Theobromine improves hyperactivity, inattention, and working memory via modulation of dopaminergic neural function in the frontal cortex of spontaneously hypertensive rats.

Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder and dopaminergic dysfunction in the prefrontal cortex (PFC) may play a role. Our previous research indicated that theobromine (TB), a methylxanthine, enhances cognitive function in rodents via the PFC. This study investigates TB's effects on hyperactivity and cognitive function in stroke-prone spontaneously hypertensive rats (SHR), an ADHD animal model. Male SHRs (6-week old) received a diet containing 0.05% TB for 40 days, while control rats received normal diets. Age-matched male Wistar-Kyoto rats (WKY) served as genetic controls. During the TB administration period, we conducted open-field tests and Y-maze tasks to evaluate hyperactivity and cognitive function, then assessed dopamine concentrations and tyrosine hydroxylase (TH), dopamine receptor D1-5 (DRD1-5), dopamine transporter (DAT), vesicular monoamine transporter-2 (VMAT-2), synaptosome-associated protein-25 (SNAP-25), and brain-derived neurotrophic factor (BDNF) expressions in the PFC. Additionally, the binding affinity of TB for the adenosine receptors (ARs) was evaluated. Compared to WKY, SHR exhibited hyperactivity, inattention and working memory deficits. However, chronic TB administration significantly improved these ADHD-like behaviors in SHR. TB administration also normalized dopamine concentrations and expression levels of TH, DRD2, DRD4, SNAP-25, and BDNF in the PFC of SHR. No changes were observed in DRD1, DRD3, DRD5, DAT, and VMAT-2 expression between SHR and WKY rats, and TB intake had minimal effects. TB was found to have affinity binding to ARs. These results indicate that long-term TB supplementation mitigates hyperactivity, inattention and cognitive deficits in SHR by modulating dopaminergic nervous function and BDNF levels in the PFC, representing a potential adjunctive treatment for ADHD.

Perilla seed oil improves bone health by inhibiting bone resorption in healthy Japanese adults: A 12-month, randomized, double-blind, placebo-controlled trial.

Accumulating evidence suggests the beneficial effect of omega-3 polyunsaturated fatty acids (PUFAs) on bone mineral density (BMD). However, the effects of perilla (Perilla frutescens) seed oil (PO), a rich source of α-linoleic acid (LNA), on human bone have not yet been elucidated. This randomized, double-blind, placebo-controlled trial investigated the effects of long-term PO intake on bone health in Japanese adults. After screening for eligibility, 52 participants (mean age 54.2 ± 6.4 years) were randomly assigned to placebo (n = 25) and PO (n = 27) groups, which received 7.0 ml of olive oil and PO daily, respectively. At baseline and 12-month, quantitative ultrasound of the right calcaneus was measured with an ultrasound bone densitometer and percentage of the Young Adult Mean (%YAM) was calculated. Serum levels of tartrate-resistant acid phosphatase 5b (TRACP-5b), and bone alkaline phosphatase (BALP) were evaluated. In addition, PUFA levels in the erythrocyte plasma membrane (RBC-PM), serum biological antioxidant potential (BAP), and diacron reactive oxygen metabolites (d-ROM) were evaluated. Compared with the placebo group, %YAM levels increased and serum TRACP-5b levels decreased significantly in the PO group at 12-month, while serum BALP levels remained unchanged. Moreover, RBC-PM LNA levels and BAP/d-ROM ratios increased significantly in the PO compared with the placebo group. These results suggest that long-term PO intake may improve age-related BMD decline by suppressing bone resorption and increasing LNA levels.

Perilla frutescens seed oil combined with Anredera cordifolia leaf powder attenuates age-related cognitive decline by reducing serum triglyceride and glucose levels in healthy elderly Japanese individuals: a possible supplement for brain health.

We have shown that Anredera cordifolia extract improves learning and memory in a senescence-accelerated mouse model, and that α-linolenic acid (ALA)-rich Perilla frutescens seed oil (PO) improves brain function in healthy Japanese adults and elderly individuals. Herein, we present a 12-month, randomised, double-blind, parallel-armed intervention trial examining the effects of PO supplementation alone or in combination with A. cordifolia leaf powder on brain function in healthy elderly Japanese individuals. Participants were randomly divided into two groups: the PO group received 1.47 mL PO (0.88 g ALA) daily via soft gelatine capsules, and the POAC group received 1.47 mL PO and 1.12 g A. cordifolia leaf powder (1.46 mg vitexin and 1.12 mg adenosine) daily. After 12 months of intervention, the POAC group showed generally higher cognitive index scores than the PO group. The beneficial effects of combined supplementation on cognitive function were associated with increased ALA and eicosapentaenoic acid levels in red blood cell plasma membranes, increased serum biological antioxidant potential, and decreased serum triglyceride, glucose, and N-(epsilon)-carboxymethyl-lysine (CML), an advanced glycation end-product and biochemical marker of oxidative stress levels. The effects of combined supplementation on cognitive function also showed a significant negative correlation with serum CML levels after 12 months of intervention. Our findings suggest that combined long-term supplementation with PO and A. cordifolia more effectively ameliorates age-related cognitive decline than PO alone. These findings may serve as a basis for the development of new supplements for brain health. Clinical Trial Registry, UMIN000040863.

