Publications by authors named "Doodipala Samba Reddy"

66 Publications

Comparative profile of refractory status epilepticus models following exposure of cholinergic agents pilocarpine, DFP, and soman.

Neuropharmacology 2021 Apr 17:108571. Epub 2021 Apr 17.

Department of Neuroscience and Experimental Therapeutics, Texas A&M University Health Science Center College of Medicine, Bryan, TX 77807.

Status epilepticus (SE) is a medical emergency with continuous seizure activity that causes profound neuronal damage, morbidity, or death. SE incidents can arise spontaneously, but mostly are elicited by seizurogenic triggers. Chemoconvulsants such as the muscarinic agonist pilocarpine and organophosphates (OP), such as the pesticide diisopropylfluorophosphate (DFP) and the nerve agent soman, can induce SE. Pilocarpine, DFP, and soman share a common feature of cholinergic crisis that transitions into a state of refractory SE, but their comparative profiles remain unclear. Here, we evaluated the comparative convulsant profile of pilocarpine, DFP, and soman to produce refractory SE and brain damage in rats. Behavioral and electrographic seizures were monitored for 24 h after exposure and the extent of brain injury was determined by histological markers of neuronal injury and degeneration. Seizures were elicited rather slowly after pilocarpine as compared to DFP or soman, which caused rapid onset of spiking that swiftly developed into persistent SE. Time-course of SE activity after DFP was comparable to that after soman, a potent nerve agent. Diazepam controlled pilocarpine-induced SE, but it was ineffective in reducing OP-induced SE. All three agents produced modestly different degrees of neuronal injury and neurodegeneration in the brain. These results reveal distinct convulsant and neuronal injury patterns following exposure to cholinergic agonists, OP pesticides, and nerve agents. A battery of SE models, especially SE induced by cholinergic agents and other etiologies including epilepsy and brain tumors, is essential to identify novel anticonvulsant therapies for the management of refractory SE.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuropharm.2021.108571DOI Listing
April 2021

Molecular mechanisms of sex differences in epilepsy and seizure susceptibility in chemical, genetic and acquired epileptogenesis.

Neurosci Lett 2021 04 18;750:135753. Epub 2021 Feb 18.

Department of Neuroscience and Experimental Therapeutics, Texas A&M University College of Medicine, Bryan, TX, United States.

This article provides a succinct overview of sex differences in epilepsy and putative molecular mechanisms underlying sex differences in seizure susceptibility in chemical, genetic, and acquired epileptogenesis. The susceptibility to excitability episodes and occurrence of epileptic seizures are generally higher in men than women. The precise molecular mechanisms remain unclear, but differences in regional morphology and neural circuits in men and women may explain differential vulnerability to seizures and epileptogenic cascades. Changes in seizure sensitivity can be attributed to steroid hormones, including fluctuations in neurosteroids as well as neuroplasticity in their receptor signaling systems. Other potential neurobiological bases for sex differences in epilepsies include differences in brain development, neurogenesis, neuronal chloride homeostasis, and neurotrophic and glial responses. In catamenial epilepsy, a gender-specific neuroendocrine condition, epileptic seizures are most often clustered around a specific menstrual period in adult women. A deeper understanding of the molecular and neural network basis of sex differences in seizures and response to antiepileptic drugs is highly warranted for designing effective, sex-specific therapies for epilepsy, epileptogenesis, and seizure disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neulet.2021.135753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994197PMC
April 2021

Does Stress Trigger Seizures? Evidence from Experimental Models.

Curr Top Behav Neurosci 2021 Feb 6. Epub 2021 Feb 6.

Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, TX, USA.

This chapter describes the experimental evidence of stress modulation of epileptic seizures and the potential role of corticosteroids and neurosteroids in regulating stress-linked seizure vulnerability. Epilepsy is a chronic neurological disorder that is characterized by repeated seizures. There are many potential causes for epilepsy, including genetic predispositions, infections, brain injury, and neurotoxicity. Stress is a known precipitating factor for seizures in individuals suffering from epilepsy. Severe acute stress and persistent exposure to stress may increase susceptibility to seizures, thereby resulting in a higher frequency of seizures. This occurs through the stress-mediated release of cortisol, which has both excitatory and proconvulsant properties. Stress also causes the release of endogenous neurosteroids from central and adrenal sources. Neurosteroids such as allopregnanolone and THDOC, which are allosteric modulators of GABA-A receptors, are powerful anticonvulsants and neuroprotectants. Acute stress increases the release of neurosteroids, while chronic stress is associated with severe neurosteroid depletion and reduced inhibition in the brain. This diminished inhibition occurs largely as a result of neurosteroid deficiencies. Thus, exogenous administration of neurosteroids (neurosteroid replacement therapy) may offer neuroprotection in epilepsy. Synthetic neurosteroid could offer a rational approach to control neurosteroid-sensitive, stress-related epileptic seizures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/7854_2020_191DOI Listing
February 2021

Brain structural and neuroendocrine basis of sex differences in epilepsy.

Handb Clin Neurol 2020 ;175:223-233

Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, TX, United States. Electronic address:

This chapter reviews the current information about sex differences in epilepsy and potential mechanisms underlying sex differences in seizure susceptibility and epilepsy. The susceptibility to and occurrence of seizures are generally higher in men than women. There is gender-specific epilepsies such as catamenial epilepsy, a neuroendocrine condition in which seizures are most often clustered around the perimenstrual or periovulatory period in adult women. Structural differences in cerebral morphology, the structural and functional circuits may render men and women differentially vulnerable to seizure disorders and epileptogenic processes. Changes in seizure sensitivity are evident at puberty, pregnancy, and menopause, often attributed to circulating steroid hormones and neurosteroids as well as neuroplasticity in receptor systems. An improved understanding of the sexual dimorphism in neural circuits and the neuroendocrine basis of sex differences or resistance to protective drugs is essential to develop sex-specific therapies for seizure conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/B978-0-444-64123-6.00016-3DOI Listing
January 2020

Sex Differences in the Epilepsies and Associated Comorbidities: Implications for Use and Development of Pharmacotherapies.

Pharmacol Rev 2020 10;72(4):767-800

Department of Molecular and Integrative Physiology, Neuroscience Program, and Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, Illinois (C.A.C.); Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas (D.S.R.); Neuroscience Department, Tufts University School of Medicine, Boston, Massachusetts (J.M.); and Departments of Pharmacology and Physiology and Neuroscience, Georgetown University, Washington, D.C. (P.A.F.).

