Vascular action of polyphenols

Dietary patterns are widely recognised as contributors to cardiovascular and cerebrovascular disease. Endothelial function, the elastic properties of large arteries and the magnitude and timing of wave reflections are important determinants of cardiovascular performance. Several epidemiological studies suggest that the regular consumption of foods and beverages rich in flavonoids is associated with a reduction in the risk of several pathological conditions ranging from hypertension to coronary heart disease, stroke and dementia. The impairment of endothelial function is directly related to ageing and an association between decreased cerebral perfusion and dementia has been shown to exist. Cerebral blood flow (CBF) must be maintained to ensure a constant delivery of oxygen and glucose as well as the removal of waste products. Increasing blood flow is one potential way for improving brain function and the prospect for increasing CBF with dietary polyphenols is extremely promising. The major polyphenols shown to have some of these effects in humans are primarily from cocoa, wine, grape seed, berries, tea, tomatoes (polyphenolics and nonpolyphenolics), soy and pomegranate. There has been a significant paradigm shift in polyphenol research during the last decade. This review summarises our current knowledge in this area and points the way for the development of new types of functional foods targeted to brain health through improving vascular health

The pharmacodynamic profile of “Blackadder” blackcurrant juice effects upon the monoamine axis in humans: A randomised controlled trial

Emerging evidence from human intervention trials indicates health benefits of consuming blackcurrant fruit, including improvements to cognitive performance, modulation of blood flow, regulation of blood glucose and inhibition of enzymes underpinning normal cognitive function. Of particular relevance is our previous demonstration of monoamine oxidase (MAO)-A and B inhibition after the consumption of a New Zealand “Blackadder” blackcurrant juice in humans. The current study uses a double-blind, placebo-controlled, randomised cross- over design to assess the pharmacodynamics of the effects on platelet MAO-B inhibition and associated substrates, plasma prolactin levels and blood glucose levels after consumption of a single serve of “Blackadder” blackcurrant juice standardised to 500 mg polyphenols. Eight healthy male (20-–35 years) participants completed the trial. Measurements were obtained at baseline 15, 30, 45, 60, 100, 120, 150, 180, 240 mins and 24 h post dose. A fast, absolute and reversible inhibition of blood platelet MAO-B (P < 0.001) and a significant but delayed reduction in plasma prolactin (P < 0.001) were observed following the consumption of “Blackadder” blackcurrant juice when compared to a placebo control. No interpretable changes in substrates of MAO or associated metabolites were seen. These data provide a clear time course of the reversible inhibition of MAO-B after the single consumption of a of New Zealand “Blackadder” blackcurrant juice standardised at 500 mg of polyphenols and, therefore, provide a therapeutic window on which to base future nutritional interventions

Acute supplementation with blackcurrant extracts modulates cognitive functioning and inhibits monoamine oxidase-B in healthy young adults

The consumption of berry fruits engenders a number of benefits in animal models, including improvements in cognitive performance, slowing of cognitive decline during natural ageing, and neuroprotection. These findings, along with limited human epidemiological evidence, suggest a potential role for the consumption of berry fruit polyphenols in improving human cognitive performance. The current study assessed the effects of two blackcurrant extracts on cognitive outcomes, mood, autonomic measures, peripheral and central monoamine tone, and anthocyanin bioavailability to plasma. A randomised, double-blind, placebo-controlled, crossover study was conducted using 36 healthy young participants (18–35 years). Findings from the intervention illustrate a cognitive benefit of acute blackcurrant supplementation in healthy young humans and the first description of a clinically significant inhibition of monoamine oxidase-B and monoamine oxidase-A using a commonly consumed fruit. These data also illustrate that compounds other than anthocyanins may be responsible for the observed in vivo MAO inhibition and that the degree of processing and the cultivar of blackcurrant fruit used substantially alter the neuroendocrinological and cognitive benefits conveyed

Inhibition of MMP-9 activity following hypoxic ischemia in the developing brain using a highly specific inhibitor

