Therapeutic potentials of plant iridoids in Alzheimer's and Parkinson's diseases: A review

摘要

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 (A beta) 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-gamma, and alpha-secretase, and decreasing the expression of beta-secretase (BACE-1) to reduce the levels of A beta oligomers (A beta(O)) deposition in brain neurons. These plant metabolites reduced the expression of GSK-3 beta 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/P13K, 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 A beta 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 A beta load from brain across the blood-brain barrier (BBB) as well as increased the expression of PPAR-gamma and ApoE proteins for clearance of A beta in ApoE mediated pathway from brain.