Extracellular cyclic GMP and its derivatives GMP and guanosine protect from oxidative glutamate toxicity.

Cell death in response to oxidative stress plays a role in a variety of neurodegenerative diseases and can be studied in detail in the neuronal cell line HT22, where extracellular glutamate causes glutathione depletion by inhibition of the glutamate/cystine antiporter system xc(-), elevation of reactive oxygen species and eventually programmed cell death caused by cytotoxic calcium influx. Using this paradigm, we screened 54 putative extracellular peptide or small molecule ligands for effects on cell death and identified extracellular cyclic guanosine monophosphate (cGMP) as a protective substance. Extracellular cGMP was protective, whereas the cell-permeable cGMP analog 8-pCPT-cGMP or the inhibition of cGMP degradation by phosphodiesterases was toxic.

Effects of dimethyl fumarate on neuroprotection and immunomodulation.

Background: Neuronal degeneration in multiple sclerosis has been linked to oxidative stress. Dimethyl fumarate is a promising novel oral therapeutic option shown to reduce disease activity and progression in patients with relapsing-remitting multiple sclerosis. These effects are presumed to originate from a combination of immunomodulatory and neuroprotective mechanisms.