Like other GABAergic agents, neurosteroids are inactive or only weakly active against seizures elicited by maximal electroshock. Neurosteroids are highly active in the 6-Hz model, a better paradigm in which limbic-like seizures are induced by electrical stimulation of lower frequency and longer duration than in the maximal electroshock test Kaminski et al.
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In addition, neurosteroids are also highly effective in suppressing seizures due to withdrawal of GABA-A receptor modulators including neurosteroids and benzodiazepines, as well as other types of agents such as ethanol and cocaine Devaud et al. In contrast to benzodiazepines, where utility in the chronic treatment of epilepsy is limited by tolerance, anticonvulsant tolerance is not evident with neurosteroids Kokate et al. Novel therapeutic approaches are being developed based on the emerging information on neurosteroid interaction with GABA-A receptors Reddy and Rogawski, ; Murashima and Yoshii, Neurosteroids may play a role in chronic epilepsy.
Neurosteroid modulation of tonic activation of extrasynaptic GABA-A receptors can regulate excitability during epileptogenicity. Given the complex plasticity in GABA-A receptors in epilepsy, it is difficult to predict the functional outcome of altered subunit compositions. A consistent finding from studies that have used various models of chronic epilepsy is that tonic conductances are largely preserved in epileptic brain around the time when synaptic inhibition is reduced Mtchedlishvili et al. All of these changes may exacerbate seizures in epileptic animals and reduce the potency but not efficacy of endogenous neurosteroids.
If local neurosteroidogenesis is enhanced, this may in part counteract the epileptogenesis-induced changes. There is emerging evidence that endogenous neurosteroids play a role in regulating epileptogenesis Edwards et al. Using the kindling model, we demonstrated that the development and persistence of limbic epileptogenesis are impaired in mice lacking PRs Reddy and Mohan, We determined the rate of rapid kindling in both control animals and those which had received injections of progesterone with or without concurrent finasteride treatment Reddy and Mohan, These findings are consistent with a contributory role of neurosteroids in limbic epileptogenesis.
Thus, it is possible that inhibition of neurosteroids could incite mechanisms that may promote 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. The Psc is a critical enzyme for the biosynthesis of neurosteroids Figure 2. It is present in neurons, oligodendrocytes, astrocytes, and activated microglia. Following pilocarpine-induced status epilepticus in the rat, the neurosteroidogenic enzyme Pscc is upregulated for several weeks, suggesting that it may be associated with promotion of neurosteroidogenesis Biagini et al. Ordinarily, rats develop spontaneous recurrent seizures following a latent period of similar duration to the period during which Pscc is elevated.
The role of neurosteroids in delaying seizure onset in the pilocarpine model is confirmed using finasteride, which can exacerbate seizures by inhibition of neurosteroid synthesis. Inhibiting neurosteroid synthesis with finasteride accelerated the onset of spontaneous recurrent seizures Biagini et al. The development of epilepsy is linked to complex alterations in neuroplastic mechanisms. Dysregulation of neurosteroid synthesis may also play a role. This premise is being tested in various epileptogenic models Reddy and Mohan, We investigated the role of the prototype endogenous neurosteroid allopregnanolone in controlling limbic epileptogenesis.
Treatment with finasteride, a neurosteroid synthesis inhibitor, resulted in a significant increase in epileptogenesis in the hippocampus kindling model Ramanathan and Reddy, Exogenous administration of allopregnanolone, at doses that produce levels similar to gonadotropins, markedly inhibited epileptogenesis.
In female epilepsy rats, finasteride treatment exacerbates seizure frequency Lawrence et al. Neurosteroid-mediated increase in tonic inhibition in the hippocampus could inhibit the spread of the seizure discharge from the hippocampal focus and thereby suppress the rate of development of behavioral kindled seizure activity without affecting the focal electrographic discharges Figure 4. The exact mechanisms are unclear. Increased tonic inhibition by allopregnanolone is shown to impair the NMDA N -methyl- D -aspartate receptor-mediated excitability in the hippocampus Shen et al. Based on these pilot studies, it is suggested that augmentation of neurosteroid synthesis may represent a unique strategy for preventing or retarding epileptogenesis.
The steroid negative modulatory action on GABA-A receptors occurs through a reduction in channel opening frequency, although the precise mechanism of block is not well understood Mienville and Vicini, ; Akk et al. Direct injection of PS to rodent brain elicits seizures which increase in severity and frequency with time and eventually progress to status epilepticus, tonic hindlimb extension, and death of the animals Kokate et al.
However, systemic administration of PS does not induce overt seizure activity Kokate et al.
The pharmacology of PS seizures is poorly understood, but both clonazepam and allopregnanolone can effectively protect against PS-induced seizure activity Kokate et al. The proconvulsant effect of DHEAS is reduced by progesterone, an intermediate precursor of neurosteroid synthesis. Moreover, exogenous application or endogenous stimulation of DHEAS modulates hippocampal GABA inhibition possibly by entraining hippocampal neurons to theta rhythm Steffensen, , suggesting a potential physiological relevance of the proconvulsant effects of DHEAS in animals. Epilepsy shows sex differences in incidence, progression, and severity, as well as in responsiveness to therapy.
