Synergistic Combinatorial Stroke Therapy: A Quantal Bioassay of a GABA Agonist and a Glutamate Antagonist

Lyden, Patrick D.; Jackson-Friedman, Catherine; Shin, Carol; Hassid, Steven

doi:10.1006/exnr.2000.7394

Cited by 47 publications

(22 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Maximal glutamate concentrations were 30 M, and the increase in GABA was up to 8 M, whereas in our culture system GABA concentrations were twice as high as those of glutamate in order to observe neuroprotection. In other experimental models of ischemia in vivo, muscimol, alone or in combination with the NMDA receptor antagonist MK-801, can prevent brain ischemic damage (Lyden et al, 2000). Baclofen has also been shown to protect against ischemic neurodegeneration, although it also causes hemorrhage (Jackson-Friedman et al, 1997).…”

Section: Discussionmentioning

confidence: 98%

High extracellular γ‐aminobutyric acid protects cultured neurons against damage induced by the accumulation of endogenous extracellular glutamate

Velasco

Tapia

2001

J of Neuroscience Research

View full text Add to dashboard Cite

The glutamate uptake inhibitor L-trans-2,4-pyrrolidine-dicarboxylate (PDC) induces glutamate accumulation and neuronal damage in cultured cells. We have used dissociated cortical cells in culture to study whether the toxicity induced by inhibiting glutamate uptake with PDC could be blocked by the simultaneous inhibition of gamma-aminobutyric acid (GABA) uptake, because both types of transporters are affected during an ischemic event. After 6 hr of exposure to 100 microM GABA or to four different GABA uptake inhibitors, the concentration of extracellular GABA was augmented from the basal 2 microM value to about 25 microM and 5 microM, respectively. These increases, however, did not result in protection against the neuronal damage induced by the accumulation of extracellular glutamate because of the simultaneous exposure to PDC. In contrast, when 100 microM GABA and an inhibitor of GABA uptake were added, after 6 hr the concentrations of GABA reached 50 microM, and neurons were protected from PDC-induced toxicity. The addition of the GABA(A) and GABA(B) receptor agonists muscimol and baclofen also partially protected against PDC-induced damage. The results suggest that the excitotoxic damage resulting from chronic gradual elevation of extracellular glutamate may be prevented by high concentrations of extracellular GABA, an effect mediated by activation of GABA(A) and GABA(B) receptors.

show abstract

Section: Discussionmentioning

confidence: 98%

High extracellular γ‐aminobutyric acid protects cultured neurons against damage induced by the accumulation of endogenous extracellular glutamate

Velasco

Tapia

2001

J of Neuroscience Research

View full text Add to dashboard Cite

show abstract

“…26,27) Hence, differences in glutamate versus GABA may be a useful correlate for ischemic excitotoxicity. Using a simplified model of excitatory versus inhibitory imbalance (i.e.…”

Section: Discussionmentioning

confidence: 99%

A Microdialysis Study of Effects of Gastrodin on Neurochemical Changes in the Ischemic/Reperfused Rat Cerebral Hippocampus

Zeng

Zhang

et al. 2007

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Gastrodin is a component extracted from the rhizome of Gastrodia elata, and has been shown to possess protective effects against neuron damage induced by simulated cerebral ischemia in previous studies. But its neurochemical effects on the ischemic brain had not been well studied. The present study aimed at evaluating the effects of gastrodin on the changes of transmitter amino acids in rat hippocampus during cerebral ischemia/reperfusion. Microdialysis sampling was performed during ischemia and early reperfusion periods in rats, and the glutamate and gamma-aminobutyric acid (GABA) in the dialysate were measured using high-performance liquid chromatography (HPLC). Administration of gastrodin (100 mg/kg) before ischemia significantly reduced the ischemia-induced elevation of glutamate levels during the postischemic period, increased the rise of extracellular GABA during the reperfusion periods, thus decreased the glutamate/GABA ratios during ischemia and reperfusion. These results provide insights to explain the neurochemical effects of gastrodin when applied prior to an ischemic event.

show abstract

“…Functional outcome does not always correlate with infarct size, but is the measure used in clinical trials of neuroprotective agents [24]. It has been reported that MK-801 prevents binding of glutamate at the NMDA subtype ionophore and limits opening of voltage-gated calcium channels [25,26]. This drug reverses the cascade of steps leading to neuronal cell death include: activation of the p38 MAPK-MEF2C (transcription factor) pathway, toxic effects of free radicals such as nitric oxide and reactive oxygen species, and activation of apoptosis-inducing enzymes including caspases [4].…”

Section: Controlmentioning

confidence: 99%

Combination Therapy of Rosiglitazone, a Peroxisome Proliferator‐Activated Receptor‐γ Ligand, and NMDA Receptor Antagonist (MK‐801) on Experimental Embolic Stroke in Rats

Allahtavakoli

Shabanzadeh

Roohbakhsh

et al. 2007

Basic Clin Pharma Tox

View full text Add to dashboard Cite

Peroxisome proliferator-activated receptor-γ (PPAR-γ ) agonists have been found to have potent anti-inflammatory actions and suggested as potential therapies for brain ischaemia. Glutamate is the most common excitatory neurotransmitter in the central nervous system and is released excessively during ischaemia. Stroke therapy will require combinations of drug classes, because no single drug class has yet been proven efficacious in human beings. The present study was conducted to assess whether N-methyl-d -aspartate (NMDA) receptor antagonist (MK-801) treatment can improve recovery from ischaemic brain injury and whether rosiglitazone, a PPAR-γ ligand, can increase its neuroprotective effect in an embolic model of stroke. Stroke was induced in rats by embolizing a preformed clot into the middle cerebral artery. Rosiglitazone (0.1 mg/kg, intraperitoneally) and MK-801 (0.1 mg/kg, intravenously) were injected immediately after embolization. Forty-eight hours later, the brains were removed, sectioned and stained with triphenyltetrazolum chloride and analysed by a commercial image processing software programme. Rosiglitazone and MK-801 alone or in combination decreased infarct volume by 49.16%, 50.26% and 81.32%, respectively (P < 0.001). Moreover, the combination therapy significantly decreased the infarct volume when compared to any drug used alone (P < 0.05). MK-801 reduced the brain oedema by 68% compared to the control group (P < 0.05), but rosiglitazone or combination did not show any significant effect. The drugs alone or in combination also demonstrated improved neurological function, but combination therapy was more effective on neurological deficits improving. Our data show that the combination of MK-801 and rosiglitazone is more neuroprotective in thromboembolic stroke than given alone; this effect perhaps represents a possible additive effect in the brain infarction.

show abstract

Synergistic Combinatorial Stroke Therapy: A Quantal Bioassay of a GABA Agonist and a Glutamate Antagonist

Cited by 47 publications

References 43 publications

High extracellular γ‐aminobutyric acid protects cultured neurons against damage induced by the accumulation of endogenous extracellular glutamate

High extracellular γ‐aminobutyric acid protects cultured neurons against damage induced by the accumulation of endogenous extracellular glutamate

A Microdialysis Study of Effects of Gastrodin on Neurochemical Changes in the Ischemic/Reperfused Rat Cerebral Hippocampus

Combination Therapy of Rosiglitazone, a Peroxisome Proliferator‐Activated Receptor‐γ Ligand, and NMDA Receptor Antagonist (MK‐801) on Experimental Embolic Stroke in Rats

Contact Info

Product

Resources

About