The epilepsies are common neurologic disorders characterized by spontaneous recurrent seizures. Boys, girls, men, and women of all ages are affected by epilepsy and, in many cases, by associated comorbidities as well. The primary courses of treatment are pharmacological, dietary, and/or surgical, depending on several factors, including the areas of the brain affected and the severity of the epilepsy. There is a growing appreciation that sex differences in underlying brain function and in the neurobiology of epilepsy are important factors that should be accounted for in the design and development of new therapies. In this review, we discuss the current knowledge on sex differences in epilepsy and associated comorbidities, with emphasis on those aspects most informative for the development of new pharmacotherapies. Particular focus is placed on sex differences in the prevalence and presentation of various focal and generalized epilepsies; psychiatric, cognitive, and physiologic comorbidities; catamenial epilepsy in women; sex differences in brain development; the neural actions of sex and stress hormones and their metabolites; and cellular mechanisms, including brain-derived neurotrophic factor signaling and neuronal-glial interactions. Further attention placed on potential sex differences in epilepsies, comorbidities, and drug effects will enhance therapeutic options and efficacy for all patients with epilepsy. SIGNIFICANCE STATEMENT: Epilepsy is a common neurological disorder that often presents together with various comorbidities. The features of epilepsy and seizure activity as well as comorbid afflictions can vary between men and women. In this review, we discuss sex differences in types of epilepsies, associated comorbidities, pathophysiological mechanisms, and antiepileptic drug efficacy in both clinical patient populations and preclinical animal models.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1124/pr.119.017392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7495340PMC
October 2020

Magnetic resonance imaging analysis of long-term neuropathology after exposure to the nerve agent soman: correlation with histopathology and neurological dysfunction.

Ann N Y Acad Sci 2020 11 15;1480(1):116-135. Epub 2020 Jul 15.

Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas.

Nerve agents (NAs) produce acute and long-term brain injury and dysfunction, as evident from the Japan and Syria incidents. Magnetic resonance imaging (MRI) is a versatile technique to examine such chronic anatomical, functional, and neuronal damage in the brain. The objective of this study was to investigate long-term structural and neuronal lesion abnormalities in rats exposed to acute soman intoxication. T2-weighted MRI images of 10 control and 17 soman-exposed rats were acquired using a Siemens MRI system at 90 days after soman exposure. Quantification of brain tissue volumes and T2 signal intensity was conducted using the Inveon Research Workplace software and the extent of damage was correlated with histopathology and cognitive function. Soman-exposed rats showed drastic hippocampal atrophy with neuronal loss and reduced hippocampal volume (HV), indicating severe damage, but had similar T2 relaxation times to the control group, suggesting limited scarring and fluid density changes despite the volume decrease. Conversely, soman-exposed rats displayed significant increases in lateral ventricle volumes and T2 times, signifying strong cerebrospinal fluid expansion in compensation for tissue atrophy. The total brain volume, thalamic volume, and thalamic T2 time were similar in both groups, however, suggesting that some brain regions remained more intact long-term after soman intoxication. The MRI neuronal lesions were positively correlated with the histological markers of neurodegeneration and neuroinflammation 90 days after soman exposure. The predominant MRI hippocampal atrophy (25%) was highly consistent with massive reduction (35%) of neuronal nuclear antigen-positive (NeuN ) principal neurons and parvalbumin-positive (PV ) inhibitory interneurons within this brain region. The HV was significantly correlated with both inflammatory markers of GFAP astrogliosis and IBA1 microgliosis. The reduced HV was also directly correlated with significant memory deficits in the soman-exposed cohort, confirming a possible neurobiological basis for neurological dysfunction. Together, these findings provide powerful insight on long-term region-specific neurodegenerative patterns after soman exposure and demonstrate the feasibility of in vivo neuroimaging to monitor neuropathology, predict the risk of neurological deficits, and evaluate response to medical countermeasures for NAs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/nyas.14431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708405PMC
November 2020

Phenobarbital as alternate anticonvulsant for organophosphate-induced benzodiazepine-refractory status epilepticus and neuronal injury.

Epilepsia Open 2020 Jun 14;5(2):198-212. Epub 2020 Apr 14.

Department of Neuroscience and Experimental Therapeutics College of Medicine Texas A&M University Health Science Center Bryan TX USA.

Objective: Organophosphates (OPs) such as diisopropylfluorophosphate (DFP) and soman are lethal chemical agents that can produce seizures, refractory status epilepticus (SE), and brain damage. There are few optimal treatments for late or refractory SE. Phenobarbital is a second-line drug for SE, usually after lorazepam, diazepam, or midazolam have failed to stop SE. Practically, 40 minutes or less is often necessary for first responders to arrive and assist in a chemical incident. However, it remains unclear whether administration of phenobarbital 40 minutes after OP intoxication is still effective. Here, we investigated the efficacy of phenobarbital treatment at 40 minutes postexposure to OP intoxication.

Methods: Acute refractory SE was induced in rats by DFP injection as per a standard paradigm. After 40 minutes, subjects were given phenobarbital intramuscularly (30-100 mg/kg) and progression of seizure activity was monitored by video-EEG recording. The extent of brain damage was assessed 3 days after DFP injections by neuropathology analysis of neurodegeneration and neuronal injury by unbiased stereology.

Results: Phenobarbital produced a dose-dependent seizure protection. A substantial decrease in SE was evident at 30 and 60 mg/kg, and a complete seizure termination was noted at 100 mg/kg within 40 minutes after treatment. Neuropathology findings showed significant neuroprotection in 100 mg/kg cohorts in brain regions associated with SE. Although higher doses resulted in greater protection against refractory SE and neuronal damage, they did not positively correlate with improved survival rate. Moreover, phenobarbital caused serious adverse effects including anesthetic or comatose state and even death.

Significance: Phenobarbital appears as an alternate anticonvulsant for OP-induced refractive SE in hospital settings. A careful risk-benefit analysis is required because of negative outcomes on survival and cardio-respiratory function. However, the need for sophisticated support and critical monitoring in hospital may preclude its use as medical countermeasure in mass casualty situations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/epi4.12389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278559PMC
June 2020

Isobolographic Analysis of Antiseizure Activity of the GABA Type A Receptor-Modulating Synthetic Neurosteroids Brexanolone and Ganaxolone with Tiagabine and Midazolam.

