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 Δ -tetrahydrocannabinol have been extensively investigated, the bioactivity of Δ -tetahydrocannabinol acid (Δ -THCA) is largely unknown, despite its occurrence in different Cannabis preparations. Here we have assessed possible neuroprotective actions of Δ -THCA through modulation of PPARγ pathways.

Experimental Approach: The effects of six phytocannabinoids on PPARγ binding and transcriptional activity were investigated. The effect of Δ -THCA on mitochondrial biogenesis and PPARγ coactivator 1-α expression was investigated in Neuro-2a (N2a) cells. The neuroprotective effect was analysed in STHdh 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 Δ -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. Δ -THCA increased mitochondrial mass in neuroblastoma N2a cells and prevented cytotoxicity induced by serum deprivation in STHdh cells and by mutHtt-q94 in N2a cells. Δ -THCA, through a PPARγ-dependent pathway, was neuroprotective in mice treated with 3-NPA, improving motor deficits and preventing striatal degeneration. In addition, Δ -THCA attenuated microgliosis, astrogliosis and up-regulation of proinflammatory markers induced by 3-NPA.

Conclusions And Implications: Δ -THCA shows potent neuroprotective activity, which is worth considering for the treatment of Huntington's disease and possibly other neurodegenerative and neuroinflammatory diseases.