Reddy D S
Department of Molecular Biomedical Sciences, North Carolina State University College of Veterinary Medicine, 4700 Hillsborough Street, Raleigh, NC 27606, USA.
Neuroscience. 2004;129(1):195-207. doi: 10.1016/j.neuroscience.2004.08.002.
Testosterone modulates seizure susceptibility in animals and humans, but the underlying mechanisms are obscure. Here, testosterone modulation of seizure susceptibility is hypothesized to occur through its conversion to neurosteroids with "anticonvulsant" and "proconvulsant" actions, and hence the net effect of testosterone on neural excitability and seizure activity depends on the levels of distinct testosterone metabolites. Testosterone undergoes metabolism to neurosteroids via two distinct pathways. Aromatization of the A-ring converts testosterone into 17beta-estradiol. Reduction of testosterone by 5alpha-reductase generates 5alpha-dihydrotestosterone (DHT), which is then converted to 3alpha-androstanediol (3alpha-Diol), a powerful GABA(A) receptor-modulating neurosteroid with anticonvulsant properties. Systemic doses of testosterone decreased seizure threshold in rats and increased the incidence and severity of pentylenetetrazol (PTZ)-induced seizures in mice. These proconvulsant effects of testosterone were associated with increases in plasma 17beta-estradiol and 3alpha-Diol concentrations. Pretreatment with letrozole, an aromatase inhibitor that blocks the conversion of testosterone to 17beta-estradiol, significantly inhibited testosterone-induced exacerbation of seizures. The 5alpha-reductase inhibitor finasteride significantly reduced 3alpha-Diol levels and also blocked letrozole's ability to inhibit the proconvulsant effects of testosterone. The 5alpha-reduced metabolites of testosterone, DHT and 3alpha-Diol, had powerful anticonvulsant activity in the PTZ test. Letrozole or finasteride had no effect on seizure protection by DHT and 3alpha-Diol, but indomethacin partially reversed DHT actions. 3alpha-Diol but not 3beta-androstanediol, a GABA(A) receptor-inactive stereoisomer, suppressed 4-aminopyridine-induced spontaneous epileptiform bursting in rat hippocampal slices. Thus, testosterone-derived neurosteroids 3alpha-Diol and 17beta-estradiol could contribute to the net cellular actions of testosterone on neural excitability and seizure susceptibility.
睾酮可调节动物和人类的癫痫易感性，但其潜在机制尚不清楚。在此，推测睾酮对癫痫易感性的调节是通过其转化为具有“抗惊厥”和“促惊厥”作用的神经甾体来实现的，因此睾酮对神经兴奋性和癫痫活动的净效应取决于不同睾酮代谢产物的水平。睾酮通过两条不同的途径代谢为神经甾体。A环的芳香化作用将睾酮转化为17β-雌二醇。5α-还原酶将睾酮还原生成5α-二氢睾酮（DHT），然后DHT再转化为3α-雄烷二醇（3α-二醇），这是一种具有抗惊厥特性的强效γ-氨基丁酸A型（GABA(A)）受体调节神经甾体。全身给予睾酮会降低大鼠的癫痫阈值，并增加小鼠戊四氮（PTZ）诱导癫痫发作的发生率和严重程度。睾酮的这些促惊厥作用与血浆中17β-雌二醇和3α-二醇浓度的升高有关。用芳香化酶抑制剂来曲唑预处理可阻断睾酮向17β-雌二醇的转化，显著抑制睾酮诱导的癫痫发作加重。5α-还原酶抑制剂非那雄胺可显著降低3α-二醇水平，还能阻断来曲唑抑制睾酮促惊厥作用的能力。睾酮的5α-还原代谢产物DHT和3α-二醇在PTZ试验中具有强大的抗惊厥活性。来曲唑或非那雄胺对DHT和3α-二醇的抗癫痫保护作用无影响，但吲哚美辛可部分逆转DHT的作用。3α-二醇而非GABA(A)受体无活性的立体异构体3β-雄烷二醇可抑制大鼠海马切片中4-氨基吡啶诱导的自发性癫痫样爆发。因此，睾酮衍生的神经甾体3α-二醇和17β-雌二醇可能有助于睾酮对神经兴奋性和癫痫易感性的细胞净作用。
