Iso-α-acids, Hop-Derived Bitter Components of Beer, Attenuate Age-Related Inflammation and Cognitive Decline

With the aging population rapidly increasing worldwide, preventive measures and treatments for age-related cognitive decline and dementia are of utmost importance. We have previously demonstrated that the consumption of iso-α-acids (IAA), which are hop-derived bitter compounds in beer, prevents the formation of disease pathology in a transgenic mouse model of Alzheimer’s disease (AD). However, the effect of IAA consumption on age-related cognitive decline is unknown. In the present study, we examined the effect of long-term and short-term dietary consumption of IAA, on age-related memory impairments and inflammation in the hippocampus of aged mice. When compared with young mice, aged mice showed impairment in spatial working memory during the Y-maze spontaneous alternation test, impairment in object recognition memory during the novel object recognition test (NORT), a pro-inflammatory hippocampal microglial phenotype with increased CD86 expression and inflammatory cytokine production, increased levels of glutamate and amyloid β1–42, and decreased levels of dopamine (DA). In aged mice fed IAA for 3 months, the age-related alterations in memory, microglial inflammation, and glutamate, amyloid β1–42, and DA levels were all significantly attenuated. Additionally, the oral administration of IAA for 7 days in aged mice with memory impairment, also improved spatial and object recognition memory. These results suggest that IAA consumption prevents inflammation in the hippocampus and ameliorates age-related cognitive decline

Hop-Derived Iso-α-Acids in Beer Improve Visual Discrimination and Reversal Learning in Mice as Assessed by a Touch Panel Operant System

Dementia and cognitive decline have become worldwide health problems due to rapid growth of the aged population in many countries. We previously demonstrated that single or short-term administration of iso-α-acids, hop-derived bitter acids in beer, improves the spatial memory of scopolamine-induced amnesia model mice in the Y-maze and enhances novel object recognition in normal mice via activation of the vagus nerve and hippocampal dopaminergic system. However, these behavioral tests do not replicate the stimulus conditions or response requirements of human memory tests, and so may have poor translational validity. In this report, we investigated the effects of iso-α-acids on visual discrimination (VD) and reversal discrimination (RD) using a touch panel-based operant system similar to that used for human working memory tests. In the VD task, scopolamine treatment reduced correct response rate and prolonged response latency in mice, deficits reversed by prior oral administration of iso-α-acids. In the RD task, administration of iso-α-acids significantly increased correct response rate compared to vehicle administration. Previous studies have reported that dopamine signaling is involved in both VD and RD learning, suggesting that enhancement of dopamine release contributes to improved memory performance in mice treated with iso-α-acids. Taken together, iso-α-acids improve VD and RD learning, which are considered high-order cognitive functions. Given the translational advantages of the touch panel-based operant system, the present study suggests that iso-α-acids could be effective for improvement of working memory in human dementia patients

Matured Hop Bitter Acids in Beer Improve Lipopolysaccharide-Induced Depression-Like Behavior

Recent studies have demonstrated a close association between neural inflammation and development of mental illnesses, such as depression. Clinical trials have reported that treatment with non-steroidal anti-inflammatory drugs is associated with reduced risk of depression. Moreover, nutritional approaches for the prevention and management of depression have garnered significant attention in recent years. We have previously demonstrated that iso-α-acids (IAAs)—the bitter components in beer—suppress hippocampal microglial inflammation, thereby improving cognitive decline. However, effects of hop-derived components other than IAAs on inflammation have not been elucidated. In the present study, we demonstrated that consumption of matured hop bitter acids (MHBAs) generated from α- and β-acids, which show a high similarity with the chemical structure of IAAs, suppress lipopolysaccharide (LPS)-induced cytokine productions in the brain. MHBAs administration increased norepinephrine (NE) secretion and reduced immobility time which represents depression-like behavior in the tail suspension test. Moreover, MHBAs components, including hydroxyallohumulinones and hydroxyalloisohumulones, reduced LPS-induced immobility time. Although further researches are needed to clarify the underlying mechanisms, these findings suggest that MHBAs reduce inflammatory cytokine productions and increase NE secretion, thereby improving depression-like behavior. Similarly, inoculation with LPS induced loss of dendritic spines, which was improved upon MHBAs administration. Additionally, vagotomized mice showed attenuated improvement of immobility time, increase in NE level, and improvement of dendrite spine density following MHBAs administration. Therefore, MHBAs activate the vagus nerve and suppress neuronal damage and depression-like behavior induced by inflammation

