Neurosteroids and epilepsy

Biagini, Giuseppe; Panuccio, Gabriella; Avoli, Massimo

doi:10.1097/wco.0b013e32833735cf

Cited by 88 publications

(66 citation statements)

References 41 publications

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“…Recent studies suggest that neurosteroids play a role in epileptogenesis (Edwards et al, 2001; Biagini et al, 2006; 2009a; 2010; Reddy et al, 2010; Reddy, 2013a). Using the kindling model, we demonstrated that the development and persistence of limbic epileptogenesis are impaired in mice lacking progesterone receptors (Reddy and Mohan, 2011).…”

Section: Anticonvulsant and Antiepileptogenic Activity Of Neurosteroidsmentioning

confidence: 99%

Neurosteroids and their role in sex-specific epilepsies

Reddy

2014

Neurobiology of Disease

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Neurosteroids are involved in sex-specific epilepsies. Allopregnanolone and related endogenous neurosteroids in the brain control excessive neuronal excitability and seizure susceptibility. Neurosteroids activate GABA-A receptors, especially extrasynaptic αβδ-GABA-A receptor subtypes that mediate tonic inhibition and thus dampen network excitability. Our studies over the past decade have shown that neurosteroids are broad-spectrum anticonvulsants and confer seizure protection in various animal models. Neurosteroids also exert antiepileptogenic effects. There is emerging evidence on a critical role for neurosteroids in the pathophysiology of the sex-specific forms of epilepsies such as catamenial epilepsy, a menstrual cycle-related seizure disorder in women. Catamenial epilepsy is a neuroendocrine condition in which seizures are clustered around specific points in the menstrual cycle, most often around the perimenstrual or periovulatory period. Apart from ovarian hormones, fluctuations in neurosteroid levels could play a critical role in this gender-specific epilepsy. Neurosteroids also regulate the plasticity of synaptic and extrasynaptic GABA-A receptors in the hippocampus and other regions involved in epilepsy pathology. Based on these studies, we proposed a neurosteroid replacement therapy for catamenial epilepsy. Thus, neurosteroids are novel drug targets for pharmacotherapy of epilepsy.

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Section: Anticonvulsant and Antiepileptogenic Activity Of Neurosteroidsmentioning

confidence: 99%

Neurosteroids and their role in sex-specific epilepsies

Reddy

2014

Neurobiology of Disease

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“…Natural neurosteroids such as allopregnanolone are not orally active, but one new synthetic neurosteroid, ganaxolone, the 3 ␤ -methyl analogue of allopregnanolone, is orally active, lacks hormonal side effects, and has entered phase II clinical trials for infantile spasms, partial seizures, and catamenial epilepsy [Reddy, 2010]. A neuroactive steroid like ganaxolone may be useful in the treatment of anxiety and seizures associated with FXS, and has advantages over benzodiazepines, given the low occurrence of side effects and evidence of preferential effects at extrasynaptic, tonically active ␦ -subunit-containing receptors [Biagini et al, 2010;Mihalek et al, 1999;Reddy, 2010].…”

Section: Gabaergic System Components As Potential Therapeutic Targetsmentioning

confidence: 99%

Fragile X Syndrome: The GABAergic System and Circuit Dysfunction

2011

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Fragile X syndrome (FXS) is a neurodevelopmental disorder characterized by intellectual disability, sensory hypersensitivity, and high incidences of autism spectrum disorders and epilepsy. These phenotypes are suggestive of defects in neural circuit development and imbalances in excitatory glutamatergic and inhibitory GABAergic neurotransmission. While alterations in excitatory synapse function and plasticity are well-established in Fmr1 knockout (KO) mouse models of FXS, a number of recent electrophysiological and molecular studies now identify prominent defects in inhibitory GABAergic transmission in behaviorally relevant forebrain regions such as the amygdala, cortex, and hippocampus. In this review, we summarize evidence for GABAergic system dysfunction in FXS patients and Fmr1 KO mouse models alike. We then discuss some of the known developmental roles of GABAergic signaling, as well as the development and refinement of GABAergic synapses as a framework for understanding potential causes of mature circuit dysfunction. Finally, we highlight the GABAergic system as a relevant target for the treatment of FXS.

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“…Several observations support this notion. In the pilocarpine model, rats develop seizures after a latent period that mirrors that of P450scc elevation, and treatment with finasteride (a neurosteroid synthesis inhibitor) is capable of reducing latency-to-seizure expression after SE, as well as exacerbating seizure intensity [215]. …”

Section: Neurosteroids As Potential Endogenous Antiepileptogenic mentioning

confidence: 99%

Novel therapeutic approaches for disease-modification of epileptogenesis for curing epilepsy

Clossen

Reddy

2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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This article describes the recent advances in epileptogenesis and novel therapeutic approaches for the prevention of epilepsy, with a special emphasis on the pharmacological basis of disease-modification of epileptogenesis for curing epilepsy. Here we assess animal studies and human clinical trials of epilepsy spanning 1982–2016. Epilepsy arises from a number of neuronal factors that trigger epileptogenesis, which is the process by which a brain shifts from a normal physiologic state to an epileptic condition. The events precipitating these changes can be of diverse origin, including traumatic brain injury, cerebrovascular damage, infections, chemical neurotoxicity, and emergency seizure conditions such as status epilepticus. Expectedly, the molecular and system mechanisms responsible for epileptogenesis are not well defined or understood. To date, there is no approved therapy for the prevention of epilepsy. Epigenetic dysregulation, neuroinflammation, and neurodegeneration appear to trigger epileptogenesis. Targeted drugs are being identified that can truly prevent the development of epilepsy in at-risk people. The promising agents include rapamycin, COX-2 inhibitors, TRK inhibitors, epigenetic modulators, JAK-STAT inhibitors, and neurosteroids. Recent evidence suggests that neurosteroids may play a role in modulating epileptogenesis. A number of promising drugs are under investigation for the prevention or modification of epileptogenesis to halt the development of epilepsy. Some drugs in development appear rational for preventing epilepsy because they target the initial trigger or related signaling pathways as the brain becomes progressively more prone to seizures. Additional research into the target validity and clinical investigation is essential to make new frontiers in curing epilepsy.

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Neurosteroids and epilepsy

Cited by 88 publications

References 41 publications

Neurosteroids and their role in sex-specific epilepsies

Neurosteroids and their role in sex-specific epilepsies

Fragile X Syndrome: The GABAergic System and Circuit Dysfunction

Novel therapeutic approaches for disease-modification of epileptogenesis for curing epilepsy

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