Metabotropic glutamate receptors prevent nitric oxide-induced programmed cell death

Abstract

Activation of metabotropic glutamate receptor (mGluR) subtypes can prevent neuronal injury through the signal transduction pathways of nitric oxide (NO). It is this link to NO free radical injury and subsequent DNA damage that is the most intriguing. We therefore examined whether neuronal protection through mGluR activation was dependent on the molecular mechanisms of programmed cell death (PCD). The NO generators sodium nitroprusside and 3-morpholino-sydnonimine were administered to induce NO toxicity in primary hippocampal neurons. PCD was documented by hematoxylin and eosin nuclear staining, DNA gel electrophoresis, transmission electron microscopy, and protein synthesis assays. Following NO exposure, PCD induction was rapid and robust in approximately 70% of the neuronal population. Activation of specific mGluR subtypes with 1S,3R-ACPD and L-AP4, agents that are neuroprotective against NO, significantly limited the progression of PCD. In contrast, antagonism of mGluRs with L-AP3 did not prevent the development of PCD. Induction of new protein synthesis, a common requisite for PCD, was evident following NO exposure, but did not appear to represent a principal pathway of modulation by the mGluR agonists. Our studies suggest that mGluR modulation of NO-induced PCD represents a primary molecular pathway responsible for neuronal survival. Further elucidation of the molecular mGluR signaling pathways may yield new insight into specific genetic regulatory mechanisms responsible for neuronal injury.

Group II metabotropic glutamate receptor activation protects striatal dopaminergic nerve terminals against MPP+‐induced neurotoxicity along with brain‐derived neurotrophic factor induction

“…1998), and β‐amyloid peptide (Copani et al. 1995) and nitric oxide‐induced programmed cell death (Vincent et al. 1997).…”

Synergism of Nitric Oxide and Iron in Killing the Transformed Murine Oligodendrocyte Cell Line N20.1

“…To examine whether the cytotoxicity of SNAP compared with that of SNP involved different mechanisms of cell death, we assessed DNA fragmentation as an indicator of apoptosis during the 18 h of incubation with SNAP or SNP. We performed a DNA laddering assay at 4, 6, 12, and 18 h, as it has been shown previously that apoptosis occurred after 6 h of incubation with SNP in hippocampal neurons (Vincent et al, 1997). With 0.5 m M SNP, no DNA ladder was seen after 4 h of incubation, but a laddering did appear after 6 h, increased after 12 h, and was still present after 18 h of incubation.…”

“…However, the mechanisms of damage and protection are not well understood. Primary oligodendrocytes in culture are more susceptible to damage by NO than astrocytes and microglia (Mitrovic et al, 1994), although not as susceptible as some types of neurons (Vincent et al, 1997). Little information is available on the differential susceptibility of oligodendrocytes at various stages of differentiation.…”

Activation of Neuroprotective Pathways by Metabotropic Group I Glutamate Receptors: A Potential Target for Drug Discovery?

“…There is an equally abundant and credible body of evidence, though, that group I mGluR stimulation could be neuroprotective. Support for this viewpoint comes from studies of nitric oxide (NO)‐ or ischemia‐induced cell death,40,41 the associated reduction of apoptosis markers,42‐44 and NMDA toxicity 45,46. Bruno et al reported that the group I agonist DHPG was protective when coapplied with NMDA, despite an increase in NMDAR‐mediated currents 47.…”