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Combination treatment with ethyl pyruvate and aspirin enhances neuroprotection in the postischemic brain.
- Source :
-
Neurotoxicity research [Neurotox Res] 2010 Jan; Vol. 17 (1), pp. 39-49. Date of Electronic Publication: 2009 Jul 28. - Publication Year :
- 2010
-
Abstract
- Ethyl pyruvate (EP), a simple aliphatic ester of pyruvic acid, has been shown to act as an anti-inflammatory molecule in various pathological conditions, which include sepsis or hemorrhagic shock. Recently, we showed that ethyl pyruvate has a neuroprotective effect in the postischemic brain and also in KA-induced pathogenesis in the brain. In this study, we examined whether aspirin augments neuroprotective effect of ethyl pyruvate in transient focal ischemia model by complementing the neuroprotective effects of ethyl pyruvate. Although, most of neuroprotective effect of aspirin has been attributed to the anti-platelet action, aspirin also has direct neuroprotective effects, including NF-kappaB inhibition. Ethyl pyruvate dose-dependently suppressed infarct formation in the postischemic brain, wherein intravenous administration of 5 mg/kg ethyl pyruvate 30 min after the occlusion reduced infarct volume to 34.5 +/- 15.5% (n = 6, P < 0.01) of that of the untreated control. In combination with aspirin (5 mg/kg, i.v.), the neuroprotective effect was enhanced, resulting in 16.0 +/- 5.9% (n = 6, P < 0.01) infarct volume. The time window for synergistic neuroprotection by ethyl pyruvate and aspirin extended to 9 h post-MCAO. The synergistic reduction in infarct volume was accompanied by suppression of the clinical manifestations associated with cerebral ischemia including motor impairment and neurological deficits. Inflammatory processes including microglial activation and proinflammatory cytokine expression were notably suppressed by the combination treatment in the postischemic brain and in primary microglia cultures, wherein ethyl pyruvate and aspirin modulate NF-kappaB signaling differentially. Aspirin interferes with IkappaB phosphorylation and degradation in the cytoplasm, possibly by specifically inhibiting IkappaB kinase-beta, whereas, the effect of ethyl pyruvate seems to occur in the nucleus, where it may interfere with the binding of NF-kappaB to responsive promoter elements in the target genes. Similar enhancement in neuroprotective effect was also observed in primary cortical cultures after NMDA or Zn(2+) treatment or oxygen-glucose deprivation. Together, these results indicate that combination treatment of ethyl pyruvate and aspirin affords synergistic neuroprotection in the postischemic brain with a wide therapeutic window, in part via differential modulation of the NF-kappaB signaling pathway.
- Subjects :
- Animals
Astringents pharmacology
Astrocytes drug effects
Brain Infarction etiology
Brain Infarction prevention & control
Cells, Cultured
Cerebral Cortex cytology
Cytokines metabolism
Disease Models, Animal
Dose-Response Relationship, Drug
Drug Therapy, Combination methods
Embryo, Mammalian
Excitatory Amino Acid Agonists pharmacology
Gene Expression Regulation drug effects
Glucose deficiency
Hypoxia
Infarction, Middle Cerebral Artery pathology
Infarction, Middle Cerebral Artery physiopathology
Male
N-Methylaspartate pharmacology
NF-kappa B metabolism
Neurons drug effects
Polysaccharides pharmacology
Rats
Rats, Sprague-Dawley
Rotarod Performance Test
Severity of Illness Index
Time Factors
Zinc Sulfate pharmacology
Aspirin therapeutic use
Infarction, Middle Cerebral Artery prevention & control
Neuroprotective Agents therapeutic use
Pyruvates therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1476-3524
- Volume :
- 17
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Neurotoxicity research
- Publication Type :
- Academic Journal
- Accession number :
- 19636661
- Full Text :
- https://doi.org/10.1007/s12640-009-9075-4