Research Division for Life Sciences, Kumamoto Health Science University, Kumamoto, Japan.
Neurotoxicology. 2010 Mar;31(2):230-8. doi: 10.1016/j.neuro.2009.12.006. Epub 2009 Dec 28.
Mad honey poisoning caused by grayanotoxin (GTX) is associated with autonomic nervous system symptoms, such as excessive perspiration, hypersalivation, vomiting, and bradycardia. Neurons in the ventromedial hypothalamus (VMH) play an important role in body homeostasis and in the activity of the autonomic nervous system. Among the 18 isoforms of GTX found in mad honey, GTX I-IV are a unique class of toxic diterpenoids; GTX III is the principal toxic isomer. In the present study, we determined the effects of GTX III on synaptic transmission in VMH neurons. Both spontaneous and evoked GABA-ergic and glutamate-ergic postsynaptic currents were measured using patch clamp recordings in single VMH neurons which had been mechanically dissociated. GTX III increased the frequency of spontaneous GABA-ergic and glutamate-ergic postsynaptic currents (sIPSCs and sEPSCs, respectively) in a dose-dependent manner without affecting their amplitude, demonstrating that GTX III enhances transmitter release from both inhibitory and excitatory nerve terminals synapsing onto VMH neurons. GTX III significantly enhanced the amplitude and the success rate (Rsuc) of both evoked inhibitory and excitatory postsynaptic currents (eIPSCs and eEPSCs, respectively), suggesting that GTX III increases the probability of transmitter release from these terminals, and also the amount of transmitter released from a single nerve terminal. The action of GTX III on sIPSC frequency was absent in a Na(+)-free solution and in the presence of tetrodotoxin (TTX; 300 nM) or cadmium (Cd(2+); 100 microM). The present study indicates that GTX increases Ca(2+) influx through voltage-dependent Ca(2+) channels secondary to activation of voltage-dependent Na(+) channels in inhibitory and excitatory nerve terminals synapsing on VMH neurons, and the subsequent increased release of GABA and glutamate from these terminals may be responsible for the autonomic symptoms of GTX intoxication.
食马桑中毒是由灰毛豆毒素（GTX）引起的，与自主神经系统症状有关，如过度出汗、唾液分泌过多、呕吐和心动过缓。腹内侧下丘脑（VMH）中的神经元在体内平衡和自主神经系统活动中发挥重要作用。在马桑中发现的 18 种 GTX 异构体中，GTX I-IV 是一类独特的有毒二萜；GTX III 是主要的有毒异构体。在本研究中，我们确定了 GTX III 对 VMH 神经元突触传递的影响。使用机械分离的单个 VMH 神经元中的膜片钳记录测量了 GABA 能和谷氨酸能突触后电流的自发性和诱发释放。GTX III 以剂量依赖性方式增加自发性 GABA 能和谷氨酸能突触后电流（sIPSCs 和 sEPSCs）的频率，而不影响其幅度，表明 GTX III 增强了从抑制性和兴奋性神经末梢释放递质，这些末梢与 VMH 神经元形成突触。GTX III 显著增强了诱发的抑制性和兴奋性突触后电流（eIPSCs 和 eEPSCs）的幅度和成功率（Rsuc），表明 GTX III 增加了这些末梢释放递质的概率，以及单个神经末梢释放的递质量。在无钠离子溶液中，GTX III 对 sIPSC 频率的作用消失，并且存在河豚毒素（TTX；300 nM）或镉（Cd 2+；100 μM）。本研究表明，GTX 通过激活 VMH 神经元上与 GABA 和谷氨酸能神经末梢形成突触的电压依赖性 Na+通道，引起 Ca 2+内流增加，继而增加这些末梢中 GABA 和谷氨酸的释放，这可能是 GTX 中毒引起自主神经症状的原因。
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