Cerebral radioprotection by pentobarbital: Dose-response characteristics and association with GABA agonist activity

Journal Article · Tue May 01 04:00:00 EDT 1990 · Journal of Neurosurgery; (USA)

DOI:https://doi.org/10.3171/jns.1990.72.5.0749· OSTI ID:6833289

Olson, J J; Friedman, R; Orr, K; Delaney, T; Oldfield, E H ^[1]

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1. National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD (USA)

Pentobarbital reduces cerebral radiation toxicity; however, the mechanism of this phenomenon remains unknown. As an anesthetic and depressant of cerebral metabolism, pentobarbital induces its effects on the central nervous system by stimulating the binding of gamma-aminobutyric acid (GABA) to its receptor and by inhibiting postsynaptic excitatory amino acid activity. The purpose of this study is to investigate the role of these actions as well as other aspects of the radioprotective activity of pentobarbital. Fischer 344 rats were separated into multiple groups and underwent two dose-response evaluations. In one set of experiments to examine the relationship of radioprotection to pentobarbital dose, a range of pentobarbital doses (0 to 75 mg/kg) were given intraperitoneally prior to a constant-level radiation dose (70 Gy). In a second series of experiments to determine the dose-response relationship of radiation protection to radiation dose, a range of radiation doses (10 to 90 Gy) were given with a single pentobarbital dose. Further groups of animals were used to evaluate the importance of the timing of pentobarbital administration, the function of the (+) and (-) isomers of pentobarbital, and the role of an alternative GABA agonist (diazepam). In addition, the potential protective effects of alternative methods of anesthesia (ketamine) and induction of cerebral hypometabolism (hypothermia) were examined. Enhancement of survival time from acute radiation injury due to high-dose single-fraction whole-brain irradiation was maximal with 60 mg/kg of pentobarbital, and occurred over the range of all doses examined between 30 to 90 Gy. Protection was seen only in animals that received the pentobarbital before irradiation. Administration of other compounds that enhance GABA binding (Saffan and diazepam) also significantly enhanced survival time.

• OSTI ID: 6833289
• Journal Information: Journal of Neurosurgery; (USA), Journal Name: Journal of Neurosurgery; (USA) Vol. 72:5; ISSN 0022-3085; ISSN JONSA
• Country of Publication: United States
• Language: English

Related Subjects

560152* -- Radiation Effects on Animals-- Animals
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
AMINO ACIDS
AMINOBUTYRIC ACID
ANESTHETICS
ANIMALS
AUTONOMIC NERVOUS SYSTEM AGENTS
AZINES
BARBITURATES
BIOCHEMICAL REACTION KINETICS
BODY
BODY TEMPERATURE
BRAIN
CARBOXYLIC ACIDS
CENTRAL NERVOUS SYSTEM
CENTRAL NERVOUS SYSTEM DEPRESSANTS
DOSE-RESPONSE RELATIONSHIPS
DOSES
DRUGS
HETEROCYCLIC COMPOUNDS
HYPNOTICS AND SEDATIVES
HYPOTHERMIA
KINETICS
MAMMALS
MEMBRANE PROTEINS
NERVOUS SYSTEM
NEUROREGULATORS
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
ORGANS
PROTEINS
PYRIMIDINES
RADIATION DOSES
RADIATION PROTECTION
RADIOSENSITIVITY EFFECTS
RATS
REACTION KINETICS
RECEPTORS
RODENTS
SURVIVAL CURVES
VERTEBRATES