Tetrahydrocannabinolic acid is a potent PPARγ agonist with neuroprotective activity.

BACKGROUND AND PURPOSE: 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.

EXPERIMENTAL APPROACH: 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).

KEY

RESULTS

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.

CONCLUSIONS AND IMPLICATIONS: Δ9 -THCA shows potent neuroprotective activity, which is worth considering for the treatment of Huntington's disease and possibly other neurodegenerative and neuroinflammatory diseases.