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Abstract #61346 Published in IGR 17-1
Inhibition of N-Methyl-D-Aspartate-Induced Retinal Neuronal Death by Polyarginine Peptides is Linked to the Attenuation of Stress-Induced Hyperpolarization of the Inner Mitochondrial Membrane Potential
Marshall J; Wong KY; Rupasinghe CN; Tiwari R; Zhao X; Berberoglu ED; Sinkler C; Liu J; Lee I; Parang K; Spaller MR; Hüttemann M; Goebel DJJournal of Biological Chemistry 2015; 290: 22030-22048
It is widely accepted that over-activation of NMDA receptors resulting in calcium overload and consequent mitochondrial dysfunction in retinal ganglion neurons, plays a significant role in promoting neurodegenerative disorders such as glaucoma. Calcium has been shown to initiate a transient hyperpolarization of the mitochondrial membrane potential triggering a burst of reactive oxygen species leading to apoptosis. Strategies that enhance cell survival signaling pathways aimed at preventing this adverse hyperpolarization of the mitochondrial membrane potential may provide a novel therapeutic intervention in retinal disease. In the retina, brain-derived neurotrophic factor (BDNF) has been shown to be neuroprotective, and our group previously reported a PSD-95/PDZ binding cyclic-peptide (CN2097) that augments brain-derived neurotrophic factor (BDNF)-induced pro-survival signaling. Here we examined the neuroprotective properties of CN2097 using an established retinal in vivo NMDA-toxicity model. CN2097 completely attenuated NMDA-induced caspase 3-dependent and -independent cell death and PARP-1 activation pathways, blocked necrosis, and fully prevented the loss of long-term ganglion cell viability. Although neuro-protection was partially dependent upon CN2097 binding to the PDZ domain of PSD-95, our results show that the polyarginine-rich transport moiety C-R(7), linked to the PDZ-PSD-95 binding cyclic-peptide, was sufficient to mediate short- and long-term protection via a mitochondrial targeting mechanism. C-R(7) localized to mitochondria and was found to reduce mitochondrial respiration, mitochondrial membrane hyperpolarization and the generation of reactive oxygen species, promoting survival of retinal neurons.
Brown University, United States;
Full articleClassification:
11.8 Neuroprotection (Part of: 11 Medical treatment)
11.14 Investigational drugs; pharmacological experiments (Part of: 11 Medical treatment)
3.8 Pharmacology (Part of: 3 Laboratory methods)
5.1 Rodent (Part of: 5 Experimental glaucoma; animal models)
