigma-1 receptors in the CNS. Sigma-1 agonists show powerful anti-amnesic and neuroprotective effects in a large variety of animal models of cognitive dysfunction involving, among others (i) pharmacologic target blockade (with muscarinic or NMDA receptor antagonists or p-chloroamphetamine); (ii) selective lesioning of cholinergic neurons; (iii) CNS administration of ␤-amyloid peptides; (iv) aging-induced memory loss, both in normal and senescentaccelerated rodents; (v) neurodegeneration induced by toxic compounds (CO, trimethyltin, cocaine), and (vi) prenatal restraint stress.

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“…Indeed, recent evidences suggested a relation between Sig-1R and the cognitive aspect of schizophrenia [72]. In the case of certain compounds, agonist stimulation of the Sig-1R apparently enhanced cognitive function, while decreasing negative symptom severity [72]. Similar cognition findings have been replicated using the high-affinity Sig-1R ligand treatment in mice following the model of phencyclidine-treatment-induced cognitive deficits [73].…”

Section: Roles Of Sig-1r In Neuropsychiatric Disordersmentioning

confidence: 78%

Section: Roles Of Sig-1r In Neuropsychiatric Disordersmentioning

confidence: 99%

Sigma-1 receptor chaperones in neurodegenerative and psychiatric disorders

Tsai¹,

Pokrass²,

Klauer

et al. 2014

Expert Opin. Ther. Targets

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Introduction Sigma-1 receptors (Sig-1Rs) are molecular chaperones that reside mainly in the endoplasmic reticulum (ER) but exist also in the proximity of the plasma membrane. Sig-1Rs are highly expressed in the CNS and are involved in many cellular processes including cell differentiation, neuritogenesis, microglia activation, protein quality control, calcium-mediated ER stress and ion channel modulation. Disturbance in any of the above cellular processes can accelerate the progression of many neurological disorders; therefore, the Sig-1R has been implicated in several neurological diseases. Areas covered This review broadly covers the functions of Sig-1Rs including several neurodegenerative disorders in humans and drug addiction-associated neurological disturbance in the case of HIV infection. We discuss how several Sig-1R ligands could be utilized in therapeutic approaches to treat those disorders. Expert opinion Emerging understanding of the cellular functions of this unique transmembrane chaperone may lead to the use of new agents or broaden the use of certain available ligands as therapeutic targets in those neurological disorders.

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Fluvoxamine as a sigma-1 receptor agonist improved cognitive impairments in a patient with schizophrenia

Cited by 31 publications

References 8 publications

Sigma-1 receptors regulate hippocampal dendritic spine formation via a free radical-sensitive mechanism involving Rac1·GTP pathway

Sigma-1 receptors regulate hippocampal dendritic spine formation via a free radical-sensitive mechanism involving Rac1·GTP pathway

The cholinergic system, sigma-1 receptors and cognition

Sigma-1 receptor chaperones in neurodegenerative and psychiatric disorders

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