Disease-modifying treatment of Parkinson's disease by phytochemicals: targeting multiple pathogenic factors

Parkinson's disease is characterized by typical motor symptoms, loss of dopamine neurons in the substantia nigra, and accumulation of Lewy body composed of mutated α-synuclein. However, now it is considered as a generalized disease with multiple pathological features. Present available treatments can ameliorate symptoms at least for a while, but only a few therapies could delay progressive neurodegeneration of dopamine neurons. Lewy body accumulates in peripheral tissues many years before motor dysfunction becomes manifest, suggesting that disease-modifying therapy should start earlier during the premotor stage. Long-termed regulation of lifestyle, diet and supplement of nutraceuticals may be possible ways for the disease-modification. Diet can reduce the incidence of Parkinson's disease and phytochemicals, major bioactive ingredients of herbs and plant food, modulate multiple pathogenic factors and exert neuroprotective effects in preclinical studies. This review presents mechanisms underlying neuroprotection of phytochemicals against neuronal cell death and α-synuclein toxicity in Parkinson's disease. Phytochemicals are antioxidants, maintain mitochondrial function and homeostasis, prevent intrinsic apoptosis and neuroinflammation, activate cellular signal pathways to induce anti-apoptotic and pro-survival genes, such as Bcl-2 protein family and neurotrophic factors, and promote cleavage of damaged mitochondria and α-synuclein aggregates. Phytochemicals prevent α-synuclein oligomerization and aggregation, and dissolve preformed α-synuclein aggregates. Novel neuroprotective agents are expected to develop based on the scaffold of phytochemicals permeable across the blood-brain-barrier, to increase the bioavailability, ameliorate brain dysfunction and prevent neurodegeneration.