J Pharmacol Exp Ther 2020 03 16;372(3):285-298. Epub 2019 Dec 16.

Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas

Epilepsy is often treated with a combination of antiepileptic drugs. Although neurosteroids are potent anticonvulsants, little is known about their combination potential for the treatment of refractory epilepsy. Here, we investigated the combination efficacy of neurosteroids allopregnanolone (AP, brexanolone) and ganaxolone (GX) with the GABA-reuptake inhibitor tiagabine (TG) or the benzodiazepine midazolam (MDZ) on tonic inhibition in dentate gyrus granule cells and seizure protection in the hippocampus kindling and 6-Hz seizure models. Isobolographic analysis indicated that combinations of GX and TG or AP and TG at three standard ratios (1:1, 3:1, and 1:3) displayed significant synergism in augmenting tonic inhibition. In pharmacological studies, GX, AP, and TG produced dose-dependent antiseizure effects in mice (ED = 1.46, 4.20, and 0.20 mg/kg, respectively). The combination of GX and TG at the fixed ratio of 1:1 exerted the greatest combination index (CI = 0.53), indicating strong synergistic interaction in seizure protection. In addition, combination regimens of AP and TG showed robust synergism for seizure protection (CI = 0.4). Finally, combination regimens of GX and MDZ elicited synergistic (CI = 0.6) responses for seizure protection. These results demonstrate striking synergism of neurosteroids and TG combination for seizure protection, likely because of their effects at extrasynaptic GABA type A (GABA-A) receptors from TG-induced elevation in GABA levels. Superadditive antiseizure activity of neurosteroid-MDZ combinations may stem from their actions at both synaptic and extrasynaptic GABA-A receptors. Together, these findings provide a potential mechanistic basis for combination potential of neurosteroids with TG or benzodiazepines for the management of refractory epilepsy, status epilepticus, and seizure disorders. SIGNIFICANCE STATEMENT: This paper investigates for the first time the potential synergistic interactions between two neurosteroids with anticonvulsant properties, allopregnanolone (brexanolone) and the very similar synthetic analog, ganaxolone, and two conventional antiepileptic drugs active at GABA type A receptors: the GABA-reuptake inhibitor tiagabine and a benzodiazepine, midazolam. The results demonstrate a synergistic protective effect of neurosteroid-tiagabine combinations, as well as neurosteroid-midazolam regimens in seizure models.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1124/jpet.119.261735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011113PMC
March 2020

Mechanism-based novel antidotes for organophosphate neurotoxicity.

Curr Opin Toxicol 2019 Apr 21;14:35-45. Epub 2019 Aug 21.

Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, TX 77807, USA.

This article describes current pursuits for developing novel antidotes for organophosphate (OP) intoxication. Recent mechanistic studies of benzodiazepine-resistant seizures have key consequences for victims of OP pesticide and nerve agent attacks. We uncovered why current therapies are not able to stop the OP-induced seizures and brain cell death and what type of drug might be better. OP exposure down regulates critical inhibitory GABA-A receptors, kills neurons, and causes massive neuroinflammation that will cause more neuronal death, which causes the problem of too few benzodiazepine receptors. The loss of inhibitory interneurons creates a self-sustaining seizure circuit and refractory status epilepticus. Thus, there is an urgent need for mechanism-based, new antidotes for OP intoxication. We have discovered neurosteroids as next-generation anticonvulsants superior to midazolam for the treatment of OP poisoning. Neurosteroids that activate both extrasynaptic and synaptic GABA-A receptors have the potential to stop seizures more effectively and safely than benzodiazepines. In addition, neurosteroids confers robust neuroprotection by reducing neuronal injury and neuroinflammation. The synthetic neurosteroid ganaxolone is being considered for advanced development as a future anticonvulsant for nerve agents. Experimental studies shows striking efficacy of ganaxolone and its analogs in OP exposure models. They are also effective in attenuating long-term neuropsychiatric deficits caused by OP exposure. Overall, neurosteroids represent rational anticonvulsants for OP intoxication, even when given late after exposure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cotox.2019.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448382PMC
April 2019

Extrasynaptic γ-aminobutyric acid type A receptor-mediated sex differences in the antiseizure activity of neurosteroids in status epilepticus and complex partial seizures.

Epilepsia 2019 04 20;60(4):730-743. Epub 2019 Mar 20.

Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas.

Objective: Sex differences are evident in the antiseizure activity of neurosteroids; however, the potential mechanisms remain unclear. In this study, we sought to determine whether differences in target extrasynaptic δ-subunit γ-aminobutyric acid type A (GABA-A) receptor expression and function underlie the sex differences in seizure susceptibility and the antiseizure activity of neurosteroids.

Methods: Sex differences in seizure susceptibility and protective activity of three distinct neurosteroids-allopregnanolone (AP), androstanediol (AD), and ganaxolone-were evaluated in the pilocarpine model of status epilepticus (SE) and kindling seizure test in mice. Immunocytochemistry was used for δGABA-A receptor expression analysis, and patch-clamp recordings in brain slices evaluated its functional currents.

Results: Sex differences were apparent in kindling epileptogenic seizures, with males exhibiting a faster progression to a fully kindled state. Neurosteroids AP, AD, or ganaxolone produced dose-dependent protection against SE and acute partial seizures. However, female mice exhibited strikingly enhanced sensitivity to the antiseizure activity of neurosteroids compared to males. Sex differences in neurosteroid protection were unrelated to pharmacokinetic factors, as plasma levels of neurosteroids associated with seizure protection were similar between sexes. Mice lacking extrasynaptic δGABA-A receptors did not exhibit sex differences in neurosteroid protection. Consistent with a greater abundance of extrasynaptic δGABA-A receptors, AP produced a significantly greater potentiation of tonic currents in dentate gyrus granule cells in females than males; however, such enhanced AP sensitivity was diminished in δGABA-A receptor knockout female mice.

Significance: Neurosteroids exhibit greater antiseizure potency in females than males, likely due to a greater abundance of extrasynaptic δGABA-A receptors that mediate neurosteroid-sensitive tonic currents and seizure protection. These findings indicate the potential to develop personalized gender-specific neurosteroid treatments for SE and epilepsy in men and women, including catamenial epilepsy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/epi.14693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6447432PMC
April 2019

Neuroimaging Biomarkers of Experimental Epileptogenesis and Refractory Epilepsy.

Int J Mol Sci 2019 Jan 8;20(1). Epub 2019 Jan 8.

Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, TX 77807, USA.

This article provides an overview of neuroimaging biomarkers in experimental epileptogenesis and refractory epilepsy. Neuroimaging represents a gold standard and clinically translatable technique to identify neuropathological changes in epileptogenesis and longitudinally monitor its progression after a precipitating injury. Neuroimaging studies, along with molecular studies from animal models, have greatly improved our understanding of the neuropathology of epilepsy, such as the hallmark hippocampus sclerosis. Animal models are effective for differentiating the different stages of epileptogenesis. Neuroimaging in experimental epilepsy provides unique information about anatomic, functional, and metabolic alterations linked to epileptogenesis. Recently, several in vivo biomarkers for epileptogenesis have been investigated for characterizing neuronal loss, inflammation, blood-brain barrier alterations, changes in neurotransmitter density, neurovascular coupling, cerebral blood flow and volume, network connectivity, and metabolic activity in the brain. Magnetic resonance imaging (MRI) is a sensitive method for detecting structural and functional changes in the brain, especially to identify region-specific neuronal damage patterns in epilepsy. Positron emission tomography (PET) and single-photon emission computerized tomography are helpful to elucidate key functional alterations, especially in areas of brain metabolism and molecular patterns, and can help monitor pathology of epileptic disorders. Multimodal procedures such as PET-MRI integrated systems are desired for refractory epilepsy. Validated biomarkers are warranted for early identification of people at risk for epilepsy and monitoring of the progression of medical interventions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms20010220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6337422PMC
January 2019

Zinc reduces antiseizure activity of neurosteroids by selective blockade of extrasynaptic GABA-A receptor-mediated tonic inhibition in the hippocampus.

Neuropharmacology 2019 04 22;148:244-256. Epub 2018 Nov 22.

Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, TX, 77807, USA. Electronic address:

Zinc is an abundant trace metal in the hippocampus nerve terminals. Previous studies demonstrate the ability of zinc to selectively block neurosteroid-sensitive, extrasynaptic GABA-A receptors in the hippocampus (Carver et al, 2016). Here we report that zinc prevents the seizure protective effects of the synthetic neurosteroid ganaxolone (GX) in an experimental model of epilepsy. GABA-gated and tonic currents were recorded from dissociated dentate gyrus granule cells (DGGCs), CA1 pyramidal cells (CA1PCs), and hippocampal slices from adult mice. Antiseizure effects of GX and the reversal of these effects by zinc were evaluated in fully-kindled mice expressing generalized (stage 5) seizures. In electrophysiological studies, zinc blocked the GABA-evoked and GX-potentiated GABA-gated chloride currents in DGGCs and CA1PCs in a concentration-dependent fashion similar to the competitive GABA-A receptor antagonists bicuculline and gabazine. Zinc completely blocked GX potentiation of extrasynaptic tonic currents, but not synaptic phasic currents. In hippocampus kindling studies, systemic administration of GX produced a dose-dependent suppression of behavioral and electrographic seizures in fully-kindled mice with complete seizure protection at the 10 mg/kg dose. However, the antiseizure effects of GX were significantly prevented by intrahippocampal administration of zinc (ED, 150 μM). The zinc antagonistic response was reversible as animals responded normally to GX administration 24 h post-zinc blockade. These results demonstrate that zinc reduces the antiseizure effects of GX by selectively blocking extrasynaptic δGABA-A receptors in the hippocampus. These pharmacodynamic interactions have clinical implications in neurosteroid therapy for brain conditions associated with zinc fluctuations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuropharm.2018.11.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6424640PMC
April 2019

Neuroendocrine aspects of improving sleep in epilepsy.

Epilepsy Res 2018 11 31;147:32-41. Epub 2018 Aug 31.

Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.

Sleep plays an intricate role in epilepsy and can affect the frequency and occurrence of seizures. With nearly 35% of U.S. adults failing to obtain the recommended 7 h of sleep every night, understanding the complex relationship between sleep and epilepsy is of utmost relevance. Sleep deprivation is a common trigger of seizures in many persons with epilepsy and sleep patterns play a role in the occurrence of seizures. Some patients have their first seizure or repeated seizures after an "all-nighter" at college or after a long period of chronic sleep deprivation. The strength of the relationship between sleep and seizures varies between patients, but improving sleep and optimizing seizure control can have significant positive effects on the quality of life for all these patients. Research has shown that the changes in the brain's electrical and hormonal activity occurring during normal sleep-wake cycles can be linked to both sleep and seizure patterns. Many questions remain to be answered about sleep and epilepsy. How can sleep deprivation trigger an epileptic seizure? How do circadian and hormonal changes influence sleep pattern and seizure occurrence? Can hormones or sleeping pills help with sleep in epilepsy? In this article we discuss these and many other questions on sleep in epilepsy, with an emphasis on sleep architecture, hormone changes, mechanistic factors, and possible prevention strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.eplepsyres.2018.08.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6192845PMC
November 2018

Midazolam-Resistant Seizures and Brain Injury after Acute Intoxication of Diisopropylfluorophosphate, an Organophosphate Pesticide and Surrogate for Nerve Agents.

J Pharmacol Exp Ther 2018 11 16;367(2):302-321. Epub 2018 Aug 16.

Department of Neuroscience and Experimental Therapeutics, Texas A&M University Health Science Center College of Medicine, Bryan, Texas

Organophosphates (OP) such as the pesticide diisopropylfluorophosphate (DFP) and the nerve agent sarin are lethal chemicals that induce seizures, status epilepticus (SE), and brain damage. Midazolam, a benzodiazepine modulator of synaptic GABA-A receptors, is currently considered as a new anticonvulsant for nerve agents. Here, we characterized the time course of protective efficacy of midazolam (0.2-5 mg/kg, i.m.) in rats exposed to DFP, a chemical threat agent and surrogate for nerve agents. Behavioral and electroencephalogram (EEG) seizures were monitored for 24 hours after DFP exposure. The extent of brain injury was determined 3 days after DFP exposure by unbiased stereologic analyses of valid markers of neurodegeneration and neuroinflammation. Seizures were elicited within ∼8 minutes after DFP exposure that progressively developed into persistent SE lasting for hours. DFP exposure resulted in massive neuronal injury or necrosis, neurodegeneration of principal cells and interneurons, and neuroinflammation as evident by extensive activation of microglia and astrocytes in the hippocampus, amygdala, and other brain regions. Midazolam controlled seizures, neurodegeneration, and neuroinflammation when given early (10 minutes) after DFP exposure, but it was less effective when given at 40 minutes or later. Delayed therapy (≥40 minutes), a simulation of the practical therapeutic window for first responders or hospital admission, was associated with reduced seizure protection and neuroprotection. These results strongly reaffirm that the DFP-induced seizures and brain damage are progressively resistant to delayed treatment with midazolam, confirming the benzodiazepine refractory SE after OP intoxication. Thus, novel anticonvulsants superior to midazolam or adjunct therapies that enhance its efficacy are needed for effective treatment of refractory SE.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1124/jpet.117.247106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6193253PMC
November 2018

Measuring Histone Deacetylase Inhibition in the Brain.

