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Cannabidiol Modulation of Ion Channels and Neuronal Excitability- [electronic resource]
![Cannabidiol Modulation of Ion Channels and Neuronal Excitability - [electronic resource]](/Users/Baul/Images/book.png)
Cannabidiol Modulation of Ion Channels and Neuronal Excitability- [electronic resource]
상세정보
- 자료유형
- 학위논문파일 국외
- 최종처리일시
- 20240214101125
- ISBN
- 9798379611361
- DDC
- 616
- 서명/저자
- Cannabidiol Modulation of Ion Channels and Neuronal Excitability - [electronic resource]
- 발행사항
- [S.l.]: : Harvard University., 2023
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2023
- 형태사항
- 1 online resource(168 p.)
- 주기사항
- Source: Dissertations Abstracts International, Volume: 84-12, Section: B.
- 주기사항
- Advisor: Bean, Bruce P.
- 학위논문주기
- Thesis (Ph.D.)--Harvard University, 2023.
- 사용제한주기
- This item must not be sold to any third party vendors.
- 초록/해제
- 요약Cannabidiol (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.
- 일반주제명
- Neurosciences.
- 일반주제명
- Pharmaceutical sciences.
- 키워드
- Cannabidiol
- 키워드
- Ion channels
- 기타저자
- Harvard University Medical Sciences
- 기본자료저록
- Dissertations Abstracts International. 84-12B.
- 기본자료저록
- Dissertation Abstract International
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■006m o d
■007cr#unu||||||||
■020 ▼a9798379611361
■035 ▼a(MiAaPQ)AAI30490189
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a616
■1001 ▼aZhang, Hanxiong Bear.▼0(orcid)0000-0003-2327-6694
■24510▼aCannabidiol Modulation of Ion Channels and Neuronal Excitability▼h[electronic resource]
■260 ▼a[S.l.]:▼bHarvard University. ▼c2023
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2023
■300 ▼a1 online resource(168 p.)
■500 ▼aSource: Dissertations Abstracts International, Volume: 84-12, Section: B.
■500 ▼aAdvisor: Bean, Bruce P.
■5021 ▼aThesis (Ph.D.)--Harvard University, 2023.
■506 ▼aThis item must not be sold to any third party vendors.
■520 ▼aCannabidiol (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.
■590 ▼aSchool code: 0084.
■650 4▼aNeurosciences.
■650 4▼aPharmaceutical sciences.
■653 ▼aCannabidiol
■653 ▼aElectrophysiology
■653 ▼aIon channels
■653 ▼aNeuronal excitability
■653 ▼aNeuropharmacology
■690 ▼a0317
■690 ▼a0572
■71020▼aHarvard University▼bMedical Sciences.
■7730 ▼tDissertations Abstracts International▼g84-12B.
■773 ▼tDissertation Abstract International
■790 ▼a0084
■791 ▼aPh.D.
■792 ▼a2023
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T16932892▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
■980 ▼a202402▼f2024
