Article - Polyphenols, Alkaloids, and Terpenoids Against Neurodegeneration: Evaluating the Neuroprotective Effects of Phytocompounds Through a Comprehensive Review of the Current Evidence.

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Take home message

From the study authors suggest that greater adherence to medication could be associated with cognitive functioning however the results were not explicit.

Evidence category

C: Non-randomized trials, observational studies, narrative reviews

Summary review

Introduction

This review aimed to provide an overview of the effects of 8 phytocompounds (polyphenols (quercetin), alkaloids (huperzine A, caffeine), terpenoids (ginkgolides), and phenolic acids (rosmarinic acid, ferulic acid, resveratrol) based on 13 clinical trials published between1999 and 2022 for their neuroprotective effects.

Important note

Whilst this review applied PRISMA guidelines and searched PubMed, Cochrane, and Embase databases with an unrestricted search period, limited information was provided.
The review provided a generalised assessment of the 8 phytocompounds, therefore 1 RCT was chosen for deeper assessment as it provided detailed statistical analysis:

Article: A randomized placebo-controlled trial of Ginkgo biloba for the prevention of cognitive decline. Hodge et al., 2008

Ginkgo biloba extract (GBE):

Objective: To assess the feasibility, safety, and efficacy of Ginkgo biloba extract (GBE) on delaying the progression to cognitive impairment in normal elderly aged 85 and older.

Methods:

42-month randomised, double blinded, placebo controlled trial

118 cognitively intact subjects (age ≥ 85), randomly assigned to standardised GBE (240 mg, divided into 80 mg, 3 times daily; n=60, mean age 87.50) or Placebo (n=58, mean age 87.43)

All participants received a multivitamin containing 40 IU of vitamin E to reduce the temptation to experiment with other supplements during the trial..
Participants were assessed at baseline and seven 6-month follow-up time points.
Kaplan-Meier survival curves were used to compare the risk of progression from Clinical Dementia Rating (CDR)
Cox Proportional Hazard Model was employed to ascertain medication adherence during the first 6 months

Results

Primary analysis: The Kaplan-Meier survival curves showed that the GBE group had a lower likelihood of progression from normal to CDR above 0.5; log-rank test showed χ2 value of 3.37 (p= 0.06).
Progression to CDR ≥ 1.0 during the follow-up was observed for 4 out of 21 cases: 3 in the placebo group and 1 in the GBE group (hazard ratio of GBE on progression to CDR = 0.5 was 0.43 (95% CI: 0.17 to 1.08, p = 0.066). The effect also did not reach statistical significance.
GBE group showed a tendency of less decline in memory function but only slightly above statistical significance
Secondary analysis: Medication adherence: 68.6% (all participants); 65.0% (GBE group) and 72.4% (placebo group)

Conclusion Ginkgo biloba extract (GBE) neither altered the risk of progression from normal to Clinical Dementia Rating (CDR) = 0.5, nor protected against a decline in memory function.

Clinical practice applications

While medication adherence is important on disease progression, the protective effects of GBE on adherence could not be confirmed and therefore results should be interpreted with caution.

Considerations for future research

Larger prevention trials taking into account medication adherence may clarify the effectiveness of GBE
Identify methods to facilitate and increase adherence in dementia prevention trials will be important

Abstract

Neurodegenerative diseases comprise a group of chronic, usually age-related, disorders characterized by progressive neuronal loss, deformation of neuronal structure, or loss of neuronal function, leading to a substantially reduced quality of life. They remain a significant focus of scientific and clinical interest due to their increasing medical and social importance. Most neurodegenerative diseases present intracellular protein aggregation or their extracellular deposition (plaques), such as α-synuclein in Parkinson's disease and amyloid beta (Aβ)/tau aggregates in Alzheimer's. Conventional treatments for neurodegenerative conditions incur high costs and are related to the development of several adverse effects. In addition, many patients are irresponsive to them. For these reasons, there is a growing tendency to find new therapeutic approaches to help patients. This review intends to investigate some phytocompounds' effects on neurodegenerative diseases. These conditions are generally related to increased oxidative stress and inflammation, so phytocompounds can help prevent or treat neurodegenerative diseases. To achieve our aim to provide a critical assessment of the current literature about phytochemicals targeting neurodegeneration, we reviewed reputable databases, including PubMed, EMBASE, and COCHRANE, seeking clinical trials that utilized phytochemicals against neurodegenerative conditions. A few clinical trials investigated the effects of phytocompounds in humans, and after screening, 13 clinical trials were ultimately included following PRISMA guidelines. These compounds include polyphenols (flavonoids such as luteolin and quercetin, phenolic acids such as rosmarinic acid, ferulic acid, and caffeic acid, and other polyphenols like resveratrol), alkaloids (such as berberine, huperzine A, and caffeine), and terpenoids (such as ginkgolides and limonene). The gathered evidence underscores that quercetin, caffeine, ginkgolides, and other phytochemicals are primarily anti-inflammatory, antioxidant, and neuroprotective, counteracting neuroinflammation, neuronal oxidation, and synaptic dysfunctions, which are crucial aspects of neurodegenerative disease intervention in various included conditions, such as Alzheimer's and other dementias, depression, and neuropsychiatric disorders. In summary, they show that the use of these compounds is related to significant improvements in cognition, memory, disinhibition, irritability/lability, aberrant behavior, hallucinations, and mood disorders.