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Browsing by Subject "Cannabidiol"
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Item The combined effects of cannabidiol and delta-9-tetrahydrocannabinol(1974) McCoy, Daniel JosephItem Differential Inhibition of Human Nav1.2 Resurgent and Persistent Sodium Currents by Cannabidiol and GS967(MDPI, 2020-04) Mason, Emily R.; Cummins, Theodore R.; Pharmacology and Toxicology, School of MedicineMany epilepsy patients are refractory to conventional antiepileptic drugs. Resurgent and persistent currents can be enhanced by epilepsy mutations in the Nav1.2 channel, but conventional antiepileptic drugs inhibit normal transient currents through these channels, along with aberrant resurgent and persistent currents that are enhanced by Nav1.2 epilepsy mutations. Pharmacotherapies that specifically target aberrant resurgent and/or persistent currents would likely have fewer unwanted side effects and be effective in many patients with refractory epilepsy. This study investigated the effects of cannbidiol (CBD) and GS967 (each at 1 μM) on transient, resurgent, and persistent currents in human embryonic kidney (HEK) cells stably expressing wild-type hNav1.2 channels. We found that CBD preferentially inhibits resurgent currents over transient currents in this paradigm; and that GS967 preferentially inhibits persistent currents over transient currents. Therefore, CBD and GS967 may represent a new class of more targeted and effective antiepileptic drugs.Item The influence of cannabidiol on the effects of delta-9-tetrahydrocannabinol(1976) Dalton, WilliamItem Nav1.1 and Nav1.6: electrophysiological properties, epilepsy-associated mutations and therapeutic targets(2016-05-25) Patel, Reesha Rajni; Cummins, Theodore R.; Hudmon, Andy; Vasko, Michael R.; Sheets, Patrick L.; Jin, XiaomingVoltage-‐gated sodium channels (VGSCs) are critical for the initiation and propagation of electrical signals in neurons; consequently they are significant regulators of neuronal excitability. They are exquisitely tuned and aberrations in their activity can lead to pathophysiological conditions. This dissertation highlights the roles of two prominent brain isoforms of VGSCs, Nav1.1 and Nav1.6. These isoforms have distinct localization in the brain. Specifically, Nav1.1 is predominantly expressed in the soma and proximal axon initial segment (AIS) of GABAergic neurons, while Nav1.6 is found at the distal AIS and nodes of Ranvier of both GABAergic and excitatory neurons. Several mutations have been identified in Nav1.1 and recently mutations in Nav1.6 have been discovered in patients with distinct epileptic phenotypes that respond poorly to current anti-epileptics. There is a need to better understand mechanistically how mutations in these channel isoforms lead to epilepsy in order to identify more efficacious treatment strategies. Therefore, the aims of this dissertation were to 1) examine the differential biophysical properties of Nav1.1 and Nav1.6, 2) determine the biophysical consequences of epilepsy-associated mutations in Nav1.1 and Nav1.6 and examine the effects of cannabinoids on wildtype and mutant channel activity and 3) test the effects of selective inhibition of Nav1.1 versus Nav1.6 on epileptiform activity. To address these aims, whole‐cell electrophysiology and mutlielectrode array recordings were used. The results demonstrate that 1) Nav1.1 and Nav1.6 have important differences in their biophysical properties that may be important in the fine‐tuning of neuronal excitability, 2) epilepsy-‐associated mutations in Nav1.1 and Nav1.6 alter several biophysical properties of the channels but have differential effects on resurgent current generation suggesting a divergence in the mechanism by which they induce epileptogenesis and cannabidiol can inhibit aberrant channel activity and reduce neuronal excitability and 3) pharmacological inhibition of Nav1.6, but not Nav1.1, abolishes epileptiform activity. Overall, this dissertation provides insight into the distinct contributions of Nav1.1 and Nav1.6 to physiological and pathophysiological firing activity and their ability to be targeted for therapeutic purposes. This knowledge is critical for understanding the potential role of VGSCs in epilepsy syndromes and identifying possible drug targets for more efficacious treatment strategies.