Activation of Sigma-1 Receptor Alleviates ER-Associated Cell Death and Microglia Activation in Traumatically Injured Mice

Abstract

Background: Endoplasmic reticulum (ER) stress and unfolded protein response (UPR) is associated with neuroinflammation and subsequent cell death following traumatic brain injury (TBI). The sigma-1 receptor (Sig-1R) acts as a dynamic pluripotent modulator of fundamental cellular processes at the mitochondria-associated membranes (MAMs). The activation of Sig-1R is neuroprotective in a variety of central nervous system diseases, but its impact on ER stress induced by traumatic brain injury is not known. This study investigated the role of Sig-1R in regulating the ER stress-mediated microglial activation and programmed cell death (apoptosis and pyroptosis) induced by TBI. Methods: Ten human brain tissues were obtained from The Tianjin Medical University General Hospital. Four normal brain tissues were obtained from patients who underwent surgery for cerebral vascular malformation, through which peripheral brain tissues were isolated. Six severe TBI tissues were from patients with brain injury caused by accidents. None of the patients had any other known neurological disorders. Mice with Sig-1R deletion using CRISPR technology were subjected to controlled cortical impact-induced injury. In parallel, wild type C57BL/6J mice were analyzed for outcomes after they were exposed to TBI and received the Sig-1R agonist PRE-084 (10 mg/kg daily for three days) either alone or in combination with the Sig-1R antagonist BD-1047 (10 mg/kg). Results: The expression of Sig-1R and the 78 kDa glucose-regulated protein, a known UPR marker, were significantly elevated in the injured cerebral tissues from TBI patients and mice subjected to TBI. PRE-084 improved neurological function, restored the cerebral cortical perfusion, and ameliorated and brain edema in C57BL/6J mice subjected to TBI by reducing endoplasmic reticulum stress-mediated apoptosis, pyroptosis, and microglia activation. The effect of PRE-084 was abolished in mice receiving Sig-1R antagonist BD-1047. Conclusions: ER stress and UPR were upregulated in TBI patients and mice subjected to TBI. Sig-1R activation by the exogenous activator PRE-084 attenuated microglial cells activation, reduced ER stress-associated programmed cell death, and restored cerebrovascular and neurological function in TBI mice.

Long-Lasting Nociplastic Pain Modulation by Repeated Administration of Sigma-1 Receptor Antagonist BD1063 in Fibromyalgia-like Mouse Models

“…The results obtained with pregabalin do not support a modulatory role of this compound in modulating glial reactivity in the spinal cord in fibromyalgia-like models. The difference between BD1063 and pregabalin could be related to the expression of their respective molecular targets, as α 2 δ 1 subunits have not been described in astrocytes and microglial cells; however, σ1R is expressed in glial cells, both in astrocytes [ 63 , 65 , 69 , 102 , 103 , 104 , 105 ] and microglial cells [ 70 , 106 , 107 , 108 , 109 , 110 , 111 ]. In this way, as reported in other models of pathological pain, such as chronic constriction injury, there is an upregulation of σ1R expression in spinal cord astrocytes, accompanied by overexpression of GFAP.…”

Naringenin Alleviates Renal Ischemia Reperfusion Injury by Suppressing ER Stress-Induced Pyroptosis and Apoptosis through Activating Nrf2/HO-1 Signaling Pathway

“…Taken together, these data demonstrated that the inhibitory effect of NRG on pyroptosis and apoptosis was at least partially dependent on the alleviation of endoplasmic reticulum stress. The phenomenon that suppression of ER stress was capable of alleviating pyroptosis was also testified in other disease models [ 63 – 65 ].…”

“…Taken together, these data demonstrated that the inhibitory effect of NRG on pyroptosis and apoptosis was at least partially dependent on the alleviation of endoplasmic reticulum stress. The phenomenon that suppression of ER stress was capable of alleviating pyroptosis was also testified in other disease models [63][64][65]. Naringenin, one polyphenolic constituent existing in dietary citrus fruits, has attracted notable attention from researchers in various fields because of its powerful pharmacological activities and promising therapeutic prospects [32].…”

Immunoproteasomes control activation of innate immune signaling and microglial function

“…In conditions of IP dysfunction, we confirmed impaired proteostasis with accumulation of ubiquitin modified proteins and decreased proteasome active sites accompanied by activation of UPR and ISR ( Figures 1 , 2 and Supplementary Figure 1-4 ). Importantly, the role of UPR and ISR in neuroinflammation has been increasingly realized ( 55 – 59 ). In line with this, loss of function mutations in the genes encoding proteasome components or their assembly factors have been found in patients with rare proteasomopathies suffering from systemic inflammation and/or neurodevelopmental delay ( 60 – 64 ).…”