Nonpsychoactive cannabidiol prevents prion accumulation and protects neurons against prion toxicity.
Prion diseases are transmissible neurodegenerative disorders characterized by the accumulation in the CNS of the protease-resistant prion protein (PrPres), a structurally misfolded isoform of its physiological counterpart PrPsen. Both neuropathogenesis and prion infectivity are related to PrPres formation. Here, we report that the nonpsychoactive cannabis constituent cannabidiol (CBD) inhibited PrPres accumulation in both mouse and sheep scrapie-infected cells, whereas other structurally related cannabinoid analogs were either weak inhibitors or noninhibitory. Moreover, after intraperitoneal infection with murine scrapie, peripheral injection of CBD limited cerebral accumulation of PrPres and significantly increased the survival time of infected mice. Mechanistically, CBD did not appear to inhibit PrPres accumulation via direct interactions with PrP, destabilization of PrPres aggregates, or alteration of the expression level or subcellular localization of PrPsen. However, CBD did inhibit the neurotoxic effects of PrPres and affected PrPres-induced microglial cell migration in a concentration-dependent manner. Our results suggest that CBD may protect neurons against the multiple molecular and cellular factors involved in the different steps of the neurodegenerative process, which takes place during prion infection. When combined with its ability to target the brain and its lack of toxic side effects, CBD may represent a promising new anti-prion drug.
Dirikoc
Sevda
S
Institut de Pharmacologie Moléculaire et Cellulaire, Unité Mixte de Recherche 6097, Centre National de la Recherche Scientifique, 06560 Valbonne, France.
Priola
Suzette A
SA
Marella
Mathieu
M
Zsürger
Nicole
N
Chabry
Joëlle
J
D000818:Animals; D002185:Cannabidiol / Q000494:pharmacology* / Q000627:therapeutic use; D002186:Cannabinoids / Q000494:pharmacology / Q000627:therapeutic use; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D017628:Microglia / Q000187:drug effects; D009410:Nerve Degeneration / Q000188:drug therapy; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D011328:Prions / Q000187:drug effects* / Q000378:metabolism / Q000633:toxicity*; D012608:Scrapie / Q000188:drug therapy* / Q000378:metabolism; D012756:Sheep; D015996:Survival Rate; D016896:Treatment Outcome