Curr Protoc Pharmacol 2018 06 7;81(1):e41. Epub 2018 Jun 7.

Center for Epigenetics & Disease Prevention, Texas A&M University Health Science Center, College of Medicine, Houston, Texas.

Histone deacetylases (HDACs) represent a family of enzymes that are targets for epigenetic modulation of genomic activity and may be beneficial in the treatment of many diseases, including cancer and central nervous system disorders. In animal models, HDAC inhibitors have neuroprotective, antiepileptogenic, and antidepressant effects. Assaying HDAC activity provides a robust method for identifying HDAC inhibitors and for assessing their effects under various physiological conditions or after pathological insults. In this unit, a simple and sensitive assay for measuring HDAC activity is described. HDAC activity in tissue lysates can be assessed fluorometrically using a Boc-Lys(Ac) HDAC activity kit. HDACs catalyze the deacetylation of the substrate Boc-Lys(Ac)-AMC. Addition of a trypsin-containing developer converts the deacetylated product to a quantifiable fluorophore that can be used both as a screening method to identify putative HDAC inhibitors and to assess the effects of these inhibitors on tissue and animal epigenetic-modulated phenotypes. © 2018 by John Wiley & Sons, Inc.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cpph.41DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6019607PMC
June 2018

Benzodiazepine-refractory status epilepticus, neuroinflammation, and interneuron neurodegeneration after acute organophosphate intoxication.

Biochim Biophys Acta Mol Basis Dis 2018 09 23;1864(9 Pt B):2845-2858. Epub 2018 May 23.

Department of Neuroscience and Experimental Therapeutics, Texas A&M University Health Science Center, College of Medicine, Bryan, TX 77807, USA. Electronic address:

Nerve agents and some pesticides such as diisopropylfluorophosphate (DFP) cause neurotoxic manifestations that include seizures and status epilepticus (SE), which are potentially lethal and carry long-term neurological morbidity. Current antidotes for organophosphate (OP) intoxication include atropine, 2-PAM and diazepam (a benzodiazepine for treating seizures and SE). There is some evidence for partial or complete loss of diazepam anticonvulsant efficacy when given 30 min or later after exposure to an OP; this condition is known as refractory SE. Effective therapies for OP-induced SE are lacking and it is unclear why current therapies do not work. In this study, we investigated the time-dependent efficacy of diazepam in the nerve agent surrogate DFP model of OP intoxication on seizure suppression and neuroprotection in rats, following an early and late therapy. Diazepam (5 mg/kg, IM) controlled seizures when given 10 min after DFP exposure ("early"), but it was completely ineffective at 60 or 120 min ("late") after DFP. DFP-induced neuronal injury, neuroinflammation, and neurodegeneration of principal cells and GABAergic interneurons were significantly reduced by early but not late therapy. These findings demonstrate that diazepam failed to control seizures, SE and neuronal injury when given 60 min or later after DFP exposure, confirming the benzodiazepine-refractory SE and brain damage after OP intoxication. In addition, this study indicates that degeneration of inhibitory interneurons and inflammatory glial activation are potential mechanisms underlying these morbid outcomes of OP intoxication. Therefore, novel anticonvulsant and neuroprotectant antidotes, superior to benzodiazepines, are desperately needed for controlling nerve agent-induced SE and brain injury.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbadis.2018.05.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6066461PMC
September 2018

3-Methyl-Neurosteroid Analogs Are Preferential Positive Allosteric Modulators and Direct Activators of Extrasynaptic -Subunit -Aminobutyric Acid Type A Receptors in the Hippocampus Dentate Gyrus Subfield.

J Pharmacol Exp Ther 2018 06 30;365(3):583-601. Epub 2018 Mar 30.

Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas

Neurosteroids are powerful modulators of -aminobutyric acid (GABA)-A receptors. Ganaxolone (3-hydroxy-3-methyl-5-pregnan-20-one, GX) and synthetic analogs of the neurosteroid allopregnanolone (AP) are designed to treat epilepsy and related conditions. However, their precise mechanism of action in native neurons remains unclear. Here, we sought to determine the mode of action of GX and its analogs at GABA-A receptors in native hippocampal neurons by analyzing extrasynaptic receptor-mediated tonic currents and synaptic receptor-mediated phasic currents. Concentration-response profiles of GX were determined in two cell types: -containing dentate gyrus granule cells (DGGCs) and 2-containing CA1 pyramidal cells (CA1PCs). GX produced significantly greater potentiation of the GABA-A receptor-activated chloride currents in DGGCs (500%) than CA1PCs (200%). In the absence of GABA, GX evoked 2-fold greater inward currents in DGGCs than CA1PCs, which were 2-fold greater than AP within DGGCs. In hippocampus slices, GX potentiated and directly activated tonic currents in DGGCs. These responses were significantly diminished in DGGCs from -subunit knockout (KO) mice, confirming GX's selectivity for GABA-A receptors. Like AP, GX potentiation of tonic currents was prevented by protein kinase C inhibition. Furthermore, GX's protection against hippocampus-kindled seizures was significantly diminished in KO mice. GX analogs exhibited greater potency and efficacy than GX on GABA-A receptor-mediated tonic inhibition. In summary, these results provide strong evidence that GX and its analogs are preferential allosteric modulators and direct activators of extrasynaptic GABA-A receptors regulating network inhibition and seizures in the dentate gyrus. Therefore, these findings provide a mechanistic rationale for the clinical use of synthetic neurosteroids in epilepsy and seizure disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1124/jpet.117.246660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5941194PMC
June 2018

Role of β-specific GABA-A receptor isoforms in the development of hippocampus kindling epileptogenesis.