Perilla seed oil in combination with nobiletin-rich ponkan powder enhances cognitive function in healthy elderly Japanese individuals: a possible supplement for brain health in the elderly.

Perilla (Perilla frutescens) seed oil (PO), rich in α-linolenic acid (ALA), can improve cognitive function in healthy elderly Japanese people. Here, supplements containing either PO alone or PO with nobiletin-rich air-dried immature ponkan powder were examined for their effects on cognitive function in 49 healthy elderly Japanese individuals. Patients were enrolled in a 12-month randomized, double-blind, parallel-armed study. Randomized participants in the PO group received soft gelatin capsules containing 1.47 mL (0.88 g of ALA) of PO daily, and those in the PO + ponkan powder (POPP) group received soft gelatin capsules containing both 1.47 mL of PO and 1.12 g ponkan powder (2.91 mg of nobiletin) daily. At the end of intervention, the POPP group showed significantly higher cognitive index scores than the PO group. The pro-cognitive effects of POPP treatment were accompanied by increases in ALA and docosahexaenoic acid levels in red blood cell plasma membranes, serum brain-derived neurotropic factor (BDNF) levels, and biological antioxidant potential. We demonstrate that 12-month intervention with POPP enhances serum BDNF and antioxidant potential, and may improve age-related cognitive impairment in healthy elderly people by increasing red blood cell ω-3 fatty acid levels. Clinical Trial Registry, UMIN000040863.

The journey from white rice to ultra-high hydrostatic pressurized brown rice: an excellent endeavor for ideal nutrition from staple food.

Although brown rice (BR) contains significantly higher levels of nutrients than the traditionally used polished white rice (WR), its consumption among the population is still not noteworthy. WR and BR are essentially same grain. The only difference between the two is the application of an exhaustive milling procedure during the processing of WR that removes all other layers of the grain except the portion of its white endosperm. BR, on the other hand, is prepared by removing only the outer hull of the rice seed. Thus, in addition to its inner endosperm, the bran and germ are also left on the BR. Hence, BR retains all its nutrients, including proteins, lipids, carbohydrates, fibers, vitamins, minerals, tocopherols, tocotrienols, γ-oryzanol, and γ-aminobutyric acid (GABA) packed into the bran and germ of the seed. Since BR tastes nutty and takes longer to cook than WR, it is not appreciated by the consumers. However, these problems have been circumvented using non-thermal ultra-high hydrostatic pressure (UHHP)-processing for the treatment of BR. A superior modification in the physicochemical and functional qualities of UHHPBR, along with its ability to curb human diseases may make it a more palatable and nutritious choice of rice over WR or the untreated-BR. Here, we have reviewed the mechanism by which UHHP treatment leads to the modification of nutrients such as proteins, lipids, carbohydrates, and fibers. We have focused on the effects of rice on cell and animal models of different conditions such as hyperlipidemia, diabetes, and hypertension and the possible mechanisms. Finally, we have emphasized the effects of UHHPBR in human cases with rare conditions such as osteoporosis and brain cognition - two age-related degenerative diseases of the elderly population.

Chronic Administration of Thymoquinone Enhances Adult Hippocampal Neurogenesis and Improves Memory in Rats Via Regulating the BDNF Signaling Pathway.

