The Interaction of the Neuroprotective Compounds Riluzole and Phenobarbital with AMPA-Type Glutamate Receptors: A Patch-Clamp Study

Jin, Lingjing; Schlesinger, Friedrich; Song, Yunping; Dengler, Reinhard; Kenn, Klaus

doi:10.1159/000268641

Cited by 18 publications

(15 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Yet, there are several indications that this may not be the case. Barbiturate anesthetics have been reported to antagonize glutamate evoked currents in spinal neurons (MacDonald and Barker, 1978a,b, 1982; Macdonald and Kelly, 1994) and to reduce recombinant AMPA-type glutamate receptor channels expressed in cell lines (Jin et al, 2010). Also, barbiturates are more efficacious than benzodiazepines to treat various brain disorders including neonatal seizures (Cheng et al, 2002; Soderpalm, 2002; Carmo and Barr, 2005; Bartha et al, 2007) raising the possibility that additional non-GABA mediated signaling may underlie a better efficacy to treat various neonatal seizures.…”

Section: Introductionmentioning

confidence: 99%

Phenobarbital but Not Diazepam Reduces AMPA/kainate Receptor Mediated Currents and Exerts Opposite Actions on Initial Seizures in the Neonatal Rat Hippocampus

Nardou¹,

Yamamoto²,

Bhar³

et al. 2011

Front. Cell. Neurosci.

View full text Add to dashboard Cite

Diazepam (DZP) and phenobarbital (PB) are extensively used as first and second line drugs to treat acute seizures in neonates and their actions are thought to be mediated by increasing the actions of GABAergic signals. Yet, their efficacy is variable with occasional failure or even aggravation of recurrent seizures questioning whether other mechanisms are not involved in their actions. We have now compared the effects of DZP and PB on ictal-like events (ILEs) in an in vitro model of mirror focus (MF). Using the three-compartment chamber with the two immature hippocampi and their commissural fibers placed in three different compartments, kainate was applied to one hippocampus and PB or DZP to the contralateral one, either after one ILE, or after many recurrent ILEs that produce an epileptogenic MF. We report that in contrast to PB, DZP aggravated propagating ILEs from the start, and did not prevent the formation of MF. PB reduced and DZP increased the network driven giant depolarizing potentials suggesting that PB may exert additional actions that are not mediated by GABA signaling. In keeping with this, PB but not DZP reduced field potentials recorded in the presence of GABA and NMDA receptor antagonists. These effects are mediated by a direct action on AMPA/kainate receptors since PB: (i) reduced AMPA/kainate receptor mediated currents induced by focal applications of glutamate; (ii) reduced the amplitude and the frequency of AMPA but not NMDA receptor mediated miniature excitatory postsynaptic currents (EPSCs); (iii) augmented the number of AMPA receptor mediated EPSCs failures evoked by minimal stimulation. These effects persisted in MF. Therefore, PB exerts its anticonvulsive actions partly by reducing AMPA/kainate receptors mediated EPSCs in addition to the pro-GABA effects. We suggest that PB may have advantage over DZP in the treatment of initial neonatal seizures since the additional reduction of glutamate receptors mediated signals may reduce the severity of neonatal seizures.

show abstract

Section: Introductionmentioning

confidence: 99%

Phenobarbital but Not Diazepam Reduces AMPA/kainate Receptor Mediated Currents and Exerts Opposite Actions on Initial Seizures in the Neonatal Rat Hippocampus

Nardou¹,

Yamamoto²,

Bhar³

et al. 2011

Front. Cell. Neurosci.

View full text Add to dashboard Cite

show abstract

“…Riluzole is the only approved treatment and prolongs median survival by about 2 to 3 months in ALS patients (Miller et al, 2012) and by 10.5% in mice (Gurney et al, 1996). Riluzole induces an inhibition of glutamate release and modulation of both alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartate (NMDA) receptors (Jin et al, 2010; Cifra et al, 2013). However, Riluzole displays other diverse and multiple non-specific pharmacological properties (Cheah et al, 2010) that may cause adverse effects such as nausea, asthenia and raised alanine transferase (Miller et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Gacyclidine improves the survival and reduces motor deficits in a mouse model of amyotrophic lateral sclerosis

Gerber

Privat

Perrin

2013

Front. Cell. Neurosci.

