RT Journal Article
T1 Tetrahydrocannabinolic acid is a potent PPARγ agonist with neuroprotective activity.
A1 Nadal, Xavier
A1 Del Rio, Carmen
A1 Casano, Salvatore
A1 Palomares, Belen
A1 Ferreiro-Vera, Carlos
A1 Navarrete, Carmen
A1 Sanchez-Carnerero, Carolina
A1 Cantarero, Irene
A1 Bellido, Maria Luz
A1 Meyer, Stefan
A1 Morello, Gaetano
A1 Appendino, Giovanni
A1 Muñoz, Eduardo
K1 Animals
K1 Cannabis
K1 Cell line, tumor
K1 Disease models, animal
K1 Dronabinol
AB Phytocannabinoids are produced in Cannabis sativa L. in acidic form and are decarboxylated upon heating, processing and storage. While the biological effects of decarboxylated cannabinoids such as Δ9 -tetrahydrocannabinol have been extensively investigated, the bioactivity of Δ9 -tetahydrocannabinol acid (Δ9 -THCA) is largely unknown, despite its occurrence in different Cannabis preparations. Here we have assessed possible neuroprotective actions of Δ9 -THCA through modulation of PPARγ pathways. The effects of six phytocannabinoids on PPARγ binding and transcriptional activity were investigated. The effect of Δ9 -THCA on mitochondrial biogenesis and PPARγ coactivator 1-α expression was investigated in Neuro-2a (N2a) cells. The neuroprotective effect was analysed in STHdhQ111/Q111 cells expressing a mutated form of the huntingtin protein and in N2a cells infected with an adenovirus carrying human huntingtin containing 94 polyQ repeats (mHtt-q94). The in vivo neuroprotective activity of Δ9 -THCA was investigated in mice intoxicated with the mitochondrial toxin 3-nitropropionic acid (3-NPA). Cannabinoid acids bind and activate PPARγ with higher potency than their decarboxylated products. Δ9 -THCA increased mitochondrial mass in neuroblastoma N2a cells and prevented cytotoxicity induced by serum deprivation in STHdhQ111/Q111 cells and by mutHtt-q94 in N2a cells. Δ9 -THCA, through a PPARγ-dependent pathway, was neuroprotective in mice treated with 3-NPA, improving motor deficits and preventing striatal degeneration. In addition, Δ9 -THCA attenuated microgliosis, astrogliosis and up-regulation of proinflammatory markers induced by 3-NPA. Δ9 -THCA shows potent neuroprotective activity, which is worth considering for the treatment of Huntington's disease and possibly other neurodegenerative and neuroinflammatory diseases.
PB John Wiley & Sons
YR 2017
FD 2017-08-17
LK http://hdl.handle.net/10668/11541
UL http://hdl.handle.net/10668/11541
LA en
NO Nadal X, Del Río C, Casano S, Palomares B, Ferreiro-Vera C, Navarrete C, et al. Tetrahydrocannabinolic acid is a potent PPARγ agonist with neuroprotective activity. Br J Pharmacol. 2017 Dec;174(23):4263-4276
NO This work was partially supported by the MINECO grantRTC-2015-3364 cofounded by the European DevelopmentRegional Fund in the Framework of the Operative Program‘Reinforcement of research, technological development andinnovation’ and by ICEX, España Exportación e Inversiones,programme INVEST IN SPAIN grant 201503487 toPhytoplant Research S.L. E.M. was also supported by theMINECO grant SAF2014-53763-P. B.P. was supported by theiPFIS programme fellowship (MINECO). We thank Dr José J.Lucas (Severo Ochoa Molecular Biology Center, Madrid,Spain) and Dr Andrea Ruiz (University Complutense ofMadrid, Spain) for providing with adenovirus carryingmHtt-q94
DS RISalud
RD Apr 10, 2025