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 STHdh^Q111/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 STHdh^Q111/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.