Related Experiment Videos
A selective N-type calcium channel antagonist protects against neuronal loss after global cerebral ischemia
K Valentino1, R Newcomb, T Gadbois
1Neurex Corp., Menlo Park, CA 94025.
Abstract:
Calcium influx is believed to play a critical role in the cascade of biochemical events leading to neuronal cell death in a variety of pathological settings, including cerebral ischemia. The synthetic omega-conotoxin peptide SNX-111, which selectively blocks depolarization-induced calcium fluxes through neuronal N-type voltage-sensitive calcium channels, protected the pyramidal neurons in the CA1 subfield of the hippocampus from damage caused by transient forebrain ischemia in the rat model of four-vessel occlusion. SNX-111 provided neuroprotection when a single bolus injection was administered intravenously up to 24 hr after the ischemic insult. These results suggest that the window of opportunity for therapeutic intervention after cerebral ischemia may be much longer than previously thought and point to the potential use of omega-conopeptides and their derivatives in the prevention or reduction of neuronal damage resulting from ischemic episodes due to cardiac arrest, head trauma, or stroke. Microdialysis studies showed that SNX-111 was 3 orders of magnitude less potent in blocking potassium-induced glutamate release in the hippocampus than the conopeptide SNX-230, which, in contrast to SNX-111, failed to show any efficacy in the four-vessel occlusion model of ischemia. These results imply that the ability of a conopeptide to block excitatory amino acid release does not correlate with its neuroprotective efficacy.
Insights
The synthetic omega-conotoxin SNX-111 protects brain cells from ischemic damage up to 24 hours after injury. This finding suggests a broader therapeutic window for stroke and head trauma treatments.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Calcium influx is a key factor in neuronal cell death during cerebral ischemia.
- Voltage-sensitive calcium channels are implicated in ischemic brain damage.
Purpose of the Study:
- To evaluate the neuroprotective potential of the synthetic omega-conotoxin SNX-111.
- To determine the therapeutic window for SNX-111 intervention after ischemic insult.
Main Methods:
- Transient forebrain ischemia was induced in a rat model (four-vessel occlusion).
- SNX-111 was administered intravenously at various time points post-ischemia.
- Neuroprotection of hippocampal CA1 pyramidal neurons was assessed.
- Microdialysis was used to measure glutamate release.
Main Results:
- SNX-111 significantly protected CA1 pyramidal neurons from ischemic damage.
- Neuroprotection was observed even when SNX-111 was administered up to 24 hours after ischemia.
- SNX-111 was less potent in blocking glutamate release compared to SNX-230, which showed no efficacy.
Conclusions:
- The therapeutic window for intervention following cerebral ischemia may be significantly longer than previously assumed.
- Omega-conopeptides like SNX-111 hold potential for preventing or reducing neuronal damage in stroke, head trauma, and cardiac arrest.
- Blocking excitatory amino acid release does not necessarily correlate with a conopeptide's neuroprotective efficacy.