Abstract | BACKGROUND AND PURPOSE: The excitotoxic effects of glutamate can be blocked almost completely with gamma-aminobutyric acid ( GABA), an inhibitory neurotransmitter, in cell culture, tissue slices, and in some animal models. After stroke in rats, we showed previously that an agonist of GABA, muscimol, was as neuroprotective as MK-801, an antagonist of glutamate. To obtain further neuroprotection and to avoid the side effects associated with high doses of MK-801, we wanted to assess the efficacy of the two agents in combination. METHODS: Treatment was administered 5 minutes after embolic cerebral ischemia in Sprague-Dawley rats. The subjects were rated using a neurological evaluation 48 hours later. Visual-spatial learning was measured 8 to 10 weeks after stroke, after which we measured the volume of each cerebral hemisphere and several large cerebral compartments. Treatment groups included saline (n = 27), MK-801 1.0 mg/kg (n = 23), muscimol 1.0 mg/kg (n = 17), and both agents together using a dose of 0.5 mg/kg each (n = 25). RESULTS: A probit analysis of the neurological ratings revealed a protective effect of muscimol used alone ( MK-801 potency ratio, 2.0; P = NS; muscimol potency ratio, 4.0; P < .05) and a protective effect of the combination (potency ratio, 5.0; P < .05). Focal ischemia caused a moderate to severe delay in the acquisition of visual-spatial information, which was completely eliminated by the combination treatment but only partially ameliorated with MK-801 or muscimol alone. Ischemia reduced the cerebral hemisphere volume from 0.42 mm3 to 0.34 mm3 (P < .0001), the volume density of cortex from 22% to 17% of total cerebral volume (P < .01), and that of hippocampus from 4.3% to 3.0% (P < .05). Only the combination was neuroprotective, as measured by the ratio of the lesioned to the contralateral hemisphere volume (P = .013). The combination treatment and MK-801 protected the hemisphere volume, the cortex, and the hippocampus and reduced the size of visible infarction. CONCLUSIONS: Combination therapy, using a glutamate antagonist and a GABA-A agonist, appeared to protect the brain and ameliorate a defect in learning behavior after stroke. The combination may have been more effective than either agent used alone, although further study of higher doses is needed.
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Authors | P D Lyden, L Lonzo |
Journal | Stroke
(Stroke)
Vol. 25
Issue 1
Pg. 189-96
(Jan 1994)
ISSN: 0039-2499 [Print] United States |
PMID | 7903492
(Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Drug Combinations
- Excitatory Amino Acid Antagonists
- Muscimol
- Glutamic Acid
- gamma-Aminobutyric Acid
- Dizocilpine Maleate
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Topics |
- Animals
- Brain
(pathology)
- Brain Ischemia
(drug therapy, pathology, physiopathology)
- Cerebral Infarction
(pathology)
- Dizocilpine Maleate
(therapeutic use)
- Drug Combinations
- Excitatory Amino Acid Antagonists
- Glutamic Acid
- Learning
(drug effects)
- Male
- Microspheres
- Motor Activity
(drug effects)
- Muscimol
(therapeutic use)
- Organ Size
- Rats
- Rats, Sprague-Dawley
- Reaction Time
(drug effects)
- gamma-Aminobutyric Acid
(physiology)
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