Selective Blockade of the Sigma 1 Receptor Has Beneficial Effects on Both Acute and Chronic Oxaliplatin-Induced Peripheral Neuropathy

Abstract The neurobiological mechanisms of obesity-induced peripheral neuropathy are poorly understood. We evaluated the role of Sigma-1 receptor (Sig-1R) and NMDA receptor (NMDARs) in the spinal cord in peripheral neuropathy using an animal model of high fat diet-induced diabetes. We examined the expression of Sig-1R and NMDAR subunits GluN2A and GluN2B along with postsynaptic density protein 95 (PSD-95) in the spinal cord after 24-week HFD treatment in both wild-type and Sig-1R−/− mice. Finally, we examined the effects of repeated intrathecal administrations of selective Sig-1R antagonists BD1047 in HFD-fed wild-type mice on peripheral neuropathy. Wild-type mice developed tactile allodynia and thermal hypoalgesia after 24-week HFD treatment. HFD-induced peripheral neuropathy correlated with increased expression of GluN2A and GluN2B subunits of NMDARs, PDS-95, and Sig-1R, as well as increased Sig-1R-NMDAR interaction in the spinal cord. In contrast, Sig-1R−/− mice did not develop thermal hypoalgesia or tactile allodynia after 24-week HFD treatment, and the levels of GluN2A, GluN2B, and PSD-95 were not altered in the spinal cord of HFD-fed Sig-1R−/− mice. Finally, repeated intrathecal administrations of selective Sig-1R antagonists BD1047 in HFD-fed wild-type mice attenuated peripheral neuropathy. Our results suggest that obesity-associated peripheral neuropathy may involve Sig-1R-mediated enhancement of NMDAR expression in the spinal cord.

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Sigma-1 Receptor Engages an Anti-Inflammatory and Antioxidant Feedback Loop Mediated by Peroxiredoxin in Experimental Colitis

Antioxidants ◽

10.3390/antiox9111081 ◽

2020 ◽

Vol 9 (11) ◽

pp. 1081

Author(s):

Nikoletta Almási ◽

Szilvia Török ◽

Zsuzsanna Valkusz ◽

Máté Tajti ◽

Ákos Csonka ◽

...

Keyword(s):

Experimental Colitis ◽

The Body ◽

Male Rats ◽

Trinitrobenzenesulfonic Acid ◽

Simultaneous Treatment ◽

Sigma 1 Receptor ◽

Beneficial Effects ◽

Chronic Inflammatory Condition ◽

Sigma 1 ◽

Inflammatory Bowel

Inflammatory bowel disease (IBD), comprising Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic inflammatory condition of the gastrointestinal tract. Since the treatment of IBD is still an unresolved issue, we designed our study to investigate the effect of a novel therapeutic target, sigma-1 receptor (σ1R), considering its ability to activate antioxidant molecules. As a model, 2,4,6-trinitrobenzenesulfonic acid (TNBS) was used to induce colitis in Wistar–Harlan male rats. To test the beneficial effects of σ1R, animals were treated intracolonically (i.c.): (1) separately with an agonist (fluvoxamine (FLV)), (2) with an antagonist of the receptor (BD1063), or (3) as a co-treatment. Our results showed that FLV significantly decreased the severity of inflammation and increased the body weight of the animals. On the contrary, simultaneous treatment of FLV with BD1063 diminished the beneficial effects of FLV. Furthermore, FLV significantly enhanced the levels of glutathione (GSH) and peroxiredoxin 1 (PRDX1) and caused a significant reduction in 3-nitrotyrosine (3-NT) levels, the effects of which were abolished by co-treatment with BD1063. Taken together, our results suggest that the activation of σ1R in TNBS-induced colitis through FLV may be a promising therapeutic strategy, and its protective effect seems to involve the antioxidant pathway system.

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Sigma-1 receptor: a new player in neuroprotection against chemotherapy-induced peripheral neuropathy

Neural Regeneration Research ◽

10.4103/1673-5374.232459 ◽

2018 ◽

Vol 13 (5) ◽

pp. 775 ◽

Cited By ~ 6

Author(s):

Jordi Bruna ◽

Roser Velasco

Keyword(s):

Peripheral Neuropathy ◽

Sigma 1 Receptor ◽

Sigma 1

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Sigma-1 Receptor: A Potential Therapeutic Target for Traumatic Brain Injury

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.685201 ◽

2021 ◽

Vol 15 ◽

Author(s):

Mingming Shi ◽

Fanglian Chen ◽

Zhijuan Chen ◽

Weidong Yang ◽

Shuyuan Yue ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Endoplasmic Reticulum ◽

Brain Injury ◽

Neurological Disorders ◽

Inflammatory Responses ◽

Current Knowledge ◽

Glutamate Excitotoxicity ◽

Sigma 1 Receptor ◽

Beneficial Effects ◽

Sigma 1

The sigma-1 receptor (Sig-1R) is a chaperone receptor that primarily resides at the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) and acts as a dynamic pluripotent modulator regulating cellular pathophysiological processes. Multiple pharmacological studies have confirmed the beneficial effects of Sig-1R activation on cellular calcium homeostasis, excitotoxicity modulation, reactive oxygen species (ROS) clearance, and the structural and functional stability of the ER, mitochondria, and MAM. The Sig-1R is expressed broadly in cells of the central nervous system (CNS) and has been reported to be involved in various neurological disorders. Traumatic brain injury (TBI)-induced secondary injury involves complex and interrelated pathophysiological processes such as cellular apoptosis, glutamate excitotoxicity, inflammatory responses, endoplasmic reticulum stress, oxidative stress, and mitochondrial dysfunction. Thus, given the pluripotent modulation of the Sig-1R in diverse neurological disorders, we hypothesized that the Sig-1R may affect a series of pathophysiology after TBI. This review summarizes the current knowledge of the Sig-1R, its mechanistic role in various pathophysiological processes of multiple CNS diseases, and its potential therapeutic role in TBI.

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