Publications by authors named "Victoria Golub"

6 Publications

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Cannabidiol Therapy for Refractory Epilepsy and Seizure Disorders.

Adv Exp Med Biol 2021 ;1264:93-110

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

Cannabis-derived cannabinoids have neuroactive properties. Recently, there has been emerging interest in the use of cannabidiol (CBD)-enriched products for treatment of drug-resistant epilepsy. In 2018, the FDA approved the use of CBD-rich Epidiolex for two severe forms of epilepsy in children (Lennox-Gastaut and Dravet syndromes). Experimental research supports the use of CBD in many CNS disorders, though the mechanisms underlying its anticonvulsant and neuroprotective effects remain unclear. CBD has been shown to reduce inflammation, protect against neuronal loss, normalize neurogenesis, and act as an antioxidant. These actions appear to be due to the multimodal mechanism of action of CBD in the brain. This chapter briefly describes the current information on cannabis pharmacology with an emphasis on the clinical utility of CBD in the treatment of refractory epilepsies and other related seizure conditions. Clinical trials are ongoing for other forms of epilepsy and refractory seizures associated with infantile spasms, tuberous sclerosis, and Rett syndrome. Overall, adjunct CBD has been found to be generally safe and effective for treatment-resistant seizures in children with severe early-onset epilepsy. Whether an add-on CBD is efficacious for the long-term treatment of various epilepsy and seizure types in adults being tested in various clinical trials.
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http://dx.doi.org/10.1007/978-3-030-57369-0_7DOI Listing
February 2021

Molecular, physiological and behavioral characterization of the heterozygous Df[h15q13]/+ mouse model associated with the human 15q13.3 microdeletion syndrome.

Brain Res 2020 11 23;1746:147024. Epub 2020 Jul 23.

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

The human 15q13.3 microdeletion syndrome (DS) is caused by a heterozygous microdeletion (MD) affecting six genes: FAN1; MTMR10; TRPM1; KLF13; OTUD7A; and CHRNA7. Carriers are at risk for intellectual disability, epilepsy, autism spectrum disorder, and schizophrenia. Here we used the Df[h15q13]/+ mouse model with an orthologous deletion to further characterize molecular, neurophysiological, and behavioral parameters that are relevant to the 15q13.3 DS. First, we verified the expression and distribution of the α7 nicotinic acetylcholine receptor (nAChR), a gene product of the CHRNA7, in cortical and subcortical areas. Results revealed similar mRNA distribution pattern in wildtype (WT) and heterozygous (Het) mice, with about half the number of α7 nAChR binding sites in mutants. Hippocampal recordings showed similar input/output responses of field excitatory post-synaptic potentials and theta-burst induced long-term potentiation in WT and Het mice. Het males exhibited impaired spatial learning acquisition in the Barnes Maze. Indicative of increased seizure susceptibility, Het mice developed secondary seizures after 6-Hz corneal stimulation, and had significantly increased sensitivity to the chemoconvulsant pentylenetetrazol resulting in increased spiking in hippocampal EEG recordings. Basal mRNA expression of brain derived neurotrophic factor and activity regulated immediate early genes (c-fos, Arc, Erg-1 and Npas4) during adolescence, a critical period of brain maturation, was unaffected by genotype. Thus, the MD did not show gross neuroanatomical, molecular, and neurophysiological abnormalities despite deficits in spatial learning and increased susceptibility to seizures. Altogether, our results verify the phenotypic profile of the heterozygous Df[h15q13]/+ mouse model and underscore its translational relevance for human 15q13.3 DS.
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http://dx.doi.org/10.1016/j.brainres.2020.147024DOI Listing
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.
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http://dx.doi.org/10.1002/epi4.12389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278559PMC
June 2020

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

The Pharmacological Basis of Cannabis Therapy for Epilepsy.

J Pharmacol Exp Ther 2016 Apr 19;357(1):45-55. Epub 2016 Jan 19.

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

Recently, cannabis has been suggested as a potential alternative therapy for refractory epilepsy, which affects 30% of epilepsy, both adults and children, who do not respond to current medications. There is a large unmet medical need for new antiepileptics that would not interfere with normal function in patients with refractory epilepsy and conditions associated with refractory seizures. The two chief cannabinoids are Δ-9-tetrahyrdrocannabinol, the major psychoactive component of marijuana, and cannabidiol (CBD), the major nonpsychoactive component of marijuana. Claims of clinical efficacy in epilepsy of CBD-predominant cannabis or medical marijuana come mostly from limited studies, surveys, or case reports. However, the mechanisms underlying the antiepileptic efficacy of cannabis remain unclear. This article highlights the pharmacological basis of cannabis therapy, with an emphasis on the endocannabinoid mechanisms underlying the emerging neurotherapeutics of CBD in epilepsy. CBD is anticonvulsant, but it has a low affinity for the cannabinoid receptors CB1 and CB2; therefore the exact mechanism by which it affects seizures remains poorly understood. A rigorous clinical evaluation of pharmaceutical CBD products is needed to establish the safety and efficacy of their use in the treatment of epilepsy. Identification of mechanisms underlying the anticonvulsant efficacy of CBD is also critical for identifying other potential treatment options.
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http://dx.doi.org/10.1124/jpet.115.230151DOI Listing
April 2016

Neurostereology protocol for unbiased quantification of neuronal injury and neurodegeneration.

Front Aging Neurosci 2015 31;7:196. Epub 2015 Oct 31.

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

Neuronal injury and neurodegeneration are the hallmark pathologies in a variety of neurological conditions such as epilepsy, stroke, traumatic brain injury, Parkinson's disease and Alzheimer's disease. Quantification of absolute neuron and interneuron counts in various brain regions is essential to understand the impact of neurological insults or neurodegenerative disease progression in animal models. However, conventional qualitative scoring-based protocols are superficial and less reliable for use in studies of neuroprotection evaluations. Here, we describe an optimized stereology protocol for quantification of neuronal injury and neurodegeneration by unbiased counting of neurons and interneurons. Every 20th section in each series of 20 sections was processed for NeuN(+) total neuron and parvalbumin(+) interneuron immunostaining. The sections that contain the hippocampus were then delineated into five reliably predefined subregions. Each region was separately analyzed with a microscope driven by the stereology software. Regional tissue volume was determined by using the Cavalieri estimator, as well as cell density and cell number were determined by using the optical disector and optical fractionator. This protocol yielded an estimate of 1.5 million total neurons and 0.05 million PV(+) interneurons within the rat hippocampus. The protocol has greater predictive power for absolute counts as it is based on 3D features rather than 2D images. The total neuron counts were consistent with literature values from sophisticated systems, which are more expensive than our stereology system. This unbiased stereology protocol allows for sensitive, medium-throughput counting of total neurons in any brain region, and thus provides a quantitative tool for studies of neuronal injury and neurodegeneration in a variety of acute brain injury and chronic neurological models.
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http://dx.doi.org/10.3389/fnagi.2015.00196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4628120PMC
November 2015