Role of hormones and neurosteroids in epileptogenesis

Abstract

This article describes the emerging evidence of hormonal influence on epileptogenesis, which is a process whereby a brain becomes progressively epileptic due to an initial precipitating event of diverse origin such as brain injury, stroke, infection, or prolonged seizures. The molecular mechanisms underlying the development of epilepsy are poorly understood. Neuroinflammation and neurodegeneration appear to trigger epileptogenesis. There is an intense search for drugs that truly prevent the development of epilepsy in people at risk. Hormones play an important role in children and adults with epilepsy. Corticosteroids, progesterone, estrogens, and neurosteroids have been shown to affect seizure activity in animal models and in clinical studies. However, the impact of hormones on epileptogenesis has not been investigated widely. There is emerging new evidence that progesterone, neurosteroids, and endogenous hormones may play a role in regulating the epileptogenesis. Corticosterone has excitatory effects and triggers epileptogenesis in animal models. Progesterone has disease-modifying activity in epileptogenic models. The antiepileptogenic effect of progesterone has been attributed to its conversion to neurosteroids, which binds to GABA-A receptors and enhances phasic and tonic inhibition in the brain. Neurosteroids are robust anticonvulsants. There is pilot evidence that neurosteroids may have antiepileptogenic properties. Future studies may generate new insight on the disease-modifying potential of hormonal agents and neurosteroids in epileptogenesis.

Action of adrenal and gonadal steroid hormones on kainic acid-evoked seizures in a rat model of epileptogenesis

“…Experimental and clinical studies have demonstrated that progesterone produces powerful anti-convulsive effects in females [3,12,13]. It has also been found in in vivo experiments that progesterone and 5a- Table 2.…”

“…Testosterone has been demonstrated to have protective action against seizures at lower doses, but to be able to enhance seizure activities at higher doses due to its conversion to estrogens [3]. Results from animal models have shown that temporal lobe seizures induced by pilocarpine or kainic acid are more frequent and severe in male than in female rats most likely due to a-aromatization of testosterone to estradiol [16].…”

“…Epilepsy is a chronic devastating disease diagnosed by occurrence of unpredictable (two or more) and recurrent (separated by at least 24 h) seizures unprovoked by any immediate identified cause [3]. The generalized or partial tonic/ clonic seizures are main pathognomonic features of most forms of epilepsy.…”

“…The anti-seizure action is indirect following progesterone conversion to the active metabolite allopregnanolone, which acts as an allosteric agonist of g-aminobutyric acid GABA A receptors. The molecular mechanism of progesterone action is still incompletely revealed and might potentially include activation of progesterone receptors, increased synthesis of neurosteroids, modulation of oxidative cascades and decrease of prostaglandin synthesis by inhibition of Phospholipase A 2 (PLA 2 ) [3,12]. Progesterone has been shown to support the normal neuronal development and protect against neuronal damage in traumatic brain injuries [14].…”

Neuronal mechanisms of epileptogenesis

“…However, the impact of hormones on epileptogenesis is still underexplored and controversial. Further studies are required in the field to generate evidences on the therapeutic potential of hormonal agents in epileptogenesis (Reddy, 2013).…”