Repeated treatment with cannabidiol but not Δ9-tetrahydrocannabinol has a neuroprotective effect without the development of tolerance

Kazuhide Hayakawa, Kenichi Mishima, Masanori Nozako, Ayumi Ogata, Mai Hazekawa, An Xin Liu, Masayuki Fujioka, Koji Abe, Nobuyoshi Hasebe, Nobuaki Egashira, Katsunori Iwasaki, Michihiro Fujiwara

Research output: Contribution to journalArticle

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Abstract

Both Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol are known to have a neuroprotective effect against cerebral ischemia. We examined whether repeated treatment with both drugs led to tolerance of their neuroprotective effects in mice subjected to 4 h-middle cerebral artery (MCA) occlusion. The neuroprotective effect of Δ9-THC but not cannabidiol was inhibited by SR141716, cannabinoid CB1 receptor antagonist. Fourteen-day repeated treatment with Δ9-THC, but not cannabidiol, led to tolerance of the neuroprotective and hypothermic effects. In addition, repeated treatment with Δ9-THC reversed the increase in cerebral blood flow (CBF), while cannabidiol did not reverse that effect. Repeated treatment with Δ9-THC caused CB1 receptor desensitization and down-regulation in MCA occluded mice. On the contrary, cannabidiol did not influence these effects. Moreover, the neuroprotective effect and an increase in CBF induced by repeated treatment with cannabidiol were in part inhibited by WAY100135, serotonin 5-HT1A receptor antagonist. Cannabidiol exhibited stronger antioxidative power than Δ9-THC in an in vitro study using the 1,1-diphenyl-2-picryhydrazyl (DPPH) radical. Thus, cannabidiol is a potent antioxidant agent without developing tolerance to its neuroprotective effect, acting through a CB1 receptor-independent mechanism. It is to be hoped that cannabidiol will have a palliative action and open new therapeutic possibilities for treating cerebrovascular disorders.

Original languageEnglish
Pages (from-to)1079-1087
Number of pages9
JournalNeuropharmacology
Volume52
Issue number4
DOIs
Publication statusPublished - Mar 2007
Externally publishedYes

Fingerprint

Cannabidiol
Dronabinol
Neuroprotective Agents
Cerebrovascular Circulation
Cannabinoid Receptor CB1
rimonabant
Serotonin 5-HT1 Receptor Antagonists
Cannabinoid Receptor Antagonists
Cerebrovascular Disorders
Middle Cerebral Artery Infarction
Middle Cerebral Artery
Brain Ischemia
Down-Regulation
Antioxidants

Keywords

  • Δ-Tetrahydrocannabinol
  • (-)-Cannabidiol
  • Cerebral ischemia
  • Neuroprotection
  • Tolerance

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Drug Discovery
  • Pharmacology

Cite this

Repeated treatment with cannabidiol but not Δ9-tetrahydrocannabinol has a neuroprotective effect without the development of tolerance. / Hayakawa, Kazuhide; Mishima, Kenichi; Nozako, Masanori; Ogata, Ayumi; Hazekawa, Mai; Liu, An Xin; Fujioka, Masayuki; Abe, Koji; Hasebe, Nobuyoshi; Egashira, Nobuaki; Iwasaki, Katsunori; Fujiwara, Michihiro.

In: Neuropharmacology, Vol. 52, No. 4, 03.2007, p. 1079-1087.

Research output: Contribution to journalArticle

Hayakawa, K, Mishima, K, Nozako, M, Ogata, A, Hazekawa, M, Liu, AX, Fujioka, M, Abe, K, Hasebe, N, Egashira, N, Iwasaki, K & Fujiwara, M 2007, 'Repeated treatment with cannabidiol but not Δ9-tetrahydrocannabinol has a neuroprotective effect without the development of tolerance', Neuropharmacology, vol. 52, no. 4, pp. 1079-1087. https://doi.org/10.1016/j.neuropharm.2006.11.005
Hayakawa, Kazuhide ; Mishima, Kenichi ; Nozako, Masanori ; Ogata, Ayumi ; Hazekawa, Mai ; Liu, An Xin ; Fujioka, Masayuki ; Abe, Koji ; Hasebe, Nobuyoshi ; Egashira, Nobuaki ; Iwasaki, Katsunori ; Fujiwara, Michihiro. / Repeated treatment with cannabidiol but not Δ9-tetrahydrocannabinol has a neuroprotective effect without the development of tolerance. In: Neuropharmacology. 2007 ; Vol. 52, No. 4. pp. 1079-1087.
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