Glutamate Increases In Vitro Survival and Proliferation and Attenuates Oxidative Stress-Induced Cell Death in Adult Spinal Cord-Derived Neural Stem/Progenitor Cells via Non-NMDA Ionotropic Glutamate Receptors

Abstract

Traumatic spinal cord injury (SCI) leads to a cascade of secondary chemical insults, including oxidative stress and glutamate excitotoxicity, which damage host neurons and glia. Transplantation of exogenous neural stem/progenitor cells (NSPCs) has shown promise in enhancing regeneration after SCI, although survival of transplanted cells remains poor. Understanding the response of NSPCs to the chemical mediators of secondary injury is essential in finding therapies to enhance survival. We examined the in vitro effects of glutamate and glutamate receptor agonists on adult rat spinal cord-derived NSPCs. NSPCs isolated from the periventricular region of the adult rat spinal cord were exposed to various concentrations of glutamate for 96 h. We found that glutamate treatment (500 μM) for 96 h significantly increased live cell numbers, reduced cell death, and increased proliferation, but did not significantly alter cell phenotype. Concurrent glutamate treatment (500 μM) in the setting of H2O2 exposure (500 μM) for 10 h increased NSPC survival compared to H2O2 exposure alone. The effects of glutamate on NSPCs were blocked by the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor antagonist GYKI-52466, but not by the N-methyl-D-aspartic acid receptor antagonist MK-801 or DL-AP5, or the mGluR3 antagonist LY-341495. Furthermore, treatment of NSPCs with AMPA, kainic acid, or the kainate receptor-specific agonist (RS)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propanoic acid mimicked the responses seen with glutamate both alone and in the setting of oxidative stress. These findings offer important insights into potential mechanisms to enhance NSPC survival and implicate a potential role for glutamate in promoting NSPC survival and proliferation after traumatic SCI.

Neurogenesis and prolongevity signaling in young germ-free mice transplanted with the gut microbiota of old mice

“…Metabolic profiling of hippocampi ( Fig. 1G) revealed elevated levels of metabolites such as taurine, choline, glutamate, and gamma-aminobutyric acid (GABA) that regulate neurogenesis and neuromaturation (14)(15)(16)(17)(18), in old MTs compared to young MTs (Table 1). As expected, neurogenesis was lower in the old donor mice compared to the young donor mice ( Fig.…”

Pretreatment with Group II Metabotropic Glutamate Receptor Agonist LY379268 Protects Neonatal Rat Brains from Oxidative Stress in an Experimental Model of Birth Asphyxia

“…The relationship between mGluRs and oxidative stress was demonstrated many years ago; however, there are relatively few studies in the literature investigating the role of mGluR2/3 in antioxidant defence. The activation of group II mGluRs has been shown to attenuate oxidative stress-induced cell death in spinal cord injury [ 14 ], protect neurons from glucose-induced oxidative injury [ 15 ], and reduce ROS production in the immature rat brain during seizures induced by a bilateral intracerebroventricular infusion of dl -homocysteic acid [ 16 ]. Recently, activation of group II mGluRs was also shown to protect against the ischemia-induced free radical programmed death of rat brain endothelial cells, although this neuroprotective effect was considered to be a complex metabotropic glutamate receptor response [ 17 ].…”

Unlocking the paradoxical endogenous stem cell response after spinal cord injury

“…In vitro studies demonstrated that high concentrations of glutamate, comparable to levels seen in vivo after SCI, lead to NSPC proliferation and enhanced survival. 31 In fact, F I G U R E 1 Cellular and genetic landscape of the spinal cord ependymal zone. Three main morphological cell types have been described within the spinal cord ependymal zone: cuboidal ependymal cells, radial ependymal cells, and tanycytes.…”

“…32 Emerging evidence suggests that AMPA receptors may be central in regulating glutamatemediated responses in adult spinal cord NSPCs. 31,33,34 AMPA receptors are transmembrane receptors comprised of tetramers of four types of subunits: GluA1, GluA2, GluA3, and GluA4. The GluA2 subunit imparts much of the receptor's characteristics with its presence rendering the receptor impermeable to calcium.…”