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Editors Selection IGR 11-1
Animal Models: Neuroprotection
Comment by Larry Wheeler on:
51679 Brimonidine blocks glutamate excitotoxicity-induced oxidative stress and preserves mitochondrial transcription factor a in ischemic retinal injury, Lee D; Kim KY; Noh YH et al., PLoS ONE, 2012; 7: e47098
Retinal ischemic injury was used to study brimonidine's effect on mitochondrial stressors such as reactive oxygen species (ROS), oxidative phosphorylation (OXPHOS) and ischemia in the damage and death of the retina. Lee et al. have reported an elegant and important set of experiments that further our understanding of the molecular mechanisms by which the selective alpha-2 agonist BMD protect retinal cells from stress and injury through effects on the mitochondria. Brimonidine modulated apoptotic cell death pathways in retinal ischemia. Western blots show that brimonidine treatment decreases BAX but increases Bcl-xl and pBAD. BAX is a pro-apoptotic member of the Bcl-2 family that is essential in many pathways of apoptosis while Bcl-xl and pBAD inhibit apoptosis. A novel finding in this study was that brimonidine inhibited the upregulation of subunits of the NMDA receptor ‐ NR1 and NR2A. Previous studies have shown that brimonidine by decreasing cellular cAMP could inhibit the NMDA receptor function and protect retinal ganglion cells (RGCs). The second novel finding was the modulation of mitochondrial transcription factor A (Tfam) that is a DNA-binding protein in the mitochrondria and has an important role in oxidative phosphorylation(OXPHOS)-mediated ATP synthesis. This protein as well as complex (I, II, III and IV) proteins are upregulated after ischemia and this mis-regulation is inhibited by treatment with brimonidine. By immunohistochemistry Tfam is upregulated in RGCs and normalized with brimonidine treatment. These data strengthen the role of the alpha-2 pathway in protecting against cellular stresses such as ischemia, ROS and their detrimental effects on the mitochondria. One of the roles mitochondria play in the cell is that of a stress sensor. Brimonidine is able to normalize or counter cellular stress by acting directly on the mitochondria at the level of the Tfam and complex proteins and affecting the levels of NR1 and NRA-2.
These data strengthen the role of the alpha-2 pathway in protecting against cellular stresses such as ischemia, ROS and their detrimental effects on the mitochondria
The authors propose that brimonidine blockage of glutamate excitotoxicity could be an additional mechanism beyond activation of the PI3K/akt pathway by the alpha-2 receptor. It would be helpful to test this idea by using selective alpha-2 antagonists and NMDA antagonists to see which block brimonidine's effects to support their hypothesis. The importance of these results suggest that many insults converge by adversely affecting the mitochondria in terms of driving apoptosis or cell dysfunction. This may be why activation of the alpha-2 pathway protects against a variety of insults.
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