Chronic treatment with a selective ligand for the sigma-1 receptor chaperone, SA4503, up-regulates BDNF protein levels in the rat hippocampus

Kikuchi-Utsumi, Kazue; Nakaki, Toshio

doi:10.1016/j.neulet.2008.05.055

Cited by 52 publications

(50 citation statements)

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“…Also, treatment with SA4503 increased spine length and spine head size of hippocampal pyramidal neurons (14). The Sig-1R and growth factors appear to act synergistically; Sig-1R stimulation increases synthesis of growth factors such as BDNF and GDNF (11), and the action of Sig-1R on neurite outgrowth is dependent on growth factors such as nerve growth factor (NGF) or BDNF (31,52,59,68). Dendritic branching is stimulated by Sig-1R activation and is diminished by Sig-1R knockdown (69).…”

Section: Sig-1r and Neuronal Plasticitymentioning

confidence: 99%

The involvement of the sigma-1 receptor in neurodegeneration and neurorestoration

Ruscher

Wieloch

2015

Journal of Pharmacological Sciences

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The sigma-1 receptor (Sig-1R) is a single 25 kD polypeptide and a chaperone protein immersed in lipid rafts of the endoplasmic reticulum (ER) where it interacts with mitochondria at the mitochondria-associated ER membrane domain (MAM). Upon activation, the Sig-1R binds to the inositol trisphosphate receptor (IP3R), and modulates cellular calcium (Ca(2+)) homeostasis. Also, the activated Sig-1R modulates plasma membrane receptor and ion channel functions, and may regulate cellular excitability. Further, the Sig-1R promotes trafficking of lipids and proteins essential for neurotransmission, cell growth and motility. Activation of the Sig-1R provides neuroprotection and is neurorestorative in cellular and animal models of neurodegenerative diseases and brain ischaemia. Neuroprotection appears to be due to inhibition of cellular Ca(2+) toxicity and/or inflammation, and neurorestoration may include balancing abberant neurotransmission or stimulation of synaptogenesis, thus remodelling brain connectivity. Single nucleotide polymorphisms and mutations of the SIGMAR1 gene worsen outcome in Alzheimer's disease and myotrophic lateral sclerosis supporting a role of Sig-1R in neurodegenerative disease. The combined neuroprotective and neurorestorative actions of the Sig-1R, provide a broad therapeutic time window of Sig-1R agonists. The Sig-1R is therefore a strong therapeutic target for the development of new treatments for neurodegenerative diseases and stroke.

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Section: Sig-1r and Neuronal Plasticitymentioning

confidence: 99%

The involvement of the sigma-1 receptor in neurodegeneration and neurorestoration

Ruscher

Wieloch

2015

Journal of Pharmacological Sciences

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“…BiP is a key regulator of endoplasmic reticulum stress transducers (Bertolotti et al, 2000), is antiapoptotic (Kudo et al, 2008;Qin et al, 2004;Yu et al, 1999) and is involved in several cellular mechanisms, including translocating newly synthesized polypeptides across the endoplasmic reticulum membrane and other chaperonine functions (Lee, 2005). It has been also demonstrated that chronic treatment with a selective ligand for the Sig-1R chaperone increases brainderived neurotrophic factor (BDNF) protein levels in the hippocampus (Kikuchi-Utsumi and Nakaki, 2008).…”

Section: Introductionmentioning

confidence: 99%

Sigma Receptor Agonist 2-(4-Morpholinethyl)1 Phenylcyclohexanecarboxylate (Pre084) Increases GDNF and BiP Expression and Promotes Neuroprotection after Root Avulsion Injury

Penas

Pascual‐Font

Mancuso

et al. 2011

Journal of Neurotrauma

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Spinal root avulsion leads to a progressive loss of axotomized motoneurons (MNs). Nowadays, there is no effective treatment to prolong MN survival that could permit recovery as a result of delayed surgical repair. Administration of Sigma-1 receptor (Sig-1R) ligands has been reported to promote beneficial effects after several types of neural injury. In order to shed light of whether Sig-1R ligands could promote MN survival after root avulsion, L4-L5 spinal roots were unilaterally avulsed in adult rats and the Sig-1R agonist Pre084 was administered at different doses. The ventral spinal cords of the animals were studied from 3 to 21 days post-operation (DPO) by using histological, immunohistochemical, and Western blot techniques. Daily treatment with 0.25 mg/kg Pre084 significantly promoted MN survival (68% vs 43% in untreated rats) at 21 DPO, an effect that was antagonized by coadministration of BD1063, an antagonist of Sig-1R. There was a reduction in astroglial- associated immunoreactivity in rats treated with Pre084. Moreover, Pre084 produced an increase in the Sig-1R co-chaperone BiP within MNs, and an increase of GDNF expression by astrocytes in the ventral horn early after injury. Although the mechanisms promoting MN survival by Pre084 remain unclear, we hypothesize that it is mediated at least in part through the increase in these cytoprotective factors. Therefore, early application of Sig-1R agonist appears to be a promising therapy to improve MN survival after root avulsion.

