Salazar Patricia, Tapia Ricardo, Rogawski Michael A
Epilepsy Research Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 49 Convent Drive Room 5A75 MSC 4457, Bethesda, MD 20892-4457, USA.
Epilepsy Res. 2003 Jun-Jul;55(1-2):71-82. doi: 10.1016/s0920-1211(03)00112-8.
The neurosteroids allopregnanolone (5alpha-pregnan-3alpha-ol-20-one; 5alpha,3alpha-P) and its 5beta-epimer pregnanolone (5beta,3alpha-P), and pregnenolone sulfate (PS) were examined for effects on spontaneous epileptiform discharges induced by 100 microM picrotoxin (PTX) and 55 microM 4-aminopyridine (4-AP) in the CA3 region of the rat hippocampal slice. At a concentration of 10 microM, 5alpha,3alpha-P partially reduced PTX-induced bursting and at 30 and 90 microM completely suppressed bursting. In contrast, 100 microM 5beta,3alpha-P failed to alter the discharge frequency. 5alpha,3alpha-P depressed 4-AP-induced bursting with similar potency as in the PTX model; 100 microM 5beta,3alpha-P was also partially effective. In the 4-AP model, 5alpha,3alpha-P inhibited both the more frequent predominantly positive-going potentials as well as the less frequent negative-going potentials that may be generated by synchronous GABAergic interneuron firing. PS enhanced the PTX bursting frequency and, in the 4-AP model, increased the frequency of negative potentials but did not alter the frequency of positive potentials. By itself, PS did not induce bursting. The effects of the steroids in the in vitro seizure models largely correspond with their activities on GABA(A) receptors; suppression of discharges may occur as a result of direct activation of these receptors rather than modulation of GABA-mediated synaptic responses. PTX and 4-AP-induced bursting in the hippocampal slice are useful models for directly assessing neurosteroid effects on seizure susceptibility under conditions that eliminate the factor of brain bioavailability.
研究了神经甾体别孕烯醇酮（5α-孕烷-3α-醇-20-酮；5α,3α-P）及其5β-差向异构体孕烯醇酮（5β,3α-P）和硫酸孕烯醇酮（PS）对大鼠海马切片CA3区由100μM印防己毒素（PTX）和55μM 4-氨基吡啶（4-AP）诱导的自发性癫痫样放电的影响。浓度为10μM时，5α,3α-P可部分降低PTX诱导的爆发性放电，浓度为30μM和90μM时可完全抑制爆发性放电。相比之下，100μM 5β,3α-P未能改变放电频率。5α,3α-P抑制4-AP诱导的爆发性放电的效力与在PTX模型中相似；100μM 5β,3α-P也有部分效果。在4-AP模型中，5α,3α-P既抑制了更频繁的主要正向电位，也抑制了可能由同步GABA能中间神经元放电产生的较不频繁的负向电位。PS提高了PTX诱导的爆发性放电频率，在4-AP模型中，增加了负向电位的频率，但未改变正向电位的频率。单独使用时，PS不会诱导爆发性放电。甾体在体外癫痫模型中的作用在很大程度上与其对GABA(A)受体的活性相对应；放电的抑制可能是由于这些受体的直接激活，而不是对GABA介导的突触反应的调节。海马切片中PTX和4-AP诱导的爆发性放电是在消除脑生物利用度因素的条件下直接评估神经甾体对癫痫易感性影响的有用模型。
