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  • It is well known that neurosteroids such

    2022-11-07

    It is well-known that neurosteroids such as testosterone and their metabolites endogenously modulate neural excitability in animals and humans. Testosterone has protective effects against seizures induced by KA and PTZ (Frye et al., 2001b; Reddy, 2004b). Estrogens, on the other hand, have proconvulsant effects in animals and humans. The role of estrogens in etiology of epilepsy is still not understood (Scharfman and MacLusky, 2006). In several studies, estrogens have shown to exacerbate seizures, for instance, in PTZ-kindled, amygdala-kindled and KA-induced seizures in rodents (Buterbaugh, 1989; Woolley, 2000). Clinically too, estrogens enhance seizures in females suffering from epilepsy (Backstrom, 1976; Morrell, 1999). The role of estrogens in enhancing seizures is controversial, but in a large number of studies, it has been shown to be proconvulsant and to enhance Fmoc-Cys(Trt)-ol excitability (Buterbaugh, 1989; Woolley, 2000). However, the molecular mechanism by which 17β-estradiol exerts proconvulsant action remains obscure. Testosterone can modulate seizures through conversion to different metabolites with proconvulsant and anticonvulsant actions by two distinct pathways. It gets converted into metabolite 17β-estradiol by aromatase enzyme which is found to be proconvulsant. On the other hand, the 5α-reductase enzyme converts testosterone into intermediate 5α-DHT, which gets further metabolized by 3α-HSOR to form 3α-Diol. 3α-Diol is Fmoc-Cys(Trt)-ol structurally related to allopregnanolone and is known to exhibit anticonvulsant effects via modulating GABAA receptors (Reddy, 2004b). 3α-Diol has protective effects against seizures induced by PTZ, picrotoxin, and beta-carboline ester (Frye et al., 2009; Reddy, 2004a, b). Many pieces of evidence exist which indicates the anticonvulsant action of allopregnanolone (Biagini et al., 2010). Recently, a study was conducted to evaluate allopregnanolone and ganaxolone induced by agent tetramethylenedisulfotetramine (TETS). Both allopregnanolone and ganaxolone terminated SE in 92% and 75% of animals respectively. Allopregnanolone was found to be more effective possibly due to greater potency on GABAA receptors (Zolkowska et al., 2018). Furthermore, in the pilocarpine model of SE, inhibition of allopregnanolone via finasteride reduced the time to onset of spontaneous seizures. These results suggest that induction of neurosteroid synthesis is related to the delayed onset of seizures (Biagini et al., 2009; Biagini et al., 2013). Similarly, in a recent clinical study, it has been shown that low levels of allopregnanolone were present in patients suffering from epilepsy (Meletti et al., 2017). As expected, letrozole significantly reduced the hippocampal levels of 17β-estradiol. Thus, it is possible that anticonvulsant effects of letrozole are mediated by reduction of proconvulsant hormone in the brain by inhibiting aromatization of testosterone to 17β-estradiol. Our results are in agreement with previous studies which showed that diminution in seizures was observed by a reduction in the level of 17β-estradiol (Rashid et al., 2015; Reddy, 2004b; Sato and Woolley, 2016). Further, finasteride and indomethacin reversed the letrozole-induced reduction of hippocampal 17β-estradiol levels. Both inhibit the enzymes 5α-reductase and 3α-HSOR, increasing the levels of testosterone, which is then aromatized into proconvusant 17β-estradiol. As a result, the incidence of seizures intensified.
    Conclusion To conclude, our findings demonstrate the anticonvulsant potential of letrozole, an aromatase inhibitor, against KA-induced seizures in mice possibly by reduction of conversion of testosterone to proconvulsant, 17β-estradiol and redirecting the synthesis of testosterone metabolite 3α-Diol with known anticonvulsant actions. Letrozole does not show neuroprotection against KA-induced neuronal damage; however, it also does not enhance the neuronal damage. Even conventional antiepileptic drugs demonstrate no significant neuroprotection as evidenced in our study with valproate and various other studies (Araujo et al., 2004; Bittigau et al., 2002). Thus, acute aromatase inhibition may be used in the treatment of status epilepticus that requires further investigations.