Pisu Maria Giuseppina, Mostallino Maria Cristina, Dore Riccardo, Mura Maria Luisa, Maciocco Elisabetta, Russo Emilio, De Sarro Giovambattista, Serra Mariangela
CNR Institute of Neuroscience, Italy.
J Neurochem. 2008 Sep;106(6):2502-14. doi: 10.1111/j.1471-4159.2008.05538.x. Epub 2008 Jul 4.
The role of neuroactive steroids and GABA(A) receptors in the generation of spontaneous spike-and-wave discharges (SWDs) was investigated in the WAG/Rij rat model of absence epilepsy. The plasma, cerebrocortical, and thalamic concentrations of the progesterone metabolite 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-TH PROG) were increased in the WAG/Rij rat at 2 months of age compared with those in control (Wistar) rats. In contrast, the brain and peripheral levels of 3alpha,5alpha-tetrahydrodeoxycorticosterone (3alpha,5alpha-TH DOC) did not differ between the two rat strains at this age. At 6 months of age, when absence epilepsy worsens in WAG/Rij rats, the plasma concentration of 3alpha,5alpha-TH PROG remained high whereas that of 3alpha,5alpha-TH DOC had increased, the cerebrocortical levels of both 3alpha,5alpha-TH PROG and 3alpha,5alpha-TH DOC had increased, and the thalamic concentrations of these metabolites had decreased. At 6 months of age the expression of the alpha(4) and delta subunits of the GABA(A) receptor in relay nuclei was increased. Finally, chronic stress induced by social isolation elicited a reduction in the amount of 3alpha,5alpha-TH PROG in the thalamus of 2-month-old WAG/Rij rats that was associated with a reduction in the number and overall duration of SWDs at 6 months of age. Absence epilepsy in the WAG/Rij rat is thus associated with changes in the abundance of neuroactive steroids and in the expression of specific GABA(A) receptor subunits in the thalamus, a brain area key to the pathophysiology of this condition.
在失神癫痫的WAG/Rij大鼠模型中，研究了神经活性甾体和γ-氨基丁酸A（GABA(A)）受体在自发性棘波-慢波放电（SWD）产生中的作用。与对照（Wistar）大鼠相比，2月龄WAG/Rij大鼠血浆、大脑皮质和丘脑孕酮代谢物3α-羟基-5α-孕烷-20-酮（3α,5α-TH PROG）的浓度升高。相比之下，在这个年龄段，两种大鼠品系的大脑和外周3α,5α-四氢脱氧皮质酮（3α,5α-TH DOC）水平没有差异。在6月龄时，当WAG/Rij大鼠的失神癫痫病情加重时，3α,5α-TH PROG的血浆浓度仍然很高，而3α,5α-TH DOC的血浆浓度升高，3α,5α-TH PROG和3α,5α-TH DOC的大脑皮质水平均升高，而这些代谢物的丘脑浓度降低。在6月龄时，中继核中GABA(A)受体α(4)和δ亚基的表达增加。最后，社会隔离诱导的慢性应激导致2月龄WAG/Rij大鼠丘脑中3α,5α-TH PROG含量减少，这与6月龄时SWD的数量和总持续时间减少有关。因此，WAG/Rij大鼠的失神癫痫与神经活性甾体丰度的变化以及丘脑中特定GABA(A)受体亚基的表达变化有关，丘脑是这种疾病病理生理学中的关键脑区。
