Citraro Rita, Russo Emilio, Di Paola Eugenio Donato, Ibbadu Guido Ferreri, Gratteri Santo, Marra Rosario, De Sarro Giovambattista
Section of Pharmacology, Department of Experimental and Clinical Medicine, Faculty of Medicine and Surgery, University of Catanzaro, Policlinico Mater Domini, Via T. Campanella, 115, 88100 Catanzaro, Italy.
Neuropharmacology. 2006 Jun;50(8):1059-71. doi: 10.1016/j.neuropharm.2006.02.011. Epub 2006 Apr 24.
Neurosteroids are synthesized in the brain and have been demonstrated to modulate various cerebral functions. Allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one), a naturally occurring neurosteroid, and ganaxolone (3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one), a synthetic derivative, are two neurosteroids acting as positive allosteric modulators of the GABA(A) receptor complex acting on a specific steroid recognition site. Both agents antagonize generalized tonic-clonic seizures in various animal models of epilepsy. Pregnenolone sulphate (3beta-hydroxy-5alpha-pregnen-20-one 3-sulphate; PS) is a negative allosteric modulator of GABA(A) receptors and a positive modulator of the NMDA receptors. We have evaluated the effects of such compounds in a genetic animal model of absence epilepsy, the WAG/Rij rat. Animals were chronically implanted with five frontoparietal cortical electrodes for electrocorticogram (EEG) recordings and bilateral guide cannulae into specific brain areas of the cortico-thalamic circuit in order to evaluate the effects of these compounds on the number and duration of epileptic spike-wave discharges (SWDs). The focal and bilateral microinjection of the two GABA(A) positive modulators into some thalamic nuclei (nucleus ventralis posteromedialis, nucleus reticularis thalami, nucleus ventralis posterolateralis was usually able to significantly worsen the occurrence of SWDs in WAG/Rij rats. Whereas both compounds were able to reduce the number and duration of SWDs when microinjected into the peri-oral region of the primary somatosensory cortex. The effects of PS were more complex depending on both the dose and the site of administration, generally, at low doses in thalamic nuclei and cortex, PS induced an increase of absence activity and a reduction at higher doses. These findings suggest that neurosteroids might play a role in absence epilepsies and that it might depend on the involvement of specific neuronal areas.
神经甾体在大脑中合成，并已被证明可调节多种脑功能。别孕烯醇酮（3α-羟基-5α-孕烷-20-酮）是一种天然存在的神经甾体，而加奈索酮（3α-羟基-3β-甲基-5α-孕烷-20-酮）是一种合成衍生物，这两种神经甾体作为GABA(A)受体复合物的正变构调节剂，作用于特定的甾体识别位点。在各种癫痫动物模型中，这两种药物均能对抗全身强直阵挛性发作。硫酸孕烯醇酮（3β-羟基-5α-孕烯-20-酮3-硫酸盐；PS）是GABA(A)受体的负变构调节剂和NMDA受体的正调节剂。我们在失神癫痫的遗传动物模型WAG/Rij大鼠中评估了这类化合物的作用。动物被长期植入五个额顶叶皮质电极用于脑电图（EEG）记录，并在皮质-丘脑回路的特定脑区双侧植入引导套管，以评估这些化合物对癫痫棘波-慢波放电（SWD）的数量和持续时间的影响。将这两种GABA(A)正调节剂局部和双侧微量注射到一些丘脑核（腹后内侧核、丘脑网状核、腹后外侧核）通常能够显著加重WAG/Rij大鼠SWD的发生。而当将这两种化合物微量注射到初级体感皮层的口周区域时，它们都能够减少SWD的数量和持续时间。PS的作用更为复杂，这取决于剂量和给药部位，一般来说，在丘脑核和皮层中低剂量时，PS会诱发失神活动增加，而在高剂量时则会减少。这些发现表明神经甾体可能在失神癫痫中起作用，并且这可能取决于特定神经元区域的参与。
