title: Finasteride inhibits the disease-modifying activity of progesterone in the hippocampus kindling model of epileptogenesis.
abstract: Progesterone (P) plays an important role in seizure susceptibility in women with epilepsy. Preclinical and experimental studies suggest that P appears to interrupt epileptogenesis, which is a process whereby a normal brain becomes progressively susceptible to recurrent, unprovoked seizures due to precipitating risk factors. Progesterone has not been investigated widely for its potential disease-modifying activity in epileptogenic models. Recently, P has been shown to exert disease-modifying effects in the kindling model of epileptogenesis. However, the mechanisms underlying the protective effects of P against epileptogenesis remain unclear. In this study, we investigated the role of P-derived neurosteroids in the disease-modifying activity of P. It is hypothesized that 5α-reductase converts P to allopregnanolone and related neurosteroids that retard epileptogenesis in the brain. To test this hypothesis, we utilized the mouse hippocampus kindling model of epileptogenesis and investigated the effect of finasteride, a 5α-reductase and neurosteroid synthesis inhibitor. Progesterone markedly retarded the development of epileptogenesis and inhibited the rate of kindling acquisition to elicit stage 5 seizures. Pretreatment with finasteride led to complete inhibition of the P-induced retardation of the limbic epileptogenesis in mice. Finasteride did not significantly influence the acute seizure expression in fully kindled mice expressing stage 5 seizures. Thus, neurosteroids that potentiate phasic and tonic inhibition in the hippocampus, such as allopregnanolone, may mediate the disease-modifying effect of P, indicating a new role of neurosteroids in acquired limbic epileptogenesis and temporal lobe epilepsy.
authors: Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M Health Science Center, Bryan, TX 77807, USA. reddy@medicine.tamhsc.edu
authors: Doodipala
authors: D
authors: Samba Reddy
authors: G
authors: G
authors: Ramanathan
mesh_terms: D058891:5-alpha Reductase Inhibitors / Q000008:administration & dosage*; D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004558:Electric Stimulation / Q000009:adverse effects; D004827:Epilepsy / Q000188:drug therapy* / Q000209:etiology; D005260:Female; D018120:Finasteride / Q000008:administration & dosage*; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology*; D007696:Kindling, Neurologic / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011374:Progesterone / Q000627:therapeutic use*; D018709:Statistics, Nonparametric
chemical_list: D058891:5-alpha Reductase Inhibitors; D000927:Anticonvulsants; D011374:Progesterone; D018120:Finasteride