Ginkgo biloba: A Leaf of Hope in the Fight against Alzheimer's Dementia: Clinical Trial Systematic Review

Abstract

Alzheimer's disease (AD) is a stealthy and progressive neurological disorder that is a leading cause of dementia in the global elderly population, imposing a significant burden on both the elderly and society. Currently, the condition is treated with medications that alleviate symptoms. Nonetheless, these drugs may not consistently produce the desired results and can cause serious side effects. Hence, there is a vigorous pursuit of alternative options to enhance the quality of life for patients. Ginkgo biloba (GB), an herb with historical use in traditional medicine, contains bioactive compounds such as terpenoids (Ginkgolides A, B, and C), polyphenols, organic acids, and flavonoids (quercetin, kaempferol, and isorhamnetin). These compounds are associated with anti-inflammatory, antioxidant, and neuroprotective properties, making them valuable for cognitive health. A systematic search across three databases using specific keywords-GB in AD and dementia-yielded 1702 documents, leading to the selection of 15 clinical trials for synthesis. In eleven studies, GB extract/EGb 761^® was shown to improve cognitive function, neuropsychiatric symptoms, and functional abilities in both dementia types. In four studies, however, there were no significant differences between the GB-treated and placebo groups. Significant improvements were observed in scores obtained from the Mini-Mental State Examination (MMSE), Short Cognitive Performance Test (SKT), and Neuropsychiatric Inventory (NPI). While the majority of synthesized clinical trials show that Ginkgo biloba has promising potential for the treatment of these conditions, more research is needed to determine optimal dosages, effective delivery methods, and appropriate pharmaceutical formulations. Furthermore, a thorough assessment of adverse effects, exploration of long-term use implications, and investigation into potential drug interactions are critical aspects that must be carefully evaluated in future studies.

Keywords: Alzheimer’s disease; EGb 761; Gingko biloba; cognitive dysfunction; flavonoids; terpenoids.

Figure 1

General mechanisms of damage in Alzheimer’s disease (AD). Many factors such as inflammation and free radicals can interfere with enzyme activation and the formation of βA plaques. This scenario leads to an increase in inflammatory factors’ release and the installation of oxidative stress, leading to neurotoxicity and AD development. APP—amyloid precursor protein; βA—β-amyloid.

Figure 2

Flow diagram showing the study selection (PRISMA guidelines) [31,32].

Figure 3

Gingko biloba tree, its bioactive compounds, classification, and chemical structures. Gingko biloba is rich in flavonoids, organic acids, polyphenols, and terpenoids. These compounds are responsible for the several biological effects of this plant.

Figure 4

Hormesis and Ginkgo biloba activation of Nrf2 pathway for neuroprotection in Alzheimer’s disease (AD). Early stages of AD display adaptive responses involving light increase in Nrf2 gene expression, a transcriptional factor whose activation induces the transcription of genes encoding cytoprotective, antioxidant proteins that decrease brain damage by beta-amyloid deposits. Ginkgo biloba’s sulforaphane can upregulate Nrf2 by a hormetic dose response, thus reducing βA-induced cognitive decline and progression of the disease. ↑—increase; Nrf2—nuclear factor erythroid 2-related factor; SFN: sulforaphane; HO-1—heme oxygenate-1; GST—glutathione S-transferase; SRXN1—sulfiredoxin 1; UGT—UDP-glucuronosyltransferase; βA—beta-amyloid. ↓: decrease; ↑: increase.

Figure 5

Some hormetic dose responses to EGb 761, according to previous studies. A. Effect of Ginkgo on viability and proliferation of mouse cochlea neural stem cells in vitro. B. Effect of Ginkgo on Sprague Dawley rat bone marrow mesenchymal stem cells survival to apoptosis in vitro. C. Effect of pretreatment Ginkgo on cell viability of H2O2-treated SH-SY5Y cells. D. Effect of Ginkgo on proliferation of MCF-7 AROM breast cancer cells. Hormetic ranges and toxic doses are different, depending on the type of model used in the study and measured endpoints. The graphic exhibits approximate doses of EGb 761 in µg/mL and their equivalent responses when compared to the control group. μg/mL: microgram/milliliters.

Figure 6

Protective mechanisms of Ginkgo biloba against Alzheimer’s disease (AD). Gingko biloba and its extracts can play protective roles against AD and can interfere with the formation of βA plaques. Furthermore, this plant can reduce inflammatory processes by down-regulating the release of pro-inflammatory cytokines such as IL-1, IL-6, and TNF- α. Moreover, it can reduce ROS generation, oxidative stress, and apoptosis. This scenario offers prevention of AD. ↑—increase; ↓—decrease; APP—amyloid precursor protein; βA—β-amyloid; GB—Ginkgo biloba; IL—interleukin; NF-KB—nuclear factor KB; ROS—reactive oxygen species; TNF-α: tumor necrosis factor-α.