Neuroprotective potentials of Lead phytochemicals against Alzheimer's disease with focus on oxidative stress-mediated signaling pathways: Pharmacokinetic challenges, target specificity, clinical trials and future perspectives

Background: Alzheimer's diseases (AD) and dementia are among the highly prevalent neurological disorders characterized by deposition of beta amyloid (A beta) plaques, dense deposits of highly phosphorylated tau proteins, insufficiency of acetylcholine (ACh) and imbalance in glutamatergic system. Patients typically experience cognitive, behavioral alterations and are unable to perform their routine activities. Evidence also suggests that inflammatory processes including excessive microglia activation, high expression of inflammatory cytokines and release of free radicals. Thus, targeting inflammatory pathways beside other targets might be the key factors to control- disease symptoms and progression. Purpose: This review is aimed to highlight the mechanisms and pathways involved in the neuroprotective potentials of lead phytochemicals. Further to provide updates regarding challenges associated with their use and their progress into clinical trials as potential lead compounds. Methods: Most recent scientific literature on pre-clinical and clinical data published in quality journals especially on the lead phytochemicals including curcumin, catechins, quercetin, resveratrol, genistein and apigenin was collected using SciFinder, PubMed, Google Scholar, Web of Science, JSTOR, EBSCO, Scopus and other related web sources. Results: Literature review indicated that the drug discovery against AD is insufficient and only few drugs are clinically approved which have limited efficacy. Among the therapeutic options, natural products have got tremendous attraction owing to their molecular diversity, their safety and efficacy. Research suggest that natural products can delay the disease onset, reduce its progression and regenerate the damage via their anti-amyloid, anti-inflammatory and antioxidant potentials. These agents regulate the pathways involved in the release of neurotrophins which are implicated in neuronal survival and function. Highly potential lead phytochemicals including curcumin, catechins, quercetin, resveratrol, genistein and apigenin regulate neuroprotective signaling pathways implicated in neurotrophins-mediated activation of tropomyosin receptor kinase (Trk) and p75 neurotrophins receptor (p75NTR) family receptors. Conclusions: Phytochemicals especially phenolic compounds were identified as highly potential molecules which ameliorate oxidative stress induced neurodegeneration, reduce A beta load and inhibit vital enzymes. Yet their clinical efficacy and bioavailability are the major challenges which need further interventions for more effective therapeutic outcomes.