Failure and rescue of preconditioning-induced neuroprotection in severe stroke-like insults

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Journal titleNeuropharmacology
SubjectNeuroprotection; Tolerance; Preconditioning; Excitotoxicity; NMDA receptor; Ischemia
AbstractPreconditioning is a well established neuroprotective modality. However, the mechanism and relative efficacy of neuroprotection between diverse preconditioners is poorly defined. Cultured neurons were preconditioned by 4-aminopyridine and bicuculline (4-AP/bic), rendering neurons tolerant to normally lethal (sufficient to kill most neurons) oxygen-glucose deprivation (OGD) or a chemical OGD-mimic, ouabain/TBOA, by suppression of extracellular glutamate (glutamateₑₓ) elevations. However, subjecting preconditioned neurons to longer-duration supra-lethal insults caused neurotoxic glutamateₑₓ elevations, thereby identifying a ‘ceiling’ to neuroprotection. Neuroprotective ‘rescue’ of neurons could be obtained by administration of an NMDA receptor antagonist, MK-801, just before glutamateₑₓ rose during these supra-lethal insults. Next, we evaluated if these concepts of glutamateₑₓ suppression during lethal OGD, and a neuroprotective ceiling requiring MK-801 rescue under supra-lethal OGD, extended to the preconditioning field. In screening a panel of 42 diverse putative preconditioners, neuroprotection against normally lethal OGD was observed in 12 cases, which correlated with glutamateₑₓ suppression, both of which could be reversed, either by the inclusion of a glutamate uptake inhibitor (TBOA, to increase glutamateₑₓ levels) during OGD or by exposure to supra-lethal OGD. Administrating MK-801 during the latter stages of supra-lethal OGD again rescued neurons, although to varying degrees dependent on the preconditioning agent. Thus, ‘stress-testing’ against the harshest ischemic-like insults yet tested identifies the most efficacious preconditioners, which dictates how early MK-801 needs to be administered during the insult in order to maintain neuroprotection. Preconditioning delays a neurotoxic rise in glutamateₑₓ levels, thereby ‘buying time’ for acute anti-excitotoxic pharmacologic rescue.
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AffiliationHuman Health Therapeutics; National Research Council Canada
Peer reviewedYes
NPARC number23000113
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Record identifier86e769ca-9796-4d38-88f0-b35a7bf2dd98
Record created2016-06-03
Record modified2016-06-03
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