Crocin, the Main Active Constituent Found in Saffron, May be Just the One for Neurogenesis and Alzheimer’s Disease
For a long time, loss of brain cells, or neurons, is considered irreversible in adult human brain. Conventional wisdom suggested that we only use the number of neurons we are born with and once the neurons die, they are not replaced by new neurons. The lack of neuron regeneration, or neurogenesis, is a major cause that we develop neurological diseases including Alzheimer’s disease (AD) as we age. Until research in 1998, this belief is found only partly true. In most part of adult human brain, neurons are not changed. Utilizing tracer and advanced carbon-14 isotope dating technologies, scientists confirmed neurogenesis continuously happens in specific regions or domains of adult human brain including hippocampus, a seahorse-shaped structure area in the brain that is important for memory formation and cognitive functions1-3. Neurogenesis seems to persist in hippocampus even among aged and patients with AD. An enhanced neurogenesis, particularly the number of newly formed neurons, is associated with better cognition and, on the other hand, decrease in neurogenesis may promote cognitive deficits in AD or exacerbate them3.
In recent years, scientists have discovered many factors, both internal and external, can influence memory and the rate of neurogenesis in the adult hippocampus. Therefore, external neuroprotectors and neurogenesis enhancers could potentially tip the turnover or balance of neurons death and genesis for better memory, prevention and treatment of AD.
A few internal factors including brain‐derived neurotrophic factor (BDNF), cAMP response element binding protein (CREB), etc. have been identified as required or important for environmental induction of neurogenesis4. Upregulation of neurotrophic factors, such as BDNF, enhances adult neurogenesis. Activation of CREB is corelated with increasing number of new neurons5. In adult brain, CREB also participates in neuronal survival, plasticity, learning, and memory through its involvement in adult hippocampal neurogenesis6. Studies have found external factors including natural components are able to affect these internal factors, which may in turn help enhance neurogenesis and improve memory and Alzheimer’s disease.
Saffron and particularly its main active constituent crocin as promising natural enhancers are believed to provide potential effects on neurogenesis, memory improvement and in prevention and treatment of Alzheimer’s disease. Findings of the most recently published research are briefly reviewed here.
As one of the most expensive spices and traditional medical herbs, saffron and its main active constituent crocin have been some of the most studied natural ingredients in recent years. Their health effects have been indicated in multiple clinical studies important for prevention and treatment of depression7, age-related macular degeneration (AMD)8, diabetic maculopathy9, and memory impairment and Alzheimer’s disease10, etc. Several animal and human studies have revealed that crocin and saffron are able to regulate the internal factors important for neurogenesis and provide better memory, cognition and anti-depressive effects through increasing protein levels of BDNF and CREB. Methamphetamine (METH) abuse disrupts memory and cognition and causes neurodegeneration. Recent research showed METH not only markedly reduced the protein expression of BDNF and CREB in hippocampus, but also significantly increased oxidative stress, neuronal death and inflammatory biomarkers11. Treatment with crocin attenuated METH-induced cognitive impairments and countered METH disruptive effects in hippocampus by including enhanced CREB and BDNF protein expression. Prior to this animal study, the effects of crocin on hyoscine (also known as scopolamine) induced memory impairment and protein and mRNA transcript levels of CREB and BDNF in rat hippocampus were evaluated12. Crocin treatment significantly increased BDNF and CREB protein and transcript levels and significantly improved memory impairment induced by hyoscine. In a separate study, morphine was found to significantly decrease BDNF and CREB gene expressions in in brain ventral tegmental area (VTA) and BDNF protein level in serum, but treatment with crocin inhibited the unfavorable effects of morphine on the neural system by enhancing BDNF and CREB gene expression in brain VTA and serum level of BDNF13. It was also suggested that improvement in levels of BDNF and CREB is involved in anti-depressant activity in hippocampus. In another study, rats in subacute exposure to organophosphate insecticide malathion were found to induce depressive‐like behavior. Malathion reduced BDNF level and increased oxidative stresses in rat hippocampus. Treatment with crocin reversed the effects of malathion on BDNF, oxidative stresses and behavior14.
