A cura di Daniele Benatti
Cocoa products and chocolate have recently been recognized as a rich source of flavonoids, mainly flavanols, potent antioxidant and anti-inflammatory agents with established benefits for cardiovascular health but largely unproven effects on neurocognition and behavior. In this article we focus on neuromodulatory and neuroprotective actions of cocoa flavanols in humans. The absorbed flavonoids penetrate and accumulate in the brain regions involved in learning and memory, especially the hippocampus.
Cocoa flavanols in the brain signaling cascades
The flavanol monoisomers epicatechin and catechin are the predominant flavonoid compounds in cocoa, with the 2-phenyl-3,4-dihydro-2H-chromen-3-ol as underlying skeleton. These monomers represent the base molecules for concatenated oligomers, the proanthocyanidins. Antioxidant properties of flavanols are chemically mediated through oxidation of two aromatic hydroxyl groups to a quinone
Animal studies show that flavanols and their metabolites can cross the blood–brain barrier, inducing beneficial effects on the brain tissue and function (angio- and neurogenesis, changes in neuron morphology) and stimulating widespread blood circulation in the brain . The most common flavanol found in cocoa, epicatechin, is rapidly absorbed in humans and is detectable in blood plasma already 30 min after intake. The epicatechin levels peak 2–3 h after intake, exhibiting a strong positive correlation with the dose of ingested chocolate , and return to baseline by 6–8 h after consumption.
Neurobiological impact of flavanols on the brain, learning, memory, and cognition are believed to occur in two major ways. First, flavonoids can specifically interact within a number of cellular signaling pathways, primarily with mitogen-activated protein (MAPK), extracellular-signal-regulated (ERK) and phosphoinositide 3-kinase (PI3-kinase/Akt) signaling cascades. These cascades trigger gene expression and protein synthesis for maintaining long-term potentiation (LTP) and establishing long-term memories. Flavonoids modulate the transcription factors engaged in signal transduction through protein-kinase inhibition, and promote the expression of brain derived neurotrophic factor (BDNF) that is critical for neurogenesis, also in adult animals, synaptic growth and neuron survival, especially in the learning- and memory-related brain regions such as the hippocampus and subventricular zone. Second, flavonoids facilitate production of the signaling molecule nitric oxide, which inhibits the incidence of atheromatous plaque adhesion molecules causing inflammation , and importantly, improves vascular endothelial function by relaxing the smooth muscle tissue of blood vessels. In this way, flavanol-rich cocoa can impose vasodilation in a nitric oxide dependent way both at the cardiovascular and peripheral levels. This in turn results in enhanced cerebral blood flow and blood perfusion throughout the central and peripheral nervous system, affording better supply of oxygen and glucose to the neurons and removal of waste metabolites in the brain and sensory systems. In addition, animal models indicate that cocoa flavonoid administration stimulates angiogenesis in the hippocampus.
Acting of cocoa flavonols in neurological disease
Observational human population studies on neuroprotective and neuromodulatory action of flavonoids, including high-flavanol cocoa, have often been poorly controlled, whereas prospective longitudinal studies remain laborious and costly.
Potent antioxidative and anti-inflammatory properties of flavonoids have been proposed to play a role in preventing mild cognitive impairment, a precursor of dementia, and Alzheimer's disease . In Alzheimer's disease, an increased production and accretion of Aβ-peptides activates microglia, resulting in release of inflammatory mediators that further enhance Aβ production, giving rise to neuronal dysfunction and cellular death. While β- and γ-secretase facilitate Aβ production, α-secretase inhibits it. Recent work in cultured human neuroblastoma cells shows that low concentrations of nitric oxide up-regulate the expression of α-secretase and down-regulate that of β-secretase. This suggests the cerebrovascular nitric oxide might inhibit Aβ production. Cocoa flavanols, especially epicatechin, act directly on the endothelium of brain vessels, stimulating activity of the endothelial nitric oxide synthase that in turn induces vasodilation and improves cerebrovascular perfusion.
So far, there does not seem to be any proven association between intake of antioxidants and vitamins and Alzheimer's disease , however, several studies did report a diminished cerebral blood flow in dementia patients.
Neuromodulation of cognition and memory
In humans, several studies have aimed to identify immediate and short-term action of cocoa flavanols on mood and cognitive performance with as yet inconclusive outcome.
In healthy young adults (n = 30, eight males; age range, 18–25 years) who consumed in a crossover, order counterbalanced design, either 35 g dark chocolate (with 720 mg of high-flavanol cocoa) or a matched quantity of white chocolate, high-flavanol cocoa improved visual contrast sensitivity (assessed by reading numbers varying in their luminance relative to background), working memory for location, choice reaction time, and the time required to detect direction of coherent motion. This outcome extends the range of cognitive functions affected by high-flavanol cocoa consumption and provides the first evidence on the immediate effects of high-flavanol cocoa on visual functions.
It was used a paired letter-digit task in healthy young female participants (n = 16; age range, 18–30 years) while recording the blood oxygenation level-dependent (BOLD) responses in an fMRI protocol following 5-day ingestion of 150 mg of cocoa flavanols. Participants had to press a key, making either one judgment in the “no switch” condition (“is the letter a vowel or consonant”, “is the digit even or odd”) or two judgments in the “switch” condition (responding both to the letter and digit). Although an overall BOLD signal increased during the cognitive task, no effects were found in response time, switch cost (the difference in response time between “switch” and “no-switch” conditions), and heart rate after consumption of this moderate dose of cocoa flavanols. Ingestion of a single acute dose (450 mg of cocoa flavanols) yielded an increased cerebral blood flow, confirming a potential of cocoa flavanols for treatment of vascular impairment such as dementia and stroke
Over a 30-day period, in an another test was administered a daily chocolate drink (250 mg or 500 mg cocoa flavanols versus low-flavanol cocoa as placebo) to 63 volunteers (aged 40–65 years). Neurocognitive changes associated with flavanol supplementation during performance of a spatial working memory task at baseline and at the end of the treatment were assessed using EEG (steady state visually evoked potentials, SSVP). Behavioral measures of accuracy and response time did not differ in a dose-dependent manner, whereas average amplitude and phase of the evoked potentials at a number of posterior parietal and centro-frontal sites significantly differed between the groups during memory encoding, the memory hold period, and retrieval. The authors assume the differences in brain activation, even in the absence of behavioral effects, point to an increased neural efficiency in spatial working memory associated with chronic cocoa flavanol consumption.
Flavonoids, potent antioxidant and anti-inflammatory agents, represent up to 20% of compounds found in cocoa beans. Flavanols, and especially epicatechin, are the most common cocoa flavonoids. The flavanol contents in cocoa products and chocolate vary greatly depending on the bean variety and origin, agricultural and processing practices. In part, the variability of flavanol contents in cocoa and chocolate may be responsible for the mixed outcomes presently observed in research on the effects of cocoa flavanols on neurocognitive and affective function, executive control, and behavior.
In future research has to combine functional neuroimaging techniques such as fMRI, EEG and MEG with neurocognitive and behavioral correlates to uncover long lasting and immediate effects of chocolate consumption on human cognition, mood, and behavior.