A randomized, open-label clinical trial in mild cognitive impairment with EGb 761 examining blood markers of inflammation and oxidative stress

Abstract

Although beta-amyloid (Aβ) and phosphorylated tau remain the preferred targets for disease-modifying treatments (DMT) against Alzheimer’s disease (AD), part of the pathophysiological mechanisms of cognitive impairment are related to neuroinflammation and oxidative stress. In mild cognitive impairment (MCI), a prodromal stage of AD and other neurodegenerative conditions, the joint appearance of inflammation, oxidative stress, and metabolic alterations are the common pathways of neurotoxicity and neurodegeneration. The standardized extract of Ginkgo biloba EGb 761 interferes with the pathogenic mechanisms involved in both the development of cognitive impairment due to AD and that of vascular origin. The primary objective of this study is to compare changes in the levels of blood markers of inflammation and oxidative stress after treatment with EGb 761 in a cohort of 100 patients with MCI. In addition, we aim to assess changes in these blood markers during an additional 12-month extension phase in which patients in the control group will also receive EGb 761 and patients in the active group will extend their treatment duration. Secondary objectives include comparing changes in neuropsychiatric and cognitive test scores between the baseline (v0) and 12-month visits (v2). This study is a Phase IV, single-center, randomized, open-label, parallel-group clinical trial consisting of the 12-month follow-up of a cohort of participants with MCI [Global Deterioration Scale (GDS) = 3] and an extension with an additional 12-month follow-up. During the first 12 months, participants will be randomized into two arms: in one arm, patients will receive 1 daily tablet of EGb 761 240 mg orally (study group, n = 50), while in the other arm, patients will not receive EGb 761 and will undergo the same assessments as the treated group (control group, n = 50). After the first 12 months of the study, patients in the EGb 761-treated group will continue treatment, and patients in the control group will be offered one EGb 761 240 mg tablet per day orally. All participants will be monitored for an additional 12 months. A battery of blood markers of inflammation and oxidative stress will be quantified at v0, v1, v2, v3, and v4. The Olink Proteomics panel of inflammation markers (https://www.olink.com/products/inflammation/) will be used to evaluate 92 proteins associated with inflammatory diseases and related biological processes. The second panel measures 92 proteins involved in neurological processes. At v0, v2, and v4, neuropsychological and neurological evaluations will be conducted in addition to vital signs and anthropometric studies using a body composition monitor with bioimpedance technology (Tanita). Sixty percent of the 100 MCI patients recruited were women. The mean age was 73.1 years, and the mean time between symptom onset and MCI diagnosis was 2.9 years. The mean Mini-Mental State Examination (MMSE) score was 26.7. Depressive and anxiety disorders, as well as vascular risk factors, were the most frequent comorbidities among the cohort. The study is still ongoing, and results for the first year of treatment (v0, v1, v2) are expected by 2023. Individuals with MCI have an elevated risk of developing dementia. EGb 761 is used worldwide for the symptomatic treatment of cognitive disorders due to its neuroprotective effects. In experimental models and clinical observational studies, EGb 761 has shown strong antioxidant and anti-inflammatory activity. As a result, this study has been proposed to evaluate the antioxidant and anti-inflammatory effects on plasma markers and their potential clinical correlation with the progression of cognitive decline in patients with MCI.Trial registration: Registro Español de estudios clínicos (REec) number 2020-003776-41, ClinicalTrials.gov Identifier: NCT05594355.

Rutin is a potent senomorphic agent to target senescent cells and can improve chemotherapeutic efficacy

“…It also displays pharmacological activities such as antimicrobial and anti‐inflammatory capacities (Panasiak et al, 1989 ), although sometimes showing counteractive activity against certain other flavonoids which exert pro‐oxidant activities by catalyzing oxygen radical generation (Hodnick et al, 1986 ). To date, rutin has been considered as a nontoxic chemical, which may be useful in numerous biomedical applications, while some rutin‐containing natural plant extracts such as Ginkgo biloba extract (GBE) demonstrated vital health benefits such as those observed in alleviation of chronic neurodegenerative diseases and reduction in extracellular amyloid beta (Aβ) plaques, typical symptoms of Alzheimer's disease (AD) (Morato et al, 2023 ). By contrast, the potential of rutin in other situation, particularly those involving antiaging properties in advanced stage and the potential of using its bioactivity in development of senotherapeutics, more specifically senomorphics, remains largely underexplored.…”

Immunological dimensions of neuroinflammation and microglial activation: exploring innovative immunomodulatory approaches to mitigate neuroinflammatory progression

“…Morató et al. ( 367 ) investigated the effects of EGb 761, the standardized extract of Ginkgo biloba , in MCI patients. Blood markers of inflammation and oxidative stress were analyzed.…”

Current Advances in Mitochondrial Targeted Interventions in Alzheimer’s Disease

“…EGb 761 ® , an extract made from the dry leaves of Ginkgo biloba, was found to have strong free radical scavenging and mitochondrial-protective properties [ 174 ], mechanisms that seem to underlie the described protective effects, such as improved neuronal function [ 175 ] and neuroinflammation [ 176 ], a shift in APP metabolism towards non-amyloidogenic pathways [ 177 ], Aβ toxicity, and cognitive performance [ 178 ]. In this context, presently, the antioxidant and anti-inflammatory effects of EGb 761 ® are being evaluated in a Phase IV randomized, open-label clinical trial in MCI subjects to identify its possible clinical correlation with cognitive outcomes (NCT05594355) [ 179 ]. Complementing the existing data on to the neuroprotective effects of EGb 761 ® , recent studies have also investigated the effects of one of its main active components, Ginkgolide B, in the AD context.…”