Alzheimer disease (AD) is one of the most prevalent and progressive neurodegenerative diseases of the central nervous system. A recent study evaluated effects of crocin on indicators of neuron death, inflammation, BDNF, tangle forming protein (Pt), and plaque forming peptide Aβ40 indicators, as well as neuronal density in CA1, CA2, and CA3 regions in hippocampus in model of Alzheimer suffering rats15. This AD model was established by injection of a chemical trimethyltin chloride (TMT), which resulted in significantly reduced level of BDNF and density of neurons in CA1, CA2 and CA3 regions of hippocampus. The levels of Pt, Aβ40, neuron death, and inflammatory indicators were significantly increased in comparison to control. However, as results of crocin treatment, the neuron death, inflammatory, Pt, and Aβ40 indicators were significantly decreased, and BDNF indicator and density of neurons in CA1, CA2, and CA3 significantly increased in the regions of hippocampus of the rats with AD. Findings of these animal studies showed that crocin prevents the accumulation of Aβ and Pt, reduces oxidative stress and inflammation, enhances levels of BDNF and CREB through neuroprotection or neurogenesis, and more importantly, crocin improves memory and learning.
Although, the effects of crocin on neuroprotection, neurogenesis and improvements in memory and learning has not been directly evaluated in human studies, crocin has been identified as the main active ingredient responsible for the health effects of saffron10. A number of clinical studies with saffron has been reported in recent years. One most recent study clinically evaluated the protective properties of the aqueous extract of saffron in patients with ischemic stroke16. Cerebral ischemic stroke is one of the leading causes of death and the most common cause of disability of humans. The initiation of inflammatory processes and release of neurotoxins in the course of cerebral ischemia would damage great numbers of neurons. Protection of the brain cells or neurons at risk and timely care within 24 h since the onset of stroke is considered critical in the treatment of stroke. In this study, patients came to emergency room with acute middle cerebral artery ischemic stroke were randomly allocated to receive either routine stroke care (control group) or routine care plus aqueous extract of saffron capsules (saffron treated group). The saffron extract was measured with 20% of crocin. Saffron delivery was based on the crocin content in each capsule. Both groups were monitored during their four-day hospital stay and the three-month follow-up period. Findings from this study showed that treatment with saffron extract (20% crocin) significantly improved the severity of stroke and activities of daily living measured by National Institute of Health Stoke Scale (NIHSS) and Barthel Scale. Their scores were significantly better than just standard care alone. Measurement of BDNF concentration in serum revealed a significant increase by saffron treatment but not in patients with standard care alone.
So far, the most direct clinical indication of crocin/saffron effects on neurogenesis was from a human study carried out by scientists at Aristotle University of Thessaloniki and the Greek Association of Alzheimer’s Disease and Related Disorders. Dr. Magda Tsolaki and her team evaluated effects of saffron (125mg/day) on patients with mild cognitive impairment (MCI) in a one-year study17. Saffron intervention resulted in improved cognitive performance and brain activity after 12 months as revealed in neuropsychological assessment, ERP response and EEG measurement, while the control group deteriorated. By volumetric MRI measurement, they observed a small volume increase on the left inferior temporal gyrus, an area close to medial temporal lobe (MTL) and hippocampus where memory is formed. This study highlighted crocin and saffron improving effects on brain activation, specific brain domains (neurogenesis), neuropsychological performance and cognitive processing in MCI patients, whereas control group exhibited worse performance after 12 months.
Additionally, a few more clinical studies have demonstrated saffron significantly improved memory and cognitive impairments in patients with Alzheimer’s disease. These findings point to saffron and more likely crocin as good choice for brain health and management of MCI and Alzheimer’s disease. That said, more clinical evaluation of crocin effects on MCI or AD should be carried out to confirm the efficacy.
