Evaluation of the Therapeutic Potentials of Chinese Herbs and Indole Compounds in Parkinson’s Cell and Animal Models

Parkinson’s disease (PD) is a common neurodegenerative disorder with selected loss of midbrain dopaminergic (DAergic) neurons. The lack of treatment to prevent the disease from progressing urges the development of new agents that may halt the rate of PD progression. Similar to other neurodegenerative diseases, there is increasing evidence that chaperones and oxidative stress participating to the pathogenesis of PD, while chaperone inducers and antioxidants may be relevant therapeutic strategies for PD. Using a spinocerebellar ataxia neurodegenerative cell models by inducible ATXN3/Q75 or TBP/Q79 expression on HEK-293 and SH-SY5Y cells, we have found prominent anti-oxidative and mitochondria biogenesis activities of Chinese herbs Glycyrrhiza inflata (G. inflata; active constituents licochalcone A and ammonium glycyrrhizinate) and Gardenia jasminoides (G. jasminoides; active constituents/metabolite geniposide, crocin and genipin), while Chinese herb Paeonia lactiflora (P. lactiflora; active constituent paeoniflorin), indole compounds (indole and derivative NC001-8) upregulated chaperones and/or autophagy. Herein we proposed the following studies to investigate the therapeutic potentials of these extracts/compounds for PD. Aim 1: Determining the neuroprotective effects of P. lactiflora, G. inflata, G. jasminoides, indole and derivative NC001-8 by SH-SY5Y DAergic cell assays (Year 1 ~ 2) In this aim, we will evaluate the effects of above Chinese herbs/indole compounds on SH-SY5Y DAergic cell model by quantification of disease phenotypes such as cell morphology, chaperone and oxidative stress marker expressions, mitochondrial and autophagy functions, cell survival, and apoptosis. Aim 2: Evaluating the chaperone and autophagy enhancement potentials of Chinese herb P. lactiflora and indole and derivative NC001-8 by PD-iPSC model (Year 2 ~ 3) We have established a PD-iPSC model, which recapitulated α-synuclein accumulation phenotype. Here this model will be used to examine the effects of Chinese herb P. lactiflora/indole compounds on α-synuclein reduction, chaperones enhancement and cell survival improvement. Aim 3: Exploring the mitochondria biogenesis enhancement and antioxidative effects of Chinese herbs G. inflata and G. jasminoides by PD-iPSC model (Year 2 ~ 3) Our PD-iPSC-derived neurons also demonstrated downregulation of a number of genes of NRF2 anti-oxidative pathways. To gain more insights of Chinese herbs G. inflata and G. jasminoides on PD treatment, the oxidative stress marker expression, mitochondrial function, apoptosis and neurite outgrowth will be evaluated by this model. Aim 4: Testing the potential of P. lactiflora, G. inflata, G. jasminoides, indole and derivative NC001-8 for treatment of PD by MPTP PD mouse model (Year 2 ~ 3) In this aim, MPTP PD mouse model will be used for the behaviour assays, and determining therapeutic index and BBB permeability of above Chinese herbs/indole compounds. Studies from this proposal will provide new insights into the PD treatment.

Project ID:PC10501-2338
External Project ID:MOST104-2314-B182-060-MY2