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder typified by a massive loss of motor neurons with few therapeutic options. The exact cause of neuronal degeneration is unknown but it is now admitted that ALS is a multifactorial disease with several mechanisms involved including glutamate excitotoxicity. More specifically, N-methyl-D-aspartate (NMDA)-mediated cell death and impairment of the glutamate-transport has been suggested to play a key role in ALS pathophysiology. Thus, evaluating NMDAR antagonists is of high therapeutic interest. Gacyclidine, also named GK11, is a high affinity non-competitive NMDAR antagonist that may protect against motor neuron death in an ALS context. Moreover, GK11 presents a low intrinsic neurotoxicity and has already been used in two clinical trials for CNS lesions. In the present study, we investigated the influence of chronic administration of two doses of GK11 (0.1 and 1 mg/kg) on the survival and the functional motor activity of hSOD1G93A mice, an animal model of ALS. Treatment started at early symptomatic age (60 days) and was applied bi-weekly until the end stage of the disease. We first confirmed that functional alteration of locomotor activity was evident in the hSOD1G93A transgenic female mice by 60 days of age. A low dose of GK11 improved the survival of the mice by 4.3% and partially preserved body weight. Improved life span was associated with a delay in locomotor function impairment. Conversely, the high dose treatment worsened motor functions. These findings suggest that chronic administration of GK11 beginning at early symptomatic stage may be beneficial for patients with ALS.

show abstract

“…Dose-dependent increasing reopening currents were registered after removing the application pulse. The reason for reopening currents can be explained by fast unbinding of blocker from the open state of the receptor after removing the agonist and the blocker, as the channel will stay open for a short time before becoming deactivated [21] .…”

Section: Discussionmentioning

confidence: 99%

“…A piezo-driven ultrafast perfusion system was used for application of the neurotransmitter glutamate with or without tested drugs to excised outside-out membrane patches or small cells, as previously described [20,21] . Using this system solutions can be applied extremely fast and removed as well, which simulates synapse conditions, and the application and washout of glutamate were 80 s and 0.5 ms [22] .…”

Section: Sem (With N As Number Of Experiments)mentioning

confidence: 99%

The Two Different Effects of the Potential Neuroprotective Compound Minocycline on AMPA-Type Glutamate Receptors

Jin

Schlesinger²,

Guan³

et al. 2012

Pharmacology

Self Cite

View full text Add to dashboard Cite

Background: Minocycline has demonstrated neuroprotective effects in experimental neurodegenerative diseases. The aim of this study was to investigate if there is any direct interaction between minocycline and the AMPA-type receptor channels, and to elucidate the underlying molecular pharmacological mechanisms. Methods: The patch-clamp technique was used combined with an ultrafast solution exchange system to investigate the interaction of minocycline with recombinant AMPA-type glutamate receptor channels (homomeric GluR2flipGQ or nondesensitizing GluR2L504Y). Results: Dose-dependent decreases in the relative peak current amplitude (rAmp) and the relative steady-state current (rC_des) were found in coapplication experiments with GluR2L504Y receptors, but not in preincubation experiments. Furthermore, coapplication of 1 or 3 mmol/l minocycline showed a decrease in the fast time constant of current decay, and reopening currents were observed. But in the test with GluR2flipGQ receptors, rAmp, relative area under the curve and rC_des increased with increasing concentrations of minocycline, and the steady-state time constant also increased when 3 µmol/l glutamate were used as agonist. Conclusion: Minocycline modulates AMPA-type receptor channels in a combination of a weaker open-channel block effect and a stronger potentiation effect, and the latter effect arises mainly from attenuating the extent of receptor desensitization.

show abstract

The Interaction of the Neuroprotective Compounds Riluzole and Phenobarbital with AMPA-Type Glutamate Receptors: A Patch-Clamp Study

Cited by 18 publications

References 66 publications

Phenobarbital but Not Diazepam Reduces AMPA/kainate Receptor Mediated Currents and Exerts Opposite Actions on Initial Seizures in the Neonatal Rat Hippocampus

Phenobarbital but Not Diazepam Reduces AMPA/kainate Receptor Mediated Currents and Exerts Opposite Actions on Initial Seizures in the Neonatal Rat Hippocampus

Gacyclidine improves the survival and reduces motor deficits in a mouse model of amyotrophic lateral sclerosis

The Two Different Effects of the Potential Neuroprotective Compound Minocycline on AMPA-Type Glutamate Receptors

Contact Info

Product

Resources

About