Perinatal hypoxic ischemic (HI) brain injury is a leading cause of long-term neurological handicap in newborn babies. Recently, excessive activity of matrix metalloproteinases (MMPs), and in particular MMP-9, has been implicated in the aetiology of HI injuries to the immature brain. Our previous study suggested that MMP-9 may be involved in the development of the delayed injury processes following HI injury to the developing brain. Given this, we therefore propose that MMP-9 may be a useful target for rescue therapies in the injured developing brain. To address this, we chose to use SB-3CT, a highly selective inhibitor that is known to target only MMP-2 and MMP-9, to attenuate the elevated MMP-9 activity seen following HI injury to the developing brain. Twenty-one-day-old postnatal Wistar rats were subjected to unilateral carotid artery occlusion followed by exposure to hypoxia (8% oxygen for 1 h). SB-3CT (50 mg/kg body weight in 25% dimethyl sulphoxide/75% polyethylene glycol) or an equal volume of vehicle or saline diluent was then administered intraperitoneally at 2, 5 and 14 h following the insult. Gelatin zymography revealed that pro-MMP-9 levels were significantly reduced at 6 h following hypoxic ischaemia (p ≤ 0.05). However, our results showed that despite significantly inhibiting brain pro-MMP-9 activity after hypoxic ischaemia, SB-3CT failed to confer significant neuroprotection in postnatal day 21 rats 3 days after an HI insult. Further investigations are warranted using a recently reported selective water-soluble version of SB-3CT or another MMP-9 selective inhibitor to resolve the role of MMP-9 in the aetiology of HI injury in the developing brain

A Single Course of Prenatal Betamethasone in the Rat Alters Postnatal Brain Cell Proliferation but not Apoptosis

The aim of this study was to determine the effects of a clinically relevant single course of prenatal betamethasone in the rat on growth parameters with particular reference to brain cell proliferation and apoptosis. We report that administration of 170 μg kg−1 betamethasone twice within 4 h to E20 pregnant rats conveys moderate somatic growth retardation. Further, using a measure of brain cell proliferation independent of blood-brain barrier (BBB) permeability, we demonstrate for the first time that betamethasone is chronically anti-proliferative to brain cells without inducing caspase-3-mediated apoptosis. More importantly we show that there is a significant and sexually divergent rebound of neural proliferation which occurs earlier in males than in females and continues until at least 21 days of postnatal life. BBB permeability to [3H]thymidine was significantly increased by steroid treatment re-iterating the fact that tracer studies not correcting for BBB permeability, such as bromodeoxyuridine (BrdU), may be questionable in this type of study. Further, prenatal steroid treatment did not alter postnatal corticosterone levels. In summary we show that prenatal betamethasone conveys significant and long-lasting side effects and that its human clinical application in preterm labour needs more careful consideration as compared to the relative ease with which it is prescribed today

Selective Losses of Brainstem Catecholamine Neurons After Hypoxia-Ischemia in the Immature Rat Pup.

Hypoxic-ischemic (HI) injury in the preterm neonate incurs numerous functional deficits, however little is known about the neurochemically-defined brain nuclei that may underpin them. Key candidates are the brainstem catecholamine neurons. Using an immature animal model, the postnatal day (P)-3 (P3) rat pup, we investigated the effects of HI on brainstem catecholamine neurons in the locus coeruleus, nucleus tractus solitarius (NTS), and ventrolateral medulla (VLM). On P21, we found that prior P3 HI significantly reduced numbers of catecholaminergic neurons in the locus coeruleus, NTS, and VLM. Only locus coeruleus A6, NTS A2, and VLM A1 noradrenergic neurons, but not NTS C2 and VLM C1 adrenergic neurons, were lost. There was also an associated reduction in dopamine-beta-hydroxylase-positive immunolabeling in the forebrain. These findings suggest neonatal HI can affect specific neurochemically-defined neuronal populations in the brainstem and that noradrenergic neurons are particularly vulnerable to HI injury

Improving the oral bioavailability of beneficial polyphenols through designed synergies

A substantial and growing consumer demand exists for plant-based functional foods that improve general health and wellbeing. Amongst consumed phytochemicals, the polyphenolic compounds tend to be the most bioactive. Many commonly consumed polyphenols have been shown to have specific and potent health-promoting activities when assessed by high-throughput in vitro assays and when administered to experimental animals by injection. However, very few have been shown to have any beneficial effects in animals or man when orally consumed, because of the poor bioavailability exhibited by most polyphenols following the ingestion. Consumed polyphenols, like most pharmaceuticals, are regarded as xenobiotics by the body and must overcome many barriers, including extensive enzymatic and chemical modification during digestion and absorption, to reach their site(s) of action. This is especially true for polyphenols targeting the brain, which is protected by the tightly regulated blood–brain barrier. Interestingly, many polyphenols are also known to specifically modify some of the metabolic and transport processes that govern bioavailability. Therefore, the opportunity exists to increase the bioactivity of beneficial polyphenols by designing specific synergistic interactions with polyphenols that improve their oral bioavailability. This hypothesis and review paper will discuss some of the endogenous systems that limit the bioavailability of ingested polyphenols to the body and the brain, and the means by which bioavailability may be improved by specifically designing synergies between orally consumed polyphenols