The incidence of epilepsy is generally higher in males than in females. More women than men are diagnosed with idiopathic generalized epilepsy, but localization-related symptomatic epilepsies are more frequent in men, and cryptogenic localization-related epilepsies are more frequent in women Hauser, ; Christensen et al. Sex differences have been described in patients with TLE, with respect to distinct regional distribution of brain dysfunction during interictal periods as well as to the extent of neuronal damage. Women tend to have less structural atrophy than men, regardless of the seizure rate.
However, the precise mechanisms underlying the sex-dependent differentiation of the specific neuronal circuits, particularly brain regions involved in seizure control, are not clear.
Jasper's Basic Mechanisms of the Epilepsies 5th Edition
Many factors are involved in determining sex differences in seizure susceptibility, including the presence of sexual dimorphism in brain structures involved in seizure generation and control, in regional connectivity, sensitivity of neurotransmitter systems, receptor distribution, and dependence on hormonal milieu and on changes in sex hormone levels during the life span. Neurosteroids exhibit a strong gender differences in their pharmacological effects with more potency in females than males Reddy, b.
Steroid hormones such as progesterone and testosterone play a key role in the gender-related differences in susceptibility to seizures. However, the precise mechanism underlying such sexual dimorphism is obscure. Many of the biological actions of steroid hormones are mediated through intracellular receptors. Studies have suggested that these sex differences in seizure sensitivity are due to gender-specific distribution of steroid hormones or other sexually dimorphic characteristics in specific brain areas relevant to epilepsy.
For example, estradiol reduces seizure-induced hippocampal injury in ovariectomized female but not in male rats, suggesting that the effects of estradiol on seizure threshold and damage may be determined by sex-related differences in the hormonal environment. Neurosteroids may play a key role in gender-related differences in seizure susceptibility Reddy, b.
Both progesterone and allopregnanolone protect against experimental seizures in both male and female mice lacking PRs Reddy et al. However, female mice exhibit significantly enhanced sensitivity to the protective activity of allopregnanolone as compared to males. In the pilocarpine seizure test, androstanediol has similar increased potency in female mice, which is not related to differences in pharmacokinetics of this neurosteroid. These results underscore the possible role of endogenous neurosteroids in gender-related differences in seizure susceptibility and protection.
Steroid hormones such as progesterone and DOC have long been known to have sedative, anesthetic, and antiseizure properties Aird, ; Gyermek et al. Studies during the past three decades have uncovered that neurosteroids mediate such rapid effects of steroid hormones in the brain Reddy et al.
Unlike steroid hormones, the acute effects of neurosteroids are not related to interactions with classical steroid hormone receptors that regulate gene transcription. Moreover, neurosteroids are not themselves active at intracellular steroid receptors. They modulate brain excitability primarily by interaction with neuronal membrane receptors and ion channels, principally GABA-A receptors. Therefore, like other GABAergic agents, neurosteroids have sedative and anxiolytic properties Reddy, a. At high doses, neurosteroids cause anesthetic effects. This feature is exemplified with alphaxolone, which was introduced as intravenous anesthetic in s.
It was withdrawn later from the market due to toxicity of the solvent used for formulation of this synthetic neurosteroid. Although natural neurosteroids can be used for therapeutic purpose in patients with epilepsy, certain obstacles prevent the clinical use of endogenous neurosteroids.
Synthetic neurosteroids, which are devoid of such hormonal actions, could provide a rational alternative approach to therapy Reddy and Kulkarni, Recently, a number of synthetic analogs of allopregnanolone and other neurosteroids are tested in animals and human trials. Results from the clinical trials of ganaxolone demonstrated a benign side effect profile Reddy and Woodward, More than subjects adults and children have received this neurosteroid in Phase 1 and 2 trials.
Overall, the drug is safe and well tolerated. The most common side effect is reversible dose-related sedation.
Jasper’s Basic Mechanisms of the Epilepsies, Fourth Edition: Epilepsia: Vol 51, No s5
Other adverse events reported by few subjects include dizziness, fatigue, and somnolence, which indicate its GABAergic effects. The major part of the pathophysiology of epilepsy is epileptogenesis, whereby a normal brain becomes progressively epileptic because of injury factors. Since the Curing Epilepsy conference in , there has been more focused research on optimizing approaches in preventing epilepsy and there is emphasis on several translation models.
Reduction in neuroinflammation and neurodegeneration is a widely targeted approach for curing epilepsy. Despite intense search for drugs that interrupt epileptogenesis, presently there is no FDA-approved drug available for prevention of epilepsy development in patients at risk. It is essential to find a lead target, such as a receptor or signaling pathway that is crucial for the progression of epileptogenesis that can be disrupted by pharmacological agents to prevent or retard epilepsy.
A variety of pharmacological agents have been tested in animal models of epileptogenesis and in clinical trials in patients with a risk factor for epilepsy. However, the outcomes are not highly promising. The pipeline of new drugs for clinical development is very limited. A summary of agents that are currently in development for epilepsy is listed in Table 5. Steroid hormones, especially corticosteroids, estrogen, and progesterone play an important role in epilepsy. Repetitive stress and corticosteroids increases the risk of epilepsy.
There is emerging evidence that neurosteroids may play a role in limbic epileptogenesis. Neurosteroids that enhance the GABAergic inhibition within the brain are potent anticonvulsants and they regulate neural excitability networks by enhancing the phasic and tonic inhibition in the hippocampus, a critical region involved in the TLE.
Tonic inhibition is therefore an attractive target for antiepileptogenic drugs Figure 4.