Therapeutic potentials of plant iridoids in Alzheimer's and Parkinson's diseases: A review.Eur J Med Chem 2019; 169:185-199EJ
Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common age-related neurodegenerative disorders, affecting several millions of aged people globally. Among these disorders, AD is more severe, affecting about 7% of individuals aged 65 and above. AD is primarily a dementia-related disorder from progressive cognitive deterioration and memory impairment, while PD is primarily a movement disorder illness having three major kinesia or movement disorder symptoms, bradykinesia (slowness of movements), hypokinesia (reduction of movement amplitude), and akinesia (absence of normal unconscious movements) along with muscle rigidity and tremor at rest. AD is characterized by deposition of extracellular beta-amyloid (Aβ) proteins and intracellular neurofibrillary tangles (NFT), composed of hyperphosphorylated tau proteins in the neurons located particularly in hippocampus and cerebral cortex regions of brain, resulting the neuronal loss, while PD is characterized by deposition of intraneuronal aggregates of mostly composed of alpha-synuclein gene as Lewy bodies (LB) in the striatal region, known as substantia nigra pars compacta (SNpc) of brain, leading to the death of dopaminergic neurons. These are known as pathological hallmarks of these diseases. However, in some overlapping cases, known as Alzheimer with Parkinson disease or vice versa, alpha-synuclein deposition in AD and tau deposition in PD patients are found. Oxidative stress-induced glial cells activation, neuroinflammation and mitochondrial dysfunction lead to various molecular events in brain neurons causing neuronal cell death in these neurodegenerative disorders. Currently used drugs for treatment of AD and PD only reduce the symptoms of these diseases, but unable to stop the process of neurodegeneration. Therefore, innovation of new synthetic drugs or discovery of natural drugs for the treatment of AD and PD, is a challenging task of basic science and clinical medicine. Plant iridoids such as catalpol and its 10-O-trans-p-coumaroyl derivative, geniposide, harpagoside, and loganin, and seco-iridoids, oleuropein and its aglycone and oleocanthal have been found to exhibit significant neuroprotective effect and the property of slowing down the process of neurogedeneration in AD and PD. These plant metabolites have been shown to ameliorate AD by increasing the expression of insulin degrading enzyme (IDE), neprilysin (NEP), PPAR-γ, and α-secretase, and decreasing the expression of β-secretase (BACE-1) to reduce the levels of Aβ oligomers (AβO) deposition in brain neurons. These plant metabolites reduced the expression of GSK-3β and its receptor gene, PTEN to reduce hyperphosphorylation of tau proteins and neurofibrillary tangles (NFTs) formation. These metabolites improved the expressions of neuroprotective proteins, Bcl-2 via activations of growth-related protein-1 receptor (GLP-1R), PKC, MEK, MAPK/PI3K, and AMPK, and suppressed the expressions of pro-apoptotic proteins, Bax and caspase-3. Furthermore, these plant metabolites improved the lysosomal autophagy process by increasing the expression levels of Beclin-1, LC3II and cathepsin B genes for clearance of Aβ and NFT, and increased the expression of transporter proteins, P-glycoprotein (P-gp) and low density lipoprotein receptor-related protein-1 (LRP-1) for the clearance of Aβ load from brain across the blood-brain barrier (BBB) as well as increased the expression of PPAR-γ and ApoE proteins for clearance of Aβ in ApoE mediated pathway from brain. Moreover, these plant metabolites reduced the cognitive impairment by increasing the expression of synaptic proteins, BDNF, PSD-95, SNAP-25, SYP and GAP-43 for improvement of learning and memory functions in AD. While among these iridoids, catalpol, 10-O-trans-p-coumaroylcatalpol, geniposide and harpagoside, in PD improved the expressions of GDNF and Bcl-2 proteins and TH-positive neurons by increasing the levels of antioxidant enzymes, SOD and GSH-PX and down-regulating insulin/IGF signalling via activation of MEK protein. Moreover, catalpol and its p-coumaroyl derivative in mutant nematode C. elegans model, up-regulated the expression of DAF-16, a FOXO family transcription factor and SKN-1 genes for improvement of lifespan and resistance against oxidative- and other stresses of mutated worms. Furthermore, geniposide increased the expression of autophagy-related LAMP-2A-protein for clearance of LB from dopaminergic neurons in PD brain via improving lysosomal autophagy process. The present review summarizes the neuroprotective activities and molecular mechanisms of these iridoids and secoiridoids, in prevention and/or treatment of both AD and PD. This review will be helpful to find out the research gap on these plant metabolites in this field to use them as potential drugs against these disorders.