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- Ernst A & Frisén J. (2015) Adult Neurogenesis in Humans- Common and Unique Traits in Mammals. PLoS Biol 13(1): e1002045. doi:10.1371/ journal.pbio.1002045.
- Tobin MK, et al. (2019) Human Hippocampal Neurogenesis Persists in Aged Adults and Alzheimer’s Disease Patients. Cell Stem Cell 2019, 24: 974–982.
- Rossi C, et al. (2006) Brain‐derived neurotrophic factor (BDNF) is required for the enhancement of hippocampal neurogenesis following environmental enrichment. EJN, 2006, 24(7): 1850-1856.
- Zhu DY, et al (2004) Activation of cAMP-response-element-binding protein (CREB) after focal cerebral ischemia stimulates neurogenesis in the adult dentate gyrus. PNAS, 2004 101(25): 9453-9457
- Ortega-Martínez S. (2015) A new perspective on the role of the CREB family of transcription factors in memory consolidation via adult hippocampal neurogenesis. Front. Mol. Neurosci. 2015, 8: 46. doi: 10.3389/fnmol.2015.00046
- Tóth B, et al. (2019) The Efficacy of Saffron in the Treatment of Mild to Moderate Depression: A Meta-analysis. Planta Med 2019; 85(01): 24-31.
- Heitmar R, et al (2019). Saffron (Crocus sativus L.) in ocular diseases: a narrative review of the existing evidence from clinical studies. Nutrients, 2019, 11, 649; doi:10.3390/nu11030649
- Sepahi et al. (2018) Effects of Crocin on Diabetic Maculopathy: A Placebo-Controlled Randomized Clinical Trial. Am J Ophthalmol. 2018, 190: 89-98.
- Finley JW & Gao S. (2017) Perspective on Crocus sativus L. (Saffron) Constituent Crocin: A Potent Water-Soluble Antioxidant and Potential Therapy for Alzheimer’s Disease. J. Agric. Food Chem. 2017, 65, 1005−1020.
- Mozaffari S, et al. (2019) Crocin Acting as a Neuroprotective Agent against Methamphetamine induced Neurodegeneration via CREB-BDNF Signaling Pathway. Iranian Journal of Pharmaceutical Research. 2019, 18 (2): 745-758.
- Behravanfar N, et al. (2017) Effects of Crocin on Spatial Memory Impairment Induced by Hyoscine and Its Effects on BDNF, CREB, and p-CREB Protein and mRNA Levels in Rat Hippocampus. Jundishapur J Nat Pharm Prod. 2017 August; 12(3 (Supp)): e64315.
- Rezai M, et al. (2018) Effect of crocin carotenoid on BDNF and CREB gene expression in brain ventral tegmental area of morphine treated rats. Asian Pac J Trop Biomed 2018, 8(8): 387-393.
- Dorri SA, et al. (2018) Involvement of brain‐derived neurotrophic factor (BDNF) on malathion induced depressive‐like behavior in subacute exposure and protective effects of Iran J Basic Med Sci, 2015, 18: 958‐966.
- Sadoughi D. (2019) The effect of crocin on apoptotic, inflammatory, BDNF, Pt, and Aβ40 indicators and neuronal density of CA1, CA2, and CA3 regions of hippocampus in the model of Alzheimer suffering rats induced with trimethyltin chloride. Comp Clin Pathol. 2019, https://doi.org/10.1007/s00580-019-02981-4.
- Asadollahi , et al. (2019) Protective properties of the aqueous extract of saffron (Crocus sativus L.) in ischemic stroke, randomized clinical trial. J Ethnopharmacol. 2019, 238: 111833.
- Tsolaki M, et al. (2016) Efficacy and Safety of Crocus sativus L. in Patients with Mild Cognitive Impairment: One Year Single-Blind Randomized, with Parallel Groups, Clinical Trial. Journal of Alzheimer’s Disease. 2016, 54: 129–133.