Thymoquinone is a pharmacologically active component of Nigella sativa Linn. seeds. Despite the diverse neuropharmacological attributes of TQ, limited reports related to adult neurogenesis and memory research are available. In this study, we investigated the effects of TQ on the proliferation and neural differentiation of cultured neural stem/progenitor cells (NSCs/NPCs). We also investigated the effect of TQ chronic administration on neurogenesis and memory in adult rats. Under proliferation conditions, TQ (0.05-0.3 µM) significantly increased NSCs/NPCs viability, neurosphere diameter, and cell count. TQ treatment under differentiation conditions increased the proportion of cells positive for Tuj1 (a neuronal marker). Furthermore, chronic oral administration of TQ (25 mg/kg/day for 12 weeks) to adult rats increased the number of bromodeoxyuridine (BrdU)-immunopositive cells double-stained with a mature neuronal marker, neuronal nuclei (NeuN), and a proliferation marker, doublecortin (Dcx), in the dentate gyrus of the hippocampus. TQ-administered rats showed a profound beneficial effect on avoidance-related learning ability, associated with an increase in the hippocampal mRNA and protein levels of brain-derived neurotrophic factor (BDNF), as measured by both real-time PCR and ELISA. Western blot analysis revealed that TQ stimulates the phosphorylation of cAMP-response element-binding protein (CREB), the upstream signaling molecule in the BDNF pathway. Furthermore, chronic administration of TQ decreased lipid peroxide and reactive oxygen species levels in the hippocampus. Taken together, our results suggest that TQ plays a role in memory improvement in adult rats and that the CREB/BDNF signaling pathways are involved in mediating the actions of TQ in hippocampal neurogenesis.

Intake of Docosahexaenoic Acid-Enriched Milk Beverage Prevents Age-Related Cognitive Decline and Decreases Serum Bone Resorption Marker Levels.

The pathogenic mechanism of dementia is still unknown, and the fundamental treatment remains to be established. Thus, there is growing interest in preventing dementia through diet. One of the functional ingredients attracting attention is docosahexaenoic acid. We conducted a 12-month, randomized, double-blind, placebo-controlled clinical trial in healthy elderly Japanese individuals with a Mini-Mental State Examination score of 28 or higher at baseline using a docosahexaenoic acid-enriched milk beverage containing 297 mg docosahexaenoic acid and 137 mg eicosapentaenoic acid. Consumption of a docosahexaenoic acid-enriched milk beverage increased the fatty acid levels of docosahexaenoic acid and eicosapentaenoic acid in erythrocyte membranes, which was the primary outcome of this study. Moreover, intake of this beverage prevented age-related cognitive decline and decreased serum bone resorption marker levels. Our data demonstrate that, even at a low dose, long-term daily intake of docosahexaenoic acid prevents dementia and may show beneficial effect on bone health.

Perilla Seed Oil Enhances Cognitive Function and Mental Health in Healthy Elderly Japanese Individuals by Enhancing the Biological Antioxidant Potential.

Oxidative stress plays an important role in age-associated cognitive decline. We recently reported that dietary intake of perilla seed oil (PO), a rich source of α-linolenic acid (LNA, C18:3, ω-3), helps in maintaining good mental health in adults. This study aimed to investigate the impacts of dietary PO intake on cognitive functions and mental health in healthy, elderly Japanese individuals. Seventy-five healthy volunteers aged 64-84 years were randomly divided into two groups: a control group and a PO-administered group. At baseline and at 12 months of intervention, cognitive function, mental health condition, fatty acid profile of the red blood cell plasma membranes (RBC-PM), and serum biochemical parameters were evaluated. Results showed that serum biological antioxidant potential and LNA levels in the RBC-PM at 12 months after the trial were significantly higher in the PO group compared to the control group. Further, both the cognitive function measures, as evaluated by the Frontal Assessment Battery test and the apathy scores, tended to be improved after 12 months in the PO group. Our results demonstrate that dietary PO intake enhances the antioxidant potential and prevents the age-related cognitive and mental decline in healthy elderly individuals by enhancing the blood LNA levels.

Anredera cordifolia extract enhances learning and memory in senescence-accelerated mouse-prone 8 (SAMP8) mice.

Learning and memory impairment may result from age-related decline in synaptic plasticity-related proteins in the hippocampus. Therefore, exploration of functional foods capable of ameliorating memory and cognition decline is an interesting endeavor in neuroscience research. We report the effects of Anredera cordifolia (AC) extract on learning and memory deficits in a senescence-accelerated mouse-prone 8 (SAMP8) mouse model, which demonstrate age-related memory deficits and related pathological changes in the brain. After 8 weeks of oral administration of AC extract, the mice were trained in the Novel Object Recognition (NOR) task, and after 7 more weeks, in the Morris Water Maze (MWM) task. Following the completion of behavioral testing, the blood biochemistry parameters, the hippocampal levels of brain-derived neurotropic factor (BDNF), PSD95, and NR2A, and the p-cAMP-response element binding (p-CREB)/CREB ratio were measured. The AC-treated group spent more time exploring the novel objects in the NOR task, and showed faster acquisition and better retention in the MWM task than the negative control (CN) group. In addition, AC enhanced the levels of the aforementioned neuronal plasticity-related proteins, and did not affect the blood biochemistry parameters. Therefore, our data suggest that the AC extract may improve learning and memory without causing any noticeable side effects in the body.