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“…Stimulation of axonal sprouting and neurogenesis is associated with improved recovery from experimental stroke. 11 Cutamesine enhances the expression of brain-derived neurotrophic factor in vivo 12 and in vitro, 6 by regulating the processing to mature, secreted brain-derived neurotrophic factor. Delayed administration of a small-molecule ligand of the brainderived neurotrophic factor tropomyosin receptor kinase B (TrkB) promoted recovery after hypoxic-ischemic stroke with a delayed treatment initiation window.…”

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Phase II Trial of the Sigma-1 Receptor Agonist Cutamesine (SA4503) for Recovery Enhancement After Acute Ischemic Stroke

Urfer

Moebius

Školoudík

et al. 2014

Stroke

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E nhancement of functional recovery during the subacute and chronic phases of stroke represents a major therapeutic goal because a significant proportion of patients have persisting neurological deficits, even with optimal acute care and conventional rehabilitation. Preclinical in vivo models suggest that a time-limited window of neuroplasticity opens after stroke.1 New therapeutic approaches that stimulate these repair mechanisms may be able to exploit this opportunity, and a range of these is currently under investigation, including small molecules that target specific processes, small molecules that have a general stimulatory effect that may aid rehabilitation, growth factors, cell therapies, and physical modulation of neuronal networks.2 The σ-1 receptor chaperone protein (Sig-1R) mediated functional recovery in a model of neuronal plasticity relevant to stroke.3 Sig-1Rs mainly reside in the endoplasmic reticulum and are enriched in the mitochondriaassociated endoplasmic reticulum membrane but can change their intracellular location in response to cellular stress. 4 The biochemical function of the Sig-1R is that of a molecular chaperone, stabilizing proteins in response to cellular stress 5 Background and Purpose-The σ-1 receptor (Sig-1R) agonist cutamesine (SA4503) enhanced functional recovery after experimental stroke with a treatment initiation window of 48 hours and chronic treatment for 28 days. We conducted a phase 2 clinical trial exploring the safety, tolerability, dose range, and functional effects of cutamesine in patients with ischemic stroke. Methods-Subjects were randomized between 48 and 72 hours after stroke to receive cutamesine 1 mg/d, 3 mg/d, or placebo for 28 days. Effects on safety and function were assessed at baseline, at end of treatment (day 28), and at end of followup (day 56). Results-In 60 patients, treatment with both cutamesine dosages was safe and well tolerated without significant differences in numbers of treatment emergent or serious adverse events. No significant effect was observed on the primary efficacy measure (change in National Institutes of Health Stroke Scale from baseline to day 56) or modified Rankin Scale and Barthel Index scores. Post hoc analysis of moderately and severely affected patients (baseline National Institutes of Health Stroke Scale, ≥7 and ≥10) showed greater National Institutes of Health Stroke Scale improvements in the 3 mg/d cutamesine group when compared with placebo (P=0.034 and P=0.038, respectively). A trend toward a higher proportion being able to complete a 10m timed walk was observed for cutamesine-treated subjects. Conclusions-Cutamesine was safe and well tolerated at both dosage levels. Although no significant effects on functional end points were seen in the population as a whole, greater improvement in National Institutes of Health Stroke Scale scores among patients with greater pretreatment deficits seen in post hoc analysis warrants further investigation. Additional studies should focus on the patient population with moderate-to-severe...

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Chronic treatment with a selective ligand for the sigma-1 receptor chaperone, SA4503, up-regulates BDNF protein levels in the rat hippocampus

Cited by 52 publications

References 18 publications

The involvement of the sigma-1 receptor in neurodegeneration and neurorestoration

The involvement of the sigma-1 receptor in neurodegeneration and neurorestoration

Sigma Receptor Agonist 2-(4-Morpholinethyl)1 Phenylcyclohexanecarboxylate (Pre084) Increases GDNF and BiP Expression and Promotes Neuroprotection after Root Avulsion Injury

Phase II Trial of the Sigma-1 Receptor Agonist Cutamesine (SA4503) for Recovery Enhancement After Acute Ischemic Stroke

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