Saffron reduces some inflammation and oxidative stress markers in donepezil-treated mild-to-moderate Alzheimer's Disease patients: A randomized double-blind placebo-control trial

Abstract

Background

Mounting evidence indicates the possible positive effects of Crocus sativus (saffron) on cognitive function in patients with Alzheimer’s Disease (AD). This study assessed the effects of saffron on cognitive outcomes and circulatory markers in patients with mild-to-moderate AD.

Methods

Sixty adults with mild-to-moderate AD were found eligible to take part in a 12-week, randomized double-blind placebo-control clinical trial with a parallel-group design. Volunteers were randomized to receive donepezil plus either saffron capsule at 15 mg/twice a day dose or placebo (n = 30 each). The main outcomes of this study were the changes in the mini-mental state examination (MMSE) score, serum inflammatory markers (IL-1β, IL-6, and TNF-α), and serum antioxidant and oxidative stress status markers (glutathione peroxidase (GPx), superoxide dismutase (SOD), malondialdehyde (MDA), and total antioxidant capacity (TAC)).

Results

MMSE score of the patients in the saffron group was not significantly different from the placebo group (p = 0.303). When compared to the placebo treatment, saffron administration significantly decreased IL-1β (p = 0.036) and MDA (p = 0.021) levels and increased TAC (p = 0.032) in the serum sample of mild-to-moderate AD patients.

Conclusion

This study showed no additional effects of saffron supplementation on cognitive outcomes in donepezil-treated mild-to-moderate AD patients; however, patients in the saffron group had improved inflammatory, antioxidant, and oxidative stress profiles compared with the placebo group, which may prove the beneficial effects of the additive on circulatory markers in AD patients.

Introduction

Alzheimer’s Disease (AD) was initially detected over a century ago, but 70 years went by before it was considered the most frequent cause of dementia and a major cause of death. The disease is characterized by life-disrupting memory loss, disorientation to time or place, difficulties in problem-solving, speaking or writing, impaired judgment, and psychiatric symptoms (Association, 2018; Fotuhi, Khalaj-Kondori, Feizi, and Talebi, 2020).

From a pathophysiological point of view, AD is accompanied by the accumulation of amyloid-β and tau tangles, leading to the cholinergic system disruption, mitochondrial dysfunction, oxidative stress, and neuroinflammation (Ahmadian et al., 2018, Majdi et al., 2020, Talebi and Ghaemian, 2020). Indeed, the accumulation of Aβ and tau alters the activity of antioxidant enzymes such as glutathione peroxidase (GPx), catalase, or superoxide dismutase (SOD), increases the production of reactive oxygen species (ROS), reactive nitrogen species (RNS), and lipid peroxidation leading to mitochondrial dysfunction (Rasi Marzabadi et al., 2021, Tönnies and Trushina, 2017). Besides, aggregates of Aβ trigger the activity of innate immunity, resulting in an inflammatory response from microglia and astrocytes manifested by the generation of pro-inflammatory cytokines (e.g., tumor necrosis factor-α (TNF-α) and interleukin (IL)−1 and 6). This in turn exacerbates oxidative stress, neuronal damage, neurodegeneration, and cognitive decline in AD (Baierle et al., 2015, Rojas-Gutierrez et al., 2017).

Saffron (Crocus sativus) is a member of the Iridaceae family with several medicinal properties attributed to its active ingredient named crocin. It has been found that saffron effectively decreases the levels of the lipid peroxidation products (e.g., malondialdehyde (MDA)) and increases the total antioxidant reactivity (TAR), as well as antioxidant enzyme activities such as GPx, glutathione reductase (GR), and SOD in the brain tissue of rats undergoing chronic stress (Bandegi, Rashidy-Pour, Vafaei, and Ghadrdoost, 2014). In addition, anti-inflammatory, and anti-Aβ aggregation properties of saffron have been proved in animal studies (Ghadrdoost et al., 2011).

Evidence emerging from human studies also proves the cognitive effects of saffron in patients with mild-to-moderate AD both in the short and long term with a favorable safety profile (Akhondzadeh et al., 2010a, Akhondzadeh et al., 2010b). Also, 1-year administration of the saffron extract was found to be comparable with memantine in decreasing cognitive impairment in patients with moderate-to-severe AD (Farokhnia et al., 2014). A recent meta-analysis study found saffron administration an effective intervention in reducing mental health problems and improving sleep conditions, but the serum level of C-reactive protein (CRP) was not significantly different between saffron and placebo groups in this study (Ghaderi et al., 2020). The aforementioned studies have not shed light on the mechanisms involved in these effects.

This study aimed to assess the effect of 12 weeks Saffrotin® capsule (ethanolic extract of saffron) administration on cognitive outcomes, as well as serum levels of anti-inflammatory, antioxidant, and oxidative stress markers in donepezil-treated mild-to-moderate AD patients.