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Cannabidiol Modulation of Ion Channels and Neuronal Excitability.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Cannabidiol Modulation of Ion Channels and Neuronal Excitability./
作者:	Zhang, Hanxiong Bear.
面頁冊數:	1 online resource (168 pages)
附註:	Source: Dissertations Abstracts International, Volume: 84-12, Section: B.
Contained By:	Dissertations Abstracts International84-12B.
標題:	Neurosciences. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=30490189click for full text (PQDT)
ISBN:	9798379611361

Cannabidiol Modulation of Ion Channels and Neuronal Excitability.
Zhang, Hanxiong Bear.

Cannabidiol Modulation of Ion Channels and Neuronal Excitability. - 1 online resource (168 pages)

Source: Dissertations Abstracts International, Volume: 84-12, Section: B.

Thesis (Ph.D.)--Harvard University, 2023.

Includes bibliographical references

Cannabidiol (CBD) is a non-intoxicating phytocannabinoid from Cannabis sativa. In human clinical trials and animal models, CBD shows anti-epileptic and analgesic efficacy. The goal of my thesis work was to explore how CBD modulates various ion channels to affect neuronal excitability.In Chapter 1, I describe CBD inhibition of primary nociceptive neuron (nociceptor) excitability at sub-micromolar concentrations. CBD is more potent than the local anesthetic bupivacaine in reducing nociceptor firing. The reduction in firing can be explained by inhibition of both tetrodotoxin (TTX)-sensitive sodium currents (mostly Nav1.7) and TTX-resistant sodium currents (Nav1.8). CBD binds particularly tightly to the slow inactivated states of Nav1.8 with a Kd (dissociation constant) of 150 nM. The data suggest a molecular explanation for CBD's analgesic effect and a strategy for analgesic drug development by targeting slow inactivated states of Nav1.8.In Chapter 2, I describe CBD inhibition of human Nav1.7 (hNav1.7) channels, with results suggesting that CBD binds tightly to inactivated states of the channel, with a Kd (dissociation constant) of 65 nM. CBD-bound hNav1.7 channels show decreased availability and slowed recovery rate. The electrophysiological data suggesting that CBD stabilizes the inactivated states of Nav1.7 channels is consistent with structures of CBD bound to hNav1.7 obtained by our collaborators, showing two distinct binding sites, including a novel binding site adjacent to the receptor site for the inactivating "wedge" of the channel. These data provide a plausible structural correlate of state-dependent inhibition of hNav1.7 by CBD and a structural blueprint for future design of CBD-based analgesic drugs with improved properties.In Chapter 3, I describe enhancement of Kv7 currents by CBD at concentrations as low as 30 nM. CBD enhances Kv7.2/7.3 current by shifting the voltage dependence of channel activation in the hyperpolarizing direction. Enhancement is observed for Kv7 channels mediating M-current in native neurons as well as for cloned human Kv7.2/7.3 channels.Together, these results show that CBD acts at sub-micromolar levels to inhibit multiple types of voltage-dependent sodium channels and to activate Kv7.2/7.3 channels and suggest that a combination of these effects may contribute to the efficacy of CBD in treating epilepsy and pain.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2023

Mode of access: World Wide Web

ISBN: 9798379611361Subjects--Topical Terms:

588700
Neurosciences.
Subjects--Index Terms:

CannabidiolIndex Terms--Genre/Form:

542853
Electronic books.

Cannabidiol Modulation of Ion Channels and Neuronal Excitability.
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500 $a Advisor: Bean, Bruce P.
502 $a Thesis (Ph.D.)--Harvard University, 2023.
504 $a Includes bibliographical references
520 $a Cannabidiol (CBD) is a non-intoxicating phytocannabinoid from Cannabis sativa. In human clinical trials and animal models, CBD shows anti-epileptic and analgesic efficacy. The goal of my thesis work was to explore how CBD modulates various ion channels to affect neuronal excitability.In Chapter 1, I describe CBD inhibition of primary nociceptive neuron (nociceptor) excitability at sub-micromolar concentrations. CBD is more potent than the local anesthetic bupivacaine in reducing nociceptor firing. The reduction in firing can be explained by inhibition of both tetrodotoxin (TTX)-sensitive sodium currents (mostly Nav1.7) and TTX-resistant sodium currents (Nav1.8). CBD binds particularly tightly to the slow inactivated states of Nav1.8 with a Kd (dissociation constant) of 150 nM. The data suggest a molecular explanation for CBD's analgesic effect and a strategy for analgesic drug development by targeting slow inactivated states of Nav1.8.In Chapter 2, I describe CBD inhibition of human Nav1.7 (hNav1.7) channels, with results suggesting that CBD binds tightly to inactivated states of the channel, with a Kd (dissociation constant) of 65 nM. CBD-bound hNav1.7 channels show decreased availability and slowed recovery rate. The electrophysiological data suggesting that CBD stabilizes the inactivated states of Nav1.7 channels is consistent with structures of CBD bound to hNav1.7 obtained by our collaborators, showing two distinct binding sites, including a novel binding site adjacent to the receptor site for the inactivating "wedge" of the channel. These data provide a plausible structural correlate of state-dependent inhibition of hNav1.7 by CBD and a structural blueprint for future design of CBD-based analgesic drugs with improved properties.In Chapter 3, I describe enhancement of Kv7 currents by CBD at concentrations as low as 30 nM. CBD enhances Kv7.2/7.3 current by shifting the voltage dependence of channel activation in the hyperpolarizing direction. Enhancement is observed for Kv7 channels mediating M-current in native neurons as well as for cloned human Kv7.2/7.3 channels.Together, these results show that CBD acts at sub-micromolar levels to inhibit multiple types of voltage-dependent sodium channels and to activate Kv7.2/7.3 channels and suggest that a combination of these effects may contribute to the efficacy of CBD in treating epilepsy and pain.
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538 $a Mode of access: World Wide Web
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653 $a Cannabidiol
653 $a Electrophysiology
653 $a Ion channels
653 $a Neuronal excitability
653 $a Neuropharmacology
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