Ginger facilitates cell migration and heat tolerance in mouse fibroblast cells.

The components of ginger root (Zingiber officinale Roscoe) are widely used for various medicinal purposes. Several bioactive compounds have been identified in ginger, including 6­, 8­ and 10­gingerols, and 6­shogaol, which are agonists of the thermo­sensors transient receptor potential (TRP) cation channel subfamily V member 1 and TRP ankyrin 1. Our previous study demonstrated that ginger powder may affect human metabolism in vivo. However, the effects of the bioactive compounds of ginger on cells have not been completely elucidated. The present study investigated whether ginger powder extracts could modify cell functions in mouse fibroblast cells. The active components of ginger powder extracts were characterized using high­performance liquid chromatography. The activation of protein kinases, actin assembly, cell migration, expression levels of heat shock proteins (HSPs) and cell viability after heat shock were analyzed in NIH3T3 mouse fibroblast cells. Subsequently, 6­, 8­, 10­ and 12­gingerols, as well as 6­, 8­ and 10­shogaols, were detected in ginger powder extracts. The levels of phosphorylated Akt, mTOR, ERK and p38 MAPK increased after a 10­min stimulation with ginger powder extracts. In addition, HSP expression levels, lamellipodia formation occurring at cell edges, cell migration and tolerance against heat shock were facilitated following ginger powder extract stimulation. These results suggest that ginger modified cell functions, including actin assembly and heat tolerance, in vitro.

Omega-3 fatty acid prevents the development of heart failure by changing fatty acid composition in the heart.

Some clinical trials showed that omega-3 fatty acid (FA) reduced cardiovascular events, but it remains unknown whether omega-3 FA supplementation changes the composition of FAs and their metabolites in the heart and how the changes, if any, exert beneficial effects on cardiac structure and function. To clarify these issues, we supplied omega-3 FA to mice exposed to pressure overload, and examined cardiac structure and function by echocardiography and a proportion of FAs and their metabolites by gas chromatography and liquid chromatography-tandem mass spectrometry, respectively. Pressure overload induced cardiac hypertrophy and dysfunction, and reduced concentration of all FAs' components and increased free form arachidonic acid and its metabolites, precursors of pro-inflammatory mediators in the heart. Omega-3 FA supplementation increased both total and free form of eicosapentaenoic acid, a precursor of pro-resolution mediators and reduced free form arachidonic acid in the heart. Omega-3 FA supplementation suppressed expressions of pro-inflammatory cytokines and the infiltration of inflammatory cells into the heart and ameliorated cardiac dysfunction and fibrosis. These results suggest that omega-3 FA-induced changes of FAs composition in the heart have beneficial effects on cardiac function via regulating inflammation.

Intake of Alpha-Linolenic Acid-Rich Perilla frutescens Leaf Powder Decreases Home Blood Pressure and Serum Oxidized Low-Density Lipoprotein in Japanese Adults.

Oxidized low-density lipoprotein (Ox-LDL) is known to be highly atherogenic. Thus, decreasing the blood levels of Ox-LDL through dietary means is an important approach to reduce cardiovascular events in high-risk individuals. In this randomized placebo-controlled human interventional trial, we aimed to evaluate whether Perilla frutescens leaf powder (PLP) ameliorates Ox-LDL and home blood pressure, along with its biological antioxidant potential. Healthy Japanese volunteers aged 30-60 years (n = 60) were randomized to PLP and placebo groups. The PLP group consumed PLP dried using a microwave under reduced pressure, and the placebo group consumed pectin fiber daily for 6 months. Home blood pressure, serum biochemical parameters, and fatty acid profiles of erythrocyte plasma membranes were analyzed. Plasma Ox-LDL levels significantly decreased in the PLP group but not in the placebo group. Mean changes in the biological antioxidant potential and alpha-linolenic acid levels in the erythrocyte plasma membrane were significantly increased in the PLP group than in the placebo group. In subjects with prehypertension (systolic blood pressure [SBP] ³ 120 mmHg), the mean reduction in morning or nocturnal SBP was significantly greater in the PLP group than in the placebo group. Thus, PLP intake may be an effective intervention to prevent cardiovascular diseases.

Twelve-month Studies on Perilla Oil Intake in Japanese Adults-Possible Supplement for Mental Health.

