Selective blockade of CaMKII-α inhibits NMDA-induced caspase-3-dependent cell death but does not arrest PARP-1 activation or loss of plasma membrane selectivity in rat retinal neurons

• Published in: Brain research 2009-02, Vol.1256, p.190-204
• Main Author: Goebel, Dennis J
• Format: Article
• Language: English
• Subjects: Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - antagonists & inhibitors; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism; Calcium/calmodulin-dependent kinase II-α blockade; Caspase 3 - metabolism; Caspase-3 activation; Cell Death - drug effects; Cell Membrane - drug effects; Cell Survival - drug effects; Enzyme Activation - drug effects; Ethidium bromide staining; Male; N-Methylaspartate - pharmacology; Necrosis; Neurology; PARP-activity; Peptides - pharmacology; Phenanthrenes - pharmacology; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases - metabolism; Rats; Rats, Sprague-Dawley; Retinal Neurons - cytology; Retinal Neurons - drug effects; Retinal Neurons - physiology; Signal Transduction - drug effects; TUNEL labeling
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2008.12.051

Abstract Calcium/calmodulin-dependent protein kinase II-α (CaMKII-α) has been implicated in a number of receptor mediated events in neurons. Pharmacological blockade of CaMKII-α has been shown to prevent phosphorylation of NMDA-R2A and R2B receptor subunits, suggesting that this enzyme may be linked to receptor trafficking of glutamate receptors and serve as a regulatory protein for neuronal cell death. In the retina, inhibition of CaMKII-α has been reported to be neuroprotective against NMDA-induced cell death by preventing the activation of the caspase-3 dependent pathway. However, the effects of CaMKII-α blockade on the caspase-3 independent, PARP-1 dependent and the non-programmed cell death pathways have not previously been investigated. In the present study, blockade of CaMKII-α with the highly specific antagonist myristoylated autocamtide-2-related inhibitory peptide (AIP) was used in a rat in vivo model of retinal toxicity to compare the effects of on NMDA-induced caspase-3-dependent, PARP-1 dependent and the non-programmed (necrosis) cell death pathways. Results confirmed that AIP fully attenuates caspase-3 activation for at least 8 h following NMDA insult and also significantly improves retinal ganglion cell survival. However, this blockade had little effect on reducing the loss of plasma membrane selectivity (LPMS, e.g. necrosis) in cells located in the ganglion cell and inner nuclear layers and did not alter NMDA-induced PARP-1 hyperactivation, or prevent TUNEL labeling following a moderate NMDA-insult. These findings support a specific role for CaMKII-α in mediating the caspase-3 dependent cell death pathway and provide evidence that it is not directly linked to the signaling of either the PARP-1 dependent or the non-programmed cell death pathways.