Protective effects of NIM811 in transient focal cerebral ischemia suggest involvement of the mitochondrial permeability transition.

Abstract

Cerebral ischemia followed by reperfusion activates numerous pathways that lead to cell death. One such pathway involves the release of large quantities of the excitatory amino acid glutamate into the synapse and activation of N-methyl-D-aspartate receptors. This causes an increase in mitochondrial calcium levels ([Ca(2+)](m)) and a production of reactive oxygen species (ROS), both of which may induce the mitochondrial permeability transition (MPT). As a consequence, there is eventual mitochondrial failure culminating in either apoptotic or necrotic cell death. Thus, agents that inhibit MPT might prove useful as therapeutic interventions in cerebral ischemia. In this study, we have investigated the neuroprotective efficacy of the novel compound NIM811. Similar in structure of its parent compound cyclosporin A, NIM811 is a potent inhibitor of the MPT. Unlike cyclosporin A, however, it is essentially void of immunosuppressive actions, allowing the role of MPT to be clarified in ischemia/reperfusion injury. The results of these studies demonstrate that NIM811 provides almost 40% protection in a model of transient focal cerebral ischemia. This was associated with a nearly 10% reduction in mitochondrial reactive species formation and 34% and 38% reduction of cytochrome c release in core and penumbra, respectively. Treatment with NIM811 also increased calcium retention capacity by approximately 20%. Interestingly, NIM811 failed to improve ischemia-induced impairment of bioenergetics. The neuroprotective effects of NIM811 were not due to drug-induced alterations in cerebral perfusion after ischemia. Activation of MPT appears to be an important process in ischemia/reperfusion injury and may be a therapeutic target.

• Authors: Amit S Korde, L Creed Pettigrew, Susan D Craddock, Chava B Pocernich, Peter C Waldmeier, William F Maragos
• Journal: Journal of neurotrauma (J Neurotrauma) Vol. 24 Issue 5 Pg. 895-908 (May 2007) ISSN: 0897-7151 [Print] United States
• PMID: 17518543 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Mitochondrial Membrane Transport Proteins
• Mitochondrial Permeability Transition Pore
• Neuroprotective Agents
• Reactive Oxygen Species
• Cyclosporine
• Cytochromes c
• (melle-4)cyclosporin

Topics

• Animals
• Brain Infarction (drug therapy, metabolism, physiopathology)
• Brain Ischemia (drug therapy, metabolism, physiopathology)
• Calcium Signaling (drug effects, physiology)
• Cell Death (drug effects, physiology)
• Cyclosporine (pharmacology, therapeutic use)
• Cytochromes c (antagonists & inhibitors, metabolism)
• Disease Models, Animal
• Energy Metabolism (drug effects, physiology)
• Male
• Mitochondrial Membrane Transport Proteins (drug effects, physiology)
• Mitochondrial Permeability Transition Pore
• Nerve Degeneration (drug therapy, metabolism, physiopathology)
• Neurons (drug effects, metabolism)
• Neuroprotective Agents (pharmacology, therapeutic use)
• Oxidative Stress (drug effects, physiology)
• Rats
• Rats, Inbred SHR
• Reactive Oxygen Species (antagonists & inhibitors, metabolism)
• Treatment Outcome