BACKGROUND: It is established that natural medicines for Parkinson's disease (PD) provide an antioxidant activity in preventing dopaminergic neurons from degeneration. However, the underlying and related molecular details remain poorly understood. METHODS AND AIM: We review published in vitro and rodent studies of natural products in PD models with the aim to identify common molecular pathways contributing to the treatment efficacy. Commonly regulated genes were identified through the systemic literature search and further analyzed from a network perspective. FINDINGS: Approximately thirty different types of natural products have been investigated for their ability to regulate protein density and gene activity in various experimental systems. Most were found to attenuate neurotoxin-induced regulations. Three common PD pathways are involved. The most studied pathway was neuronal development/anti-apoptosis consisting of Bax/Bcl-2, caspases 3/9, and MAPK signaling. Another well studied was anti-inflammation comprising iNOS, nNOS, Nrf2/ARE, cytokines, TNFα, COX2 and MAPK signaling. The third pathway referred to dopamine transmission modulation with upregulated VMAT2, DAT, NURR1 and GDNF levels. To date, HIPK2, a conserved serine/threonine kinase and transcriptional target of Nrf2 in an anti-apoptosis signaling pathway, is the first protein identified as the direct binding target of a natural product (ZMHC). IMPLICATIONS: Natural products may utilize multiple and intercellular pathways at various steps to prevent DA neurons from degeneration. Molecular delineation of the mechanisms of actions is revealing new, perhaps combinational therapeutic approaches to stop the progression of DA degeneration.

Department of Neurology People's Hospital of Dongxihu District Wuhan Hubei 430040 China

Department of Neurology Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei 430022 China

Department of Neurology Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei 430022 China; Department of Neurology People's Hospital of Dongxihu District Wuhan Hubei 430040 China

Department of Neurology Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei 430022 China; Department of Neurology the 1st Affiliated Hospital of USTC Division of Life Sciences and Medicine University of Science and Technology of China Hefei Anhui 230001 China

Laboratory of Psychiatric Neurogenomics McLean Hospital Harvard Medical School Belmont MA 02478 United States

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