Abstract
Neuroinflammation and oxidative stress are hallmarks of various neurological diseases. However, whether and how the redox processes control neuroinflammation is incompletely understood. We hypothesized that increasing cellular glutathione (GSH) levels would inhibit neuroinflammation. A series of thiol compounds were identified to elevate cellular GSH levels by a novel approach (i.e. post-translational activation of glutamate cysteine ligase (GCL), the rate-limiting enzyme in GSH biosynthesis). These small thiol-containing compounds were examined for their ability to increase intracellular GSH levels in a murine microglial cell line (BV2), of which dimercaprol (2,3-dimercapto-1-propanol (DMP)) was found to be the most effective compound. DMP increased GCL activity and decreased LPS-induced production of pro-inflammatory cytokines and inducible nitric-oxide synthase induction in BV2 cells in a concentration-dependent manner. The ability of DMP to elevate GSH levels and attenuate LPS-induced pro-inflammatory cytokine production was inhibited by buthionine sulfoximine, an inhibitor of GCL. DMP increased the expression of GCL holoenzyme without altering the expression of its subunits or Nrf2 target proteins (NQO1 and HO-1), suggesting a post-translational mechanism. DMP attenuated LPS-induced MAPK activation in BV2 cells, suggesting the MAPK pathway as the signaling mechanism underlying the effect of DMP. Finally, the ability of DMP to increase GSH via GCL activation was observed in mixed cerebrocortical cultures and N27 dopaminergic cells. Together, the data demonstrate a novel mechanism of GSH elevation by post-translational activation of GCL. Post-translational activation of GCL offers a novel targeted approach to control inflammation in chronic neuronal disorders associated with impaired adaptive responses.
Highlights
Neuroinflammation and oxidative stress are hallmarks of various neurological diseases
GSH is utilized as a substrate for glutathione peroxidases that are responsible for the detoxification of hydrogen peroxide (H2O2) and glutathione S-transferases involved in the removal of xenobiotics [7, 8]
Data are represented as mean Ϯ S.E.. n ϭ 5– 6 for heme oxygenase-1 (HO-1) and NADPH dehydrogenase quinone 1 (NQO1) and 3 for nuclear Nrf2 per group
Summary
Neuroinflammation and oxidative stress are hallmarks of various neurological diseases. A series of thiol compounds were identified to elevate cellular GSH levels by a novel approach (i.e. post-translational activation of glutamate cysteine ligase (GCL), the rate-limiting enzyme in GSH biosynthesis). Post-translational Activation of GCL neuroinflammation plays a causative rather than an ancillary role in the etiology of neurological diseases such as PD, AD, MS, and epilepsy (19 –21). This suggests that targeting inflammation may be an important therapeutic avenue for disease modification. Activation of Nrf, which up-regulates GSH biosynthesis, has been identified as a therapeutic target in various neurological disorders, including epilepsy [34] and MS [35, 36]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