Epilepsy Behav 2018 05 26;82:57-63. Epub 2018 Mar 26.

Department of Pharmacology, School of Medicine, University of California, Irvine, California, United States.

Objective: Subunit-specific positive allosteric modulators (PAMs) of gamma-aminobutyric acid-A (GABA-A) receptors are commonly used to uncover the role of GABA-A receptor isoforms in brain function. Recently, we have designed novel PAMs selective for β-subunit containing GABA-A receptors (β-selective PAMs) that are nonbenzodiazepine site-mediated and do not show an α-subunit isoform selectivity, yet exhibit anxiolytic efficacy with reduced potential for sedation, cognitive impairment, and tolerance. In this study, we used three novel β-selective PAMs (2-261, 2-262, and 10029) with differential β-subunit potency to identify the role of β-selective receptor isoforms in limbic epileptogenesis.

Methods: Experimental epileptogenesis was induced in mice by daily hippocampus stimulations until each mouse showed generalized (stage 5) seizures. Patch-clamp electrophysiology was used to record GABA-gated currents. Brain levels of β-selective PAMs were determined for mechanistic correlations.

Results: Treatment with the β-selective PAMs 2-261 (30mg/kg), 2-262 (10mg/kg), and 10029 (30mg/kg), 30min prior to stimulations, significantly suppressed the rate of development of kindled seizure activity without affecting the afterdischarge (AD) signal, indicating their disease-modifying activity. The β-selective agents suppressed chemical epileptogenesis in the pentylenetetrazol model. Test doses of these agents were devoid of acute antiseizure activity in the kindling model.

Conclusion: These findings demonstrate that β-selective PAMs can moderately retard experimental epileptogenesis, indicating the protective role of β-subunit GABA-A receptor isoforms in the development of epilepsy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yebeh.2018.02.020DOI Listing
May 2018

GABA-A Receptors Mediate Tonic Inhibition and Neurosteroid Sensitivity in the Brain.

Vitam Horm 2018 9;107:177-191. Epub 2018 Feb 9.

College of Medicine, Texas A&M University Health Science Center, Bryan, TX, United States. Electronic address:

Neurosteroids like allopregnanolone (AP) are positive allosteric modulators of synaptic and extrasynaptic GABA-A receptors. AP and related neurosteroids exhibit a greater potency for δ-containing extrasynaptic receptors. The δGABA-A receptors, which are expressed extrasynaptically in the dentate gyrus and other regions, contribute to tonic inhibition, promoting network shunting as well as reducing seizure susceptibility. Levels of endogenous neurosteroids fluctuate with ovarian cycle. Natural and synthetic neurosteroids maximally potentiate tonic inhibition in the hippocampus and provide robust protection against a variety of limbic seizures and status epilepticus. Recently, a consensus neurosteroid pharmacophore model has been proposed at extrasynaptic δGABA-A receptors based on structure-activity relationship for functional activation of tonic currents and seizure protection. Aside from anticonvulsant actions, neurosteroids have been found to be powerful anxiolytic and anesthetic agents. Neurosteroids and Zn have preferential affinity for δ-containing receptors. Thus, Zn can prevent neurosteroid activation of extrasynaptic δGABA-A receptor-mediated tonic inhibition. Recently, we demonstrated that Zn selectively inhibits extrasynaptic δGABA-A receptors and thereby fully prevents AP activation of tonic inhibition and seizure protection. We confirmed that neurosteroids exhibit greater sensitivity at extrasynaptic δGABA-A receptors. Overall, extrasynaptic GABA-A receptors are primary mediators of tonic inhibition in the brain and play a key role in the pathophysiology of epilepsy and other neurological disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/bs.vh.2017.12.001DOI Listing
November 2018

Genetic and Molecular Regulation of Extrasynaptic GABA-A Receptors in the Brain: Therapeutic Insights for Epilepsy.

J Pharmacol Exp Ther 2018 02 15;364(2):180-197. Epub 2017 Nov 15.

Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas

GABA-A receptors play a pivotal role in many brain diseases. Epilepsy is caused by acquired conditions and genetic defects in GABA receptor channels regulating neuronal excitability in the brain. The latter is referred to as GABA channelopathies. In the last two decades, major advances have been made in the genetics of epilepsy. The presence of specific GABAergic genetic abnormalities leading to some of the classic epileptic syndromes has been identified. Advances in molecular cloning and recombinant systems have helped characterize mutations in GABA-A receptor subunit genes in clinical neurology. GABA-A receptors are the prime targets for neurosteroids (NSs). However, GABA-A receptors are not static but undergo rapid changes in their number or composition in response to the neuroendocrine milieu. This review describes the recent advances in the genetic and neuroendocrine control of extrasynaptic and synaptic GABA-A receptors in epilepsy and its impact on neurologic conditions. It highlights the current knowledge of GABA genetics in epilepsy, with an emphasis on the neuroendocrine regulation of extrasynaptic GABA-A receptors in network excitability and seizure susceptibility. Recent advances in molecular regulation of extrasynaptic GABA-A receptor-mediated tonic inhibition are providing unique new therapeutic approaches for epilepsy, status epilepticus, and certain brain disorders. The discovery of an extrasynaptic molecular mechanism represents a milestone for developing novel therapies such as NS replacement therapy for catamenial epilepsy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1124/jpet.117.244673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5771312PMC
February 2018

Epigenetic Histone Deacetylation Inhibition Prevents the Development and Persistence of Temporal Lobe Epilepsy.

J Pharmacol Exp Ther 2018 01 3;364(1):97-109. Epub 2017 Nov 3.

