Pharmacological preconditioning with GYKI 52466: a prophylactic approach to neuroprotection

Abstract

Some toxins and drugs can trigger lasting neuroprotective mechanisms that enable neurons to resist a subsequent severe insult. This “pharmacological preconditioning” has far-reaching implications for conditions in which blood flow to the brain is interrupted. We have previously shown that in vitro preconditioning with the AMPA receptor antagonist GYKI 52466 induces tolerance to kainic acid (KA) toxicity in hippocampus. This effect persists well after washout of the drug and may be mediated via inverse agonism of G-protein coupled receptors (GPCRs). Given the amplifying nature of metabotropic modulation, we hypothesized that GYKI 52466 may be effective in reducing seizure severity at doses well below those normally associated with adverse side effects. Here we report that pharmacological preconditioning with low-dose GYKI imparts a significant protection against KA-induced seizures in vivo. GYKI (3 mg/kg, s.c.), 90–180 min prior to high-dose KA, markedly reduced seizure scores, virtually abolished all level 3 and level 4 seizures, and completely suppressed KA-induced hippocampal c-FOS expression. In addition, preconditioned animals exhibited significant reductions in high frequency/high amplitude spiking and ECoG power in the delta, theta, alpha, and beta bands during KA. Adverse behaviors often associated with higher doses of GYKI were not evident during preconditioning. The fact that GYKI is effective at doses well-below, and at pre-administration intervals well-beyond previous studies, suggests that a classical blockade of ionotropic AMPA receptors does not underlie anticonvulsant effects. Low-dose GYKI preconditioning may represent a novel, prophylactic strategy for neuroprotection in a field almost completely devoid of effective pharmaceuticals.

Glutamate Excitotoxicity Is Involved in the Induction of Paralysis in Mice after Infection by a Human Coronavirus with a Single Point Mutation in Its Spike Protein

“…To verify the noncytotoxic effect of the GYKI-52466 solution, sham-infected mice received the same dose of AMPA receptor antagonist. As described in the literature, this pharmacological dose has been reported to have no behavioral effects and to induce neuroprotective actions (20,40).…”

Cardiac electrographic and morphological changes following status epilepticus: Effect of clonidine

“…KA administration resulted in a rapid induction of hypoactivity followed by WDS behaviours before developing limbic seizures. 21 Clonidine was effective in slowing the onset to seizure behaviours, decreasing cumulative seizure score and WDS behaviours. This was similar to previous reports where clonidine decreased WDS and protected against limbic seizures.…”

“…Transmitter implantation and electrode positioning procedures were performed as previously described. 13,21 Animals were housed individually post-surgery and left to recovery for 7 days before seizure induction.…”

Src/CK2/PTEN-Mediated GluN2B and CREB Dephosphorylations Regulate the Responsiveness to AMPA Receptor Antagonists in Chronic Epilepsy Rats

“…GYKI 52,466 (10 mg/kg) is another non-competitive AMPAR negative allosteric modulator, which shows effective anti-convulsive effects in a number of epilepsy models. However, GYKI 52,466 debilitates motor and cognitive side effects have been routinely documented at doses over 20 mg/kg [ 33 , 34 ]. Thus, it is likely that AMPAR antagonists may be more effective to inhibit spontaneous seizure activity than NMDAR antagonists.…”