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Preventing Ca2+-mediated nitrosative stress in neurodegenerative diseases: possible pharmacological strategies

Tomohiro Nakamura1, Stuart A Lipton

  • 1Center for Neuroscience, Aging and Stem Cell Research, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.

Cell Calcium
|January 12, 2010
PubMed

Insights

Excessive NMDA receptor activity causes calcium influx, leading to neurodegeneration via nitric oxide (NO) and misfolded proteins. Novel drugs like Memantine and pro-electrophiles offer potential therapeutic interventions.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Pharmacology

Background:

  • Overactivation of NMDA receptors leads to excessive calcium influx, a key factor in neurodegenerative diseases.
  • Calcium dysregulation generates free radicals (ROS/RNS), including nitric oxide (NO), which promote neuronal damage.
  • Free radicals contribute to misfolded protein production, mitochondrial dysfunction, and apoptosis.

Purpose of the Study:

  • To review emerging evidence on the role of calcium-induced NO production in neurodegeneration.
  • To discuss the mechanisms by which NO contributes to misfolded protein accumulation and mitochondrial damage.
  • To explore novel pharmacological agents for interrupting these pathological pathways.

Main Methods:

  • Literature review focusing on the molecular mechanisms of NMDA receptor overactivation and calcium signaling.
  • Analysis of studies investigating the role of nitric oxide (NO) in protein misfolding and mitochondrial fragmentation.
  • Evaluation of the therapeutic potential of NMDA receptor antagonists and pro-electrophiles.

Main Results:

  • Excessive calcium-induced NO production contributes to misfolded proteins via S-nitrosylation of parkin and protein-disulfide isomerase.
  • NO-induced S-nitrosylation of dynamin-related protein 1 leads to mitochondrial fragmentation and synaptic damage.
  • NMDA receptor antagonists (Memantine, NitroMemantine) and pro-electrophiles show promise in mitigating these effects.

Conclusions:

  • Targeting NMDA receptor overactivation and oxidative stress presents a viable therapeutic strategy for neurodegenerative conditions.
  • Pharmacological agents that modulate calcium influx and cellular redox balance can protect neurons.
  • Further research into NMDA receptor antagonists and pro-electrophiles is warranted for neuroprotection.

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