The effect of chronic administration of the sigma agonist: 1,3-di-o-tolyl-guanidine (DTG), in neonatal ventral hippocampal lesioned (nVHL) rats, on the immobility by clamping and dorsal immobility, were investigated. ...The effect of chronic administration of the sigma agonist: 1,3-di-o-tolyl-guanidine (DTG), in neonatal ventral hippocampal lesioned (nVHL) rats, on the immobility by clamping and dorsal immobility, were investigated. The nVHL increases the duration of immobility by clamping, but does not affect the duration of the dorsal immobility. We found that DTG augments the duration of the dorsal immobility in the unlesioned rats, but does not modify the duration of immobility induced by clamping the neck. DTG also counteracts the increase in the duration of the immobility by clamping produced by nVHL. However, the increase in the duration of the dorsal immobility produced by DTG is counteracted by nVHL. These results are discussed with respect to the differential effect on the two immobility responses tested, suggesting that they are different forms of immobility mediated by different mechanisms although they behaviorally share common characteristics.展开更多
Initially thought to be an opioid receptor subtype, Sigma-1 receptors (S1R) are now known to be unique proteins that have chaperone-like properties. As such, they play critical roles in cellular signaling, homeostasis...Initially thought to be an opioid receptor subtype, Sigma-1 receptors (S1R) are now known to be unique proteins that have chaperone-like properties. As such, they play critical roles in cellular signaling, homeostasis, and cell survival. These roles offer significant insight for understanding homeostasis of normal physiologic processes, and the pathophysiologic consequences of disruption of normal function. Because of the broad nature of chaperone action, S1R agonists and antagonists represent potential drug discovery goals for the pharmacotherapeutic treatment of a variety of disorders that result from dysfunctional proteins. The present study summarizes the S1R as a pharmacologic chaperone crucial for protein folding and cellular homeostasis. Through literature review and thermodynamic analysis, it explores how S1R stabilizes target proteins, influencing neuroprotection and potential drug therapies. The binding of chaperones to target proteins is thermodynamically favorable, offering insights into treating diseases linked to protein misfolding.展开更多
Chemotherapy-induced peripheral neuropathy is a very frequent neurological complication in cancer. Oxaliplatin（OXA） is a platinum analogue used as a first-line agent in the treatment of colorectal cancer. OXA induce...Chemotherapy-induced peripheral neuropathy is a very frequent neurological complication in cancer. Oxaliplatin（OXA） is a platinum analogue used as a first-line agent in the treatment of colorectal cancer. OXA induced peripheral neuropathy（OIN） is the main toxicity both during and after the completion of chemotherapy that presents as two distinct syndromes： acute and chronic neuropathy. None of the neuroprotective agents previously tested had prevented or limited the acute and/or chronic OIN. MR309（previously developed as E-52862） is a novel selective sigma-1 receptor（S1R） antagonist with preclinical analgesic activity in OXA-induced neuropathic pain in animal models. This review analyzes the results of the recently published phase Ⅱ, randomized, double-blind, placebo-controlled clinical trial including 124 patients with colorectal cancer（CRC） treated with MR309. This study shows encouraging findings in the setting of neuroprotection against OIN with an acceptable safety profile. The study demonstrated MR309 usefulness in decreasing acute OIN, by reducing cold hypersensitivity experienced by patients, and pointed to the amelioration of chronic OIN by lowering the proportion of patients who developed severe chronic OIN. In addition, we provide a summary and discussion on the pathways that can be modulated by the S1R to explain the observed clinical benefits in the OIN.展开更多
文摘The effect of chronic administration of the sigma agonist: 1,3-di-o-tolyl-guanidine (DTG), in neonatal ventral hippocampal lesioned (nVHL) rats, on the immobility by clamping and dorsal immobility, were investigated. The nVHL increases the duration of immobility by clamping, but does not affect the duration of the dorsal immobility. We found that DTG augments the duration of the dorsal immobility in the unlesioned rats, but does not modify the duration of immobility induced by clamping the neck. DTG also counteracts the increase in the duration of the immobility by clamping produced by nVHL. However, the increase in the duration of the dorsal immobility produced by DTG is counteracted by nVHL. These results are discussed with respect to the differential effect on the two immobility responses tested, suggesting that they are different forms of immobility mediated by different mechanisms although they behaviorally share common characteristics.
文摘Initially thought to be an opioid receptor subtype, Sigma-1 receptors (S1R) are now known to be unique proteins that have chaperone-like properties. As such, they play critical roles in cellular signaling, homeostasis, and cell survival. These roles offer significant insight for understanding homeostasis of normal physiologic processes, and the pathophysiologic consequences of disruption of normal function. Because of the broad nature of chaperone action, S1R agonists and antagonists represent potential drug discovery goals for the pharmacotherapeutic treatment of a variety of disorders that result from dysfunctional proteins. The present study summarizes the S1R as a pharmacologic chaperone crucial for protein folding and cellular homeostasis. Through literature review and thermodynamic analysis, it explores how S1R stabilizes target proteins, influencing neuroprotection and potential drug therapies. The binding of chaperones to target proteins is thermodynamically favorable, offering insights into treating diseases linked to protein misfolding.
文摘Chemotherapy-induced peripheral neuropathy is a very frequent neurological complication in cancer. Oxaliplatin（OXA） is a platinum analogue used as a first-line agent in the treatment of colorectal cancer. OXA induced peripheral neuropathy（OIN） is the main toxicity both during and after the completion of chemotherapy that presents as two distinct syndromes： acute and chronic neuropathy. None of the neuroprotective agents previously tested had prevented or limited the acute and/or chronic OIN. MR309（previously developed as E-52862） is a novel selective sigma-1 receptor（S1R） antagonist with preclinical analgesic activity in OXA-induced neuropathic pain in animal models. This review analyzes the results of the recently published phase Ⅱ, randomized, double-blind, placebo-controlled clinical trial including 124 patients with colorectal cancer（CRC） treated with MR309. This study shows encouraging findings in the setting of neuroprotection against OIN with an acceptable safety profile. The study demonstrated MR309 usefulness in decreasing acute OIN, by reducing cold hypersensitivity experienced by patients, and pointed to the amelioration of chronic OIN by lowering the proportion of patients who developed severe chronic OIN. In addition, we provide a summary and discussion on the pathways that can be modulated by the S1R to explain the observed clinical benefits in the OIN.
