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FIGURE 4. From: Role of hormones and neurosteroids in epileptogenesis.

Potential molecular mechanisms of neurosteroid interruption of epileptogenesis. In the brain, allopregnanolone and related neurosteroids may retard epileptogenesis by the interruption of one or more of the pathways leading to development of epilepsy, which generally occurs following an initial precipitating event. Neurosteroids such as allopregnanolone binds to synaptic and extrasynaptic GABA-A receptors and enhances phasic and tonic inhibition within the brain, and thereby may affect epileptogenesis. Other potential mechanisms include modulation of neuroinflammation and neurogenesis in the brain.

Doodipala Samba Reddy. Front Cell Neurosci. 2013;7:115.

FIGURE 3. From: Role of hormones and neurosteroids in epileptogenesis.

Neurosteroid modulation of GABA-A receptors in the brain. Allopregnanolone and related neurosteroids binds and enhances GABA-A receptor-mediated inhibition in the brain. GABA-A receptors are pentameric with five protein subunits that form the chloride ion channel pore. Neurosteroids directly binds to the “neurosteroid binding sites” and potentiate the GABA-gated chloride currents. The neurosteroid binding sites are distinct from sites for GABA, benzodiazepines, and barbiturates. There are two types of GABA-A receptors with different functions. Post-synaptic GABA-A receptors, which are pentameric chloride channels composed of 2α2βγ subunits, mediate the phasic portion of GABAergic inhibition, while extrasynaptic GABA-A receptors, pentamers composed of 2α2βδ subunits, primarily contribute to tonic inhibition in the hippocampus. Neurosteroids activate both synaptic and extrasynaptic receptors and enhance the phasic and tonic inhibition, and thereby promote maximal network inhibition in the brain.

Doodipala Samba Reddy. Front Cell Neurosci. 2013;7:115.

FIGURE 2. From: Role of hormones and neurosteroids in epileptogenesis.

Biosynthesis and targets of steroid hormones and neurosteroids in the brain. Enzymatic pathways for the production of three prototype neurosteroids allopregnanolone, THDOC, and androstanediol are illustrated from cholesterol. Steroid hormones progesterone, deoxycorticosterone, and testosterone undergo two sequential A-ring reduction steps catalyzed by 5α-reductase and 3α-HSOR to form the 5α,3α-reduced neurosteroids. The conversion of intermediate precursor steroids into neurosteroids occurs in the hippocampus and several other regions within the brain, where they can affect neuronal function. As evident from the pathways, many modifications are made by the same enzymes, which can be blocked by specific inhibitors (trilostane, finasteride, and indomethacin). There are two mechanisms by which steroid hormones affects neuronal function: (i) binding to steroid receptors (PRs, ARs, or MRs; left panel) and (ii) conversion to GABA-A receptor-modulating neurosteroids (right panel). Progesterone, deoxycorticosterone, or testosterone binding to their cognate steroid receptors could lead to activation of gene expression in the brain. Neurosteroids rapidly modulate neuronal excitability by direct interaction with inhibitory GABA-A receptors in the brain.

Doodipala Samba Reddy. Front Cell Neurosci. 2013;7:115.

FIGURE 1. From: Role of hormones and neurosteroids in epileptogenesis.

Pathophysiology of epileptogenesis. Epileptogenesis is the process whereby a normal brain becomes progressively epileptic because of precipitating injury or risk factors such as TBI, stroke, brain infections, or prolonged seizures. Epilepsy development can be described in three stages: (1) the initial injury (epileptogenic event); (2) the latent period (silent period with no seizure activity); and (3) chronic period with spontaneous recurrent seizures. Although the precise mechanisms underlying spatial and temporal events remain unclear, epileptogenesis may involve an interaction of acute and delayed anatomic, molecular, and physiological events that are both complex and multifaceted. The initial precipitating factor activates diverse signaling events, such as inflammation, oxidation, apoptosis, neurogenesis, and synaptic plasticity, which eventually lead to structural and functional changes in neurons. These changes are eventually manifested as abnormal hyperexcitability and spontaneous seizures.

Doodipala Samba Reddy. Front Cell Neurosci. 2013;7:115.

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