Gastrodia elata prevents huntingtin aggregations through activation of the adenosine A _2A receptor and ubiquitin proteasome system

Ethnopharmacological relevance: Gastrodia elata Blume (Fam. Orchidaceae) is a traditional Chinese herbal medicine for treating headaches, dizziness, tetanus, epilepsy, and numbness of the limbs, which suggests that it has neuroprotective effect. Aim of the study: To validate the neuroprotection of Gastrodia elata in preventing neurodegenerations, such as Huntington's disease (HD). Materials and methods: MTT assay was used to validate the protection of Gastrodia elata. In pheochromocytoma (PC12) cell. Transient transfection of mutant huntingtin (Htt) in PC12 cell was used as an in vitro model of HD. Filter retardation assay was used to measure Htt-induced protein aggregations. Proteasome activity was monitored by transfection of pZsProSensor-1 and imaged by a confocal laser scanning microscope. Results: This protection of Gastrodia elata could be blocked by an A _2A-R antagonist and a protein kinase A (PKA) inhibitor, indicating an A _2A-R signaling event. Gastrodia elata could reverse mutant Htt-induced protein aggregations and proteasome de-activation through A _2A-R signaling. In addition, activation of PKA tended to activate proteasome activity and reduce mutant Htt protein aggregations. The proteasome inhibitor, MG 132, blocked Gastrodia elata-mediated suppression of mutant Htt aggregations. Conclusion: Gastrodia elata prevented mutant Htt aggregations and increased proteasomal activity by targeting the A _2A-R through PKA-dependent pathway.