Lallement G, Foquin A, Baubichon D, Burckhart M F, Carpentier P, Canini F
Unité de Neuropharmacologie, Centre de Recherches du Service de Santé des Armées, La Tronche, France.
Neurotoxicology. 1998 Dec;19(6):759-66.
Stress due to forced swimming was recently shown to allow penetration of pyridostigmine (PYR) into the brain of mice. Accordingly, it was suggested that in troops exposed to emotional stress under conditions of war, as during the Gulf War, the BBB may have unexpectedly become permeable to PYR thus leading to an increased frequency of CNS symptoms. In this study, the entry of PYR into the brain was investigated in guinea pigs subjected to different heat stress levels. In a first group, guinea pigs were maintained at room temperature for 2 hours, their core temperature remaining stable at about 39.8 degrees C. In a second group, animals were placed in a climatic chamber in order to keep their core temperature at 41.5 degrees C for 2 hours. In a third group, animals were subjected to a high ambient temperature (42.6 degrees C) during about 2 hours and developed heatstroke symptoms, their core temperature progressively increasing and reaching around 44.3 degrees C. In each group, the stress of the animals was assessed by measuring the increase of plasma cortisol level. PYR (0.2 mg/kg, s.c.) was injected 90 minutes after beginning the experiment. Penetration of the drug into the brain was examined by measurement of acetylcholinesterase (AChE) activity in the cortex, the striatum and the hippocampus of the animals 30 minutes after PYR administration. A passage of this drug into the brain was also evaluated autoradiographically after i.v. injection of tritiated PYR 90 minutes after the beginning of the experiment (100 microCi/animal). Whatever the group examined, no entry of PYR into the CNS could be detected. Exposure to an ambient temperature at 42.6 degrees C for 2 hours resulted by itself in a partial inhibition of cerebral AChE activity. Our results, which agree with previous data obtained in humans exposed to heat stress, are opposite to the recent research showing a central passage of PYR in mice following a forced swim stress test. This demonstrated that the penetration of PYR into the brain of rodents under stress depends on the experimental conditions used (animal species, nature of the stressor, etc.). Extrapolations to humans of results primarily obtained in rodents about central passage of a drug under stress must thus be done very carefully.
最近研究表明，强迫游泳造成的应激可使吡啶斯的明（PYR）进入小鼠大脑。因此有人提出，在战争等情况下，如海湾战争期间，暴露于情绪应激的部队中，血脑屏障（BBB）可能意外地对PYR变得通透，从而导致中枢神经系统（CNS）症状出现频率增加。在本研究中，我们研究了处于不同热应激水平的豚鼠中PYR进入大脑的情况。第一组豚鼠在室温下饲养2小时，其核心体温保持在约39.8℃稳定。第二组动物被置于气候箱中，以使它们的核心体温在41.5℃保持2小时。第三组动物在约2小时内处于高温环境（42.6℃）并出现中暑症状，其核心体温逐渐升高并达到约44.3℃。在每组中，通过测量血浆皮质醇水平的升高来评估动物的应激情况。在实验开始90分钟后皮下注射PYR（0.2mg/kg）。在给予PYR 30分钟后，通过测量动物大脑皮层、纹状体和海马体中的乙酰胆碱酯酶（AChE）活性来检查药物进入大脑的情况。在实验开始90分钟后静脉注射氚标记的PYR（100μCi/动物）后，也通过放射自显影评估该药物进入大脑的情况。无论检查哪一组，均未检测到PYR进入中枢神经系统。暴露于42.6℃的环境温度2小时本身会导致大脑AChE活性部分受到抑制。我们的结果与先前在暴露于热应激的人类中获得的数据一致，与最近关于强迫游泳应激试验后PYR在小鼠中进入中枢的研究结果相反。这表明应激条件下PYR进入啮齿动物大脑取决于所使用的实验条件（动物种类、应激源性质等）。因此，将主要在啮齿动物中获得的关于应激条件下药物进入中枢的结果外推至人类时必须非常谨慎。
