Nature-origin phthalides for Parkinson's disease drug development

Parkinson's disease (PD) is a neurodegenerative disorder characterised by neuronal loss in the substantia nigra, α-synuclein accumulation, mitochondrial impairment, oxidative stress, neuroinflammation, and apoptotic cell death. Although various pharmacological treatments, including levodopa and dopamine receptor agonists, can ameliorate PD symptoms, no disease-modifying agents with neuroprotective effects are currently available to prevent progression of neurodegeneration. As a result, there is a growing need for novel disease-modifying agents, particularly for agents with multi-target neuroprotective activity. Lactone derivatives, collectively called phthalides, from various medicinal plants, particularly from compounds of Ligusticum chuanxiong and Angelica sinensis, have been lately identified as promising drugs in this context. In the following review, a comprehensive discussion is given about the etiology of PD, its progression, molecular correlations with the pathogenesis process, latest pharmacological treatments, adverse effects with prolonged administration of drugs, etiology, and relevance of naturally occurring phthalide compounds such as DL-3-n-butylphthalide, ligustilide, senkyunolide H, sedanolide, neocnidilide, among others, with regards to their activity as neuroprotective agents in animal studies of Parkinson's disease. Results from in vitro as well as animal studies highlight their anti-oxidative, anti-inflammatory, anti-ferroptotic, anti-α-synuclein, as well as anti-MAO-B activity, and their roles as multi-target drugs in the context of disease pathogenesis.