β-lactolin, a Monoamine Oxidase B Inhibitory Lactopeptide, Suppresses Reactive Oxygen Species Production in Lipopolysaccharide-Stimulated Astrocytes

Astrocytes are known to regulate normal brain function. Monoamine oxidase B (MAO-B), an enzyme highly expressed in astrocytes, metabolizes dopamine (DA) and induces reactive oxygen species (ROS) production. We have previously reported that β-lactolin, a whey-derived glycine–threonine–tryptophan–tyrosine tetrapeptide, improves memory impairment in mice by regulating the dopaminergic system; however, the effects of β-lactolin on astrocytes remain unclear. Herein, we investigated the effects of β-lactolin on cultured murine astrocytes. First, we measured intracellular ROS production in lipopolysaccharide-stimulated reactive astrocytes treated with or without β-lactolin, and then determined the role of β-lactolin in DA metabolism in astrocytes by measuring MAO-B enzyme activity and the levels of DA, and its metabolites, in DA-pretreated astrocytes. We found that β-lactolin significantly suppressed ROS production in lipopolysaccharide-stimulated reactive astrocytes (p = 2.76 × 10−6), inhibited MAO-B activity (p = 2.65 × 10−2) and increased intracellular DA levels (p = 1.08 × 10−3), suggesting that β-lactolin could inhibit DA metabolism in astrocytes. These results illustrate the novel protective effects of β-lactolin on reactive astrocytes and suggest their involvement in the memory-improving effects of β-lactolin via the dopaminergic system

Theaflavins Improve Memory Impairment and Depression-Like Behavior by Regulating Microglial Activation

Inflammation in the brain is associated with various disorders including Alzheimer’s disease and depression. Thus, inflammation has received increasing attention regarding preventive approaches to such disorders. Epidemiological investigations have reported that drinking tea reduces the risk of dementia and depression. Theaflavins, a polyphenol found in black tea, are known to have anti-oxidative and anti-inflammation effects, but the effects of theaflavins on cognitive decline and depression induced by inflammation have not been investigated. To address this research gap, the present study assessed whether theaflavins could protect synapses and dendrites damaged by inflammation and prevent concomitant memory impairment and depression-like behavior in mice. Intracerebroventricular injection with lipopolysaccharide (LPS) induces neural inflammation associated with reduced spontaneous alternations in the Y-maze test and increased immobility in the tail suspension test, indicating impaired spatial memory and depression-like behavior, respectively. Oral administration with theaflavins prevented these behavioral changes induced by LPS. Theaflavins also suppressed productions of inflammatory cytokines and prevented dendritic atrophy and spine loss in the brain. Notably, theaflavins have a stronger anti-inflammatory effect than other polyphenols such as catechin, chlorogenic acid, and caffeic acid. These results suggest that theaflavins can suppress neural inflammation and prevent the symptoms of inflammation-related brain disorders

Tryptophan-Tyrosine Dipeptide, the Core Sequence of β-Lactolin, Improves Memory by Modulating the Dopamine System

Tryptophan-tyrosine (WY)-related peptides including the β-lactopeptide of the glycine-threonine-tryptophan-tyrosine peptide, β-lactolin, improve spatial memory. However, whether and how the WY dipeptide as the core sequence in WY-related peptides improves memory functions has not been investigated. This study assessed the pharmacological effects of the WY dipeptide on memory impairment to elucidate the mechanisms. Here, we showed that oral administration of dipeptides of WY, tryptophan-methionine (WM), tryptophan-valine, tryptophan-leucine, and tryptophan-phenylalanine improved spontaneous alternation of the Y-maze test in scopolamine-induced amnesic mice. In contrast, tyrosine-tryptophan, methionine-tryptophan, tryptophan, tyrosine, and methionine had no effect. These results indicated that the conformation of dipeptides with N-terminal tryptophan is required for their memory improving effects. WY dipeptide inhibited the monoamine oxidase B activity in vitro and increased dopamine levels in the hippocampus and frontal cortex, whereas tryptophan did not cause these effects. In addition, the treatment with SCH-23390, a dopamine D1-like receptor antagonist, and the knockdown of the hippocampal dopamine D1 receptor partially attenuated the memory improvement induced by the WY dipeptide. Importantly, WY dipeptide improved the spontaneous alternations of the Y-maze test in aged mice. These results suggest that the WY dipeptide restores memory impairments by augmenting dopaminergic activity. The development of supplements rich in these peptides might help to prevent age-related cognitive decline