Kokate T G, Juhng K N, Kirkby R D, Llamas J, Yamaguchi S, Rogawski M A
Neuronal Excitability Section, Epilepsy Research Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 10, Room 5N-250, Bethesda, MD 20892-1408, USA.
Brain Res. 1999 Jun 12;831(1-2):119-24. doi: 10.1016/s0006-8993(99)01287-1.
Pregnenolone sulfate (PS) is an endogenous neurosteroid known to antagonize GABA(A) receptor-mediated inhibitory responses and potentiate NMDA receptor-mediated excitatory responses in vitro. To assess the actions of the steroid as a modulator of seizure susceptibility in vivo, PS (30-300 nmol) was administered intracerebroventricularly in mice. At doses of 50 to 150 nmol, PS elicited seizures characterized by head jerks, rearing and falling, severe forelimb and hindlimb clonus, opisthotonos and explosive running. The seizures increased in severity and frequency with time and eventually progressed to status epilepticus, tonic hindlimb extension and death. The doses producing convulsions in 50% (CD(50)) and 97% (CD(97)) of animals were 92 and 205 nmol, respectively. A subconvulsant dose of PS (50 nmol) significantly increased the convulsant potencies of systemically administered pentylenetetrazol (30-50 mg/kg) and NMDA (50-100 mg/kg). Systemically administered PS at doses as high as 100 mg/kg failed to induce seizures or alter the convulsant potencies of pentylenetetrazol and NMDA. Protection against PS (205 nmol)-induced seizures and lethality was conferred by the GABA(A) receptor positive allosteric modulators clonazepam and allopregnanolone, and by the NMDA receptor antagonists dizocilpine and (R)-CPP. The overall pharmacological profile suggests that the convulsant actions of PS are mediated predominantly via its effects on GABA(A) receptors, and also possibly by effects on NMDA receptors.
硫酸孕烯醇酮（PS）是一种内源性神经甾体，已知其在体外可拮抗GABA(A)受体介导的抑制反应，并增强NMDA受体介导的兴奋反应。为了评估该甾体在体内作为癫痫易感性调节剂的作用，将PS（30 - 300 nmol）经脑室注射到小鼠体内。在50至150 nmol的剂量下，PS引发的癫痫发作表现为头部抽搐、竖毛和跌倒、严重的前肢和后肢阵挛、角弓反张和爆发性奔跑。癫痫发作的严重程度和频率随时间增加，最终发展为癫痫持续状态、后肢强直性伸展和死亡。在50%（CD(50)）和97%（CD(97)）的动物中产生惊厥的剂量分别为92和205 nmol。亚惊厥剂量的PS（50 nmol）显著增加了全身给药的戊四氮（30 - 50 mg/kg）和NMDA（50 - 100 mg/kg）的惊厥效力。高达100 mg/kg剂量的全身给药PS未能诱发癫痫发作或改变戊四氮和NMDA的惊厥效力。GABA(A)受体正向变构调节剂氯硝西泮和别孕烯醇酮，以及NMDA受体拮抗剂地佐环平（MK-801）和（R）-CPP可预防PS（205 nmol）诱导的癫痫发作和致死性。总体药理学特征表明，PS的惊厥作用主要通过其对GABA(A)受体的作用介导，也可能通过对NMDA受体的作用介导。