Department of Neuroscience and Experimental Therapeutics, Texas A&M University Health Science Center, College of Medicine, Bryan, Texas

Epilepsy is a chronic brain disease characterized by repeated unprovoked seizures. Currently, no drug therapy exists for curing epilepsy or disease modification in people at risk. Despite several emerging mechanisms, there have been few studies of epigenetic signaling in epileptogenesis, the process whereby a normal brain becomes progressively epileptic because of precipitating factors. Here, we report a novel role of histone deacetylation as a critical epigenetic mechanism in epileptogenesis. Experiments were conducted using the histone deacetylase (HDAC) inhibitor sodium butyrate in the hippocampus kindling model of temporal lobe epilepsy (TLE), a classic model heavily used to approve drugs for treatment of epilepsy. Daily treatment with butyrate significantly inhibited HDAC activity and retarded the development of limbic epileptogenesis without affecting after-discharge signal. HDAC inhibition markedly impaired the persistence of seizure expression many weeks after epilepsy development. Moreover, subchronic HDAC inhibition for 2 weeks resulted in a striking retardation of epileptogenesis. HDAC inhibition, unexpectedly, also showed erasure of the epileptogenic state in epileptic animals. Finally, butyrate-treated animals exhibited a powerful reduction in mossy fiber sprouting, a morphologic index of epileptogenesis. Together these results underscore that HDAC inhibition prevents the development of TLE, indicating HDAC's critical signaling role in epileptogenesis. These findings, therefore, envisage a unique novel therapy for preventing or curing epilepsy by targeting the epigenetic HDAC pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1124/jpet.117.244939DOI Listing
January 2018

Atomic force microscopy investigations of fibronectin and α5β1-integrin signaling in neuroplasticity and seizure susceptibility in experimental epilepsy.

Epilepsy Res 2017 12 24;138:71-80. Epub 2017 Oct 24.

Department of Neuroscience and Experimental Therapeutics, Texas A&M University Health Science Center, College of Medicine, Bryan, TX 77807, USA. Electronic address:

Extracellular matrix protein-integrin interaction on neurons plays an important role in the development of neuroplasticity in the brain. However, the role of fibronectin-integrin signaling in epilepsy is elusive. Here, we examined the functional role of fibronectin-integrin signaling by utilizing a combination approach involving atomic force microscopy (AFM), immunocytochemistry, and pharmacology in epileptic mouse dentate gyrus granule cells (DGGCs). There was marked increase in the fibronectin receptor α5β1-integrin staining intensity in DGGCs in epileptic mice. In the AFM study, the unbinding force and binding probability between the fibronectin-coated AFM probe and the membrane integrins were significantly reduced; while the cell stiffness was strikingly increased in epileptic DGGCs. Pretreatment with α5β1-integrin monoclonal antibody partially reversed this membrane dysfunction. In patch-clamp recordings, fibronectin significantly inhibited GABA current, while RGD, which is known to disrupt fibronectin-integrin-dependent cell adhesive events, strikingly enhanced GABA tonic currents in DGGCs in hippocampal slices. The α5β1-integrin antibody significantly reduced 4-aminopyridine-induced epileptiform discharges in brain slices. In systemic behavioral studies, susceptibility to hippocampus kindling epileptogenesis was significantly attenuated in mice treated with RGD or β1-integrin antibody. These pilot studies provide new insights on the functional role of integrin receptor signaling in epileptogenesis and may help identify novel targets for the prevention and treatment of epilepsy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.eplepsyres.2017.10.013DOI Listing
December 2017

Neurocysticercosis as an infectious acquired epilepsy worldwide.

Seizure 2017 Nov 7;52:176-181. Epub 2017 Oct 7.

Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, TX 77807, USA.

Aside from brain injury and genetic causes, there is emerging information on brain infection and inflammation as a common cause of epilepsy. Neurocysticercosis (NCC), the most common cause of epilepsy worldwide, is caused by brain cysts from the Taenia solium tapeworm. In this article, we provide a critical analysis of current and emerging information on the relationship between NCC infection and epilepsy occurrence. We searched PubMed and other databases for reports on the prevalence of NCC and incidence of epilepsy in certain regions worldwide. NCC is caused by brain cysts from the T. solium and related tapeworms. Many people with NCC infection may develop epilepsy but the rates are highly variable. MRI imaging shows many changes including localization of cysts as well as the host response to treatment. Epilepsy, in a subset of NCC patients, appears to be due to hippocampal sclerosis. Serologic and brain imaging profiles are likely diagnostic biomarkers of NCC infection and are also used to monitor the course of treatments. Limited access to these tools is a key limitation to identify and treat NCC-related epilepsy in places with high prevalence of this parasite infestation. Overall, NCC is a common infection in many patients with epilepsy worldwide. Additional clinical and animal studies could confirm common pathology of NCC as a postinfectious epilepsy that is curable.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.seizure.2017.10.004DOI Listing
November 2017

A resurging boom in new drugs for epilepsy and brain disorders.

Expert Rev Clin Pharmacol 2018 Jan 23;11(1):27-45. Epub 2017 Oct 23.

a Department of Neuroscience and Experimental Therapeutics, College of Medicine , Texas A&M Health Science Center , Bryan , TX , USA.

Introduction: Epilepsy is one of the most common neurological diseases affecting approximately 50 million people worldwide. Despite many advances in epilepsy research, nearly a third of patients with epilepsy have refractory or pharmacoresistant epilepsy. Despite the approval of a dozen antiepileptic drugs (AEDs) over the past decade, there are no agents that halt the development of epilepsy. Thus, newer and better AEDs that can prevent refractory seizures and modify the disease are needed for curing epilepsy. Areas covered: In this article, we highlight the recent advances and emerging trends in new and innovative drugs for epilepsy and seizure disorders. We review in detail top new drugs that are currently in clinical trials or agents that are under development and have novel mechanisms of action. Expert commentary: Among the new agents under clinical investigation, the majority were originally developed for treating other neurological diseases (everolimus, fenfluramine, nalutozan, bumetanide, and valnoctamide); several have mechanisms of action similar to those of conventional AEDs (AP, ganaxolone, and YKP3089); and some new agents represent novel mechanisms of actions (huperzine-A, cannabidiol, tonabersat, and VX-765).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/17512433.2018.1386553DOI Listing
January 2018

Response to: 'Birth control in epilepsy: we need to know more'.

Expert Rev Neurother 2017 06 10;17(6):523. Epub 2017 Apr 10.

a Department of Neuroscience and Experimental Therapeutics , College of Medicine, Texas A&M University Health Science Center , Bryan , TX , USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14737175.2017.1314183DOI Listing
June 2017

Epigenetic interventions for epileptogenesis: A new frontier for curing epilepsy.

Pharmacol Ther 2017 Sep 6;177:108-122. Epub 2017 Mar 6.

Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M Health Science Center, Bryan, TX 77807, USA. Electronic address:

This article highlights the emerging therapeutic potential of specific epigenetic modulators as promising antiepileptogenic or disease-modifying agents for curing epilepsy. Currently, there is an unmet need for antiepileptogenic agents that truly prevent the development of epilepsy in people at risk. There is strong evidence that epigenetic signaling, which exerts high fidelity regulation of gene expression, plays a crucial role in the pathophysiology of epileptogenesis and chronic epilepsy. These modifications are not hard-wired into the genome and are constantly reprogrammed by environmental influences. The potential epigenetic mechanisms, including histone modifications, DNA methylation, microRNA-based transcriptional control, and bromodomain reading activity, can drastically alter the neuronal gene expression profile by exerting their summative effects in a coordinated fashion. Such an epigenetic intervention appears more rational strategy for preventing epilepsy because it targets the primary pathway that initially triggers the numerous downstream cellular and molecular events mediating epileptogenesis. Among currently approved epigenetic drugs, the majority are anticancer drugs with well-established profiles in clinical trials and practice. Evidence from preclinical studies supports the premise that these drugs may be applied to a wide range of brain disorders. Targeting histone deacetylation by inhibiting histone deacetylase enzymes appears to be one promising epigenetic therapy since certain inhibitors have been shown to prevent epileptogenesis in animal models. However, developing neuronal specific epigenetic modulators requires rational, pathophysiology-based optimization to efficiently intercept the upstream pathways in epileptogenesis. Overall, epigenetic agents have been well positioned as new frontier tools towards the national goal of curing epilepsy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pharmthera.2017.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5565684PMC
September 2017

Catamenial-like seizure exacerbation in mice with targeted ablation of extrasynaptic δGABA-a receptors in the brain.

J Neurosci Res 2017 10 25;95(10):1906-1916. Epub 2017 Feb 25.

Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas.

Neurosteroids play a key role in catamenial epilepsy, a menstrual cycle-related seizure clustering in women with epilepsy. While neurosteroids act on all GABA-A receptor isoforms, they cause greater effects on extrasynaptic δGABA-A receptors that mediate tonic inhibition in the brain. Previously, we identified a potential GABA-A receptor mechanism for catamenial epilepsy. However, the precise functional role of extrasynaptic δGABA-A receptors in the pathophysiology of catamenial epilepsy remains unclear. In this study, we utilized mice lacking extrasynaptic δGABA-A receptors (δKO) to investigate whether reduction of tonic inhibition affects catamenial seizure susceptibility or intensity. Intact female wildtype (WT) and δKO mice were subjected to hippocampus kindling until they exhibited stage 5 seizures. Elevated gonadal hormone-based neurosteroid levels were induced by standard gonadotropin regimen and neurosteroid withdrawal (NSW) was triggered by finasteride. NSW increased susceptibility to, as well the intensity of evoked catamenial-like seizures in WT and δKO mice. However, fully kindled δKO mice exhibited an accelerated and augmented response to NSW, with a more rapid increase in seizure susceptibility and intensity than WT mice undergoing the NSW paradigm. Moreover, δKO mice in NSW showed reduced benzodiazepine sensitivity, but in stark contrast to the increased neurosteroid sensitivity observed in WT animals, δKO mice displayed no change in neurosteroid sensitivity in response to NSW. The increased catamenial seizure exacerbation and alterations in antiseizure drug responses are consistent with NSW-induced changes in the abundance of δGABA-A receptors. Collectively, these findings provide evidence of a potential protective role for extrasynaptic δGABA-A receptors in catamenial-like seizures. © 2017 Wiley Periodicals, Inc.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jnr.24028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5561461PMC
October 2017

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

Biochim Biophys Acta Mol Basis Dis 2017 06 5;1863(6):1519-1538. Epub 2017 Feb 5.

Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, TX 77807, USA. Electronic address:

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbadis.2017.02.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5474195PMC
June 2017

PR-independent neurosteroid regulation of α2-GABA-A receptors in the hippocampus subfields.

Brain Res 2017 03 28;1659:142-147. Epub 2017 Jan 28.

Department of Neuroscience and Experimental Therapeutics, Texas A&M University Health Science Center, College of Medicine, Bryan, TX 77807, USA.

Progesterone (P) binding to the intracellular progesterone receptors (PRs) plays a key role in epilepsy via modulation of GABA-A receptor plasticity in the brain. This is thought to occur via conversion of P to neurosteroids such as allopregnanolone, an allosteric modulator of GABA-A receptors. In the female brain, the composition of GABA-A receptors is not static and undergoes dynamic spatial changes in response to fluctuations in P and neurosteroid levels. Synaptic α2-containing GABA-A receptors contribute to phasic neuronal excitability and seizure susceptibility. However, the mechanisms underlying α2-subunit plasticity remain unclear. Here, we utilized the neurosteroid synthesis inhibitor finasteride and PR knockout mice to investigate the role of PRs in α2-subunit in the hippocampus. α2-Subunit expression was significantly upregulated during the high-P state of diestrous stage and with P treatment in wildtype and PR knockout mice. In contrast, there was no change in α2-subunit expression when metabolism of P into neurosteroids was blocked by finasteride in both genotypes. These findings suggest that ovarian cycle-related P and neurosteroids regulate α2-GABA-A receptor expression in the hippocampus via a non-PR pathway, which may be relevant to menstrual-cycle related brain conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.brainres.2017.01.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5367384PMC
March 2017

Sex differences in the anticonvulsant activity of neurosteroids.

J Neurosci Res 2017 01;95(1-2):661-670

Department of Neuroscience and Experimental Therapeutics, Texas A&M University Health Sciences Center, College of Medicine, Bryan, Texas.

Epilepsy is one of the leading causes of chronic neurological morbidity worldwide. Acquired epilepsy may result from a number of conditions, such as brain injury, anoxia, tumors, stroke, neurotoxicity, and prolonged seizures. Sex differences have been observed in many seizure types; however, some sex-specific seizure disorders are much more prevalent in women. Despite some inconsistencies, substantial data indicates that sensitivity to seizure stimuli differs between the sexes. Men generally exhibit greater seizure susceptibility than women, whereas many women with epilepsy experience a cyclical occurrence of seizures that tends to center around the menstrual period, which has been termed catamenial epilepsy. Some epilepsy syndromes show gender differences with female predominance or male predominance. Steroid hormones, endogenous neurosteroids, and sexually dimorphic neural networks appear to play a key role in sex differences in seizure susceptibility. Neurosteroids, such as allopregnanolone, reflect sex differences in their anticonvulsant activity. This Review provides a brief overview of the evidence for sex differences in epilepsy and how sex differences influence the use of neurosteroids in epilepsy and epileptogenesis. © 2016 Wiley Periodicals, Inc.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jnr.23853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5120602PMC
January 2017