Perilla oil (PO), rich in α-linolenic acid (LNA, C18:3, ω-3), is increasingly alleged to have numerous health benefits in humans. However, the current reports detailing the effects of PO on human mental health are not adequate. Therefore, in the current investigation we compared the effects of PO or placebo treatment on the mental condition of healthy adult Japanese volunteers. At baseline and after 12 months of treatment, mental health condition was assessed using the Zung Self-Rating Depression Scale (SDS) and Apathy Scale, and serum biochemical parameters were determined. From baseline to 12 months of intervention, both SDS depression and apathy scores improved significantly in the PO-administered group. Compared to those of control group, serum norepinephrine and serotonin levels after 12 months decreased in the PO-administered group. The enhanced mental state observed in PO-subjects was accompanied by LNA level increases in erythrocyte plasma membranes. Our data demonstrate that PO intake enhances blood LNA levels and may maintain healthy mental conditions in adult subjects.

Salivary Immunoglobulin A Secretion and Polymeric Ig Receptor Expression in the Submandibular Glands Are Enhanced in Heat-Acclimated Rats.

Salivary immunoglobulin A (IgA) plays a critical role in mucosal immunity. Chronic exposure to moderate heat induces heat acclimation, which modifies salivary functions. However, the changes in salivary IgA secretion in heat-acclimated rats are unclear. In this study, we investigated salivary IgA secretion and the expression of polymeric Ig receptor (pIgR), a key mediator of mucosal IgA secretion, in the submandibular glands (SMGs) of heat-acclimated rats. Following maintenance at an ambient temperature (Ta) of 24 ± 0.1 °C for 10 days, male Wistar rats were subjected to Ta of 32 ± 0.2 °C for 5 days (HE group) for heat acclimation or maintained at Ta of 24 ± 0.1°C (CN group). The rats were then anesthetized, pilocarpine (0.5 mg/kg) was intraperitoneally injected, and saliva was collected. Afterward, the SMGs and plasma were sampled. The salivary IgA concentration and IgA flow rate were significantly higher in the HE group than in the CN group. Similarly, SMG pIgR expression was significantly higher in HE rats. The levels of plasma cytokines, including interleukin (IL)-5, IL-6, and interferon-γ, were significantly greater in HE rats than in CN rats. Heat acclimation may enhance oral immunity through salivary IgA secretion and pIgR upregulation in the SMGs.

Docosahexaenoic Acid (DHA, C22:6, ω-3) Composition of Milk and Mammary Gland Tissues of Lactating Mother Rats Is Severely Affected by Lead (Pb) Exposure.

Docosahexaenoic acid (DHA, C22:6, ω-3), an ω-3 polyunsaturated fatty acid (PUFA), is critical for brain growth, development, and cognitive ability. It is consumed by offspring via milk during lactation. However, the toxic heavy metal lead (Pb) readily passes into the mammary glands of mother animals and then to offspring through milk. Here, we investigated whether DHA composition of milk and mammary gland tissues is affected by Pb exposure. Mother rats were exposed to Pb via drinking water (0.1%). The fatty acid profile and levels of reduced glutathione (GSH), lipid peroxide (LPO), and pro-inflammatory TNF-α in milk and mammary tissues were measured. Levels of DHA and antioxidant GSH decreased (P < 0.05), while LPO and TNF-α levels increased (P < 0.05) both in milk and mammary tissues. Our results suggest that toxic Pb exposure can upset the level of milk DHA, which may affect brain growth and development, and hence cognitive ability in adulthood and later life.

Sub-Chronic Consumption of Dark Chocolate Enhances Cognitive Function and Releases Nerve Growth Factors: A Parallel-Group Randomized Trial.

Previous research has shown that habitual chocolate intake is related to cognitive performance and that frequent chocolate consumption is significantly associated with improved memory. However, little is known about the effects of the subchronic consumption of dark chocolate (DC) on cognitive function and neurotrophins. Eighteen healthy young subjects (both sexes; 20-31 years old) were randomly divided into two groups: a DC intake group (n = 10) and a cacao-free white chocolate (WC) intake group (n = 8). The subjects then consumed chocolate daily for 30 days. Blood samples were taken to measure plasma levels of theobromine (a methylxanthine most often present in DC), nerve growth factor (NGF), and brain-derived neurotrophic factor, and to analyze hemodynamic parameters. Cognitive function was assessed using a modified Stroop color word test and digital cancellation test. Prefrontal cerebral blood flow was measured during the tests. DC consumption increased the NGF and theobromine levels in plasma, enhancing cognitive function performance in both tests. Interestingly, the DC-mediated enhancement of cognitive function was observed three weeks after the end of chocolate intake. WC consumption did not affect NGF and theobromine levels or cognitive performance. These results suggest that DC consumption has beneficial effects on human health by enhancing cognitive function.

Influence of Ultra-High Hydrostatic Pressurizing Brown Rice on Cognitive Functions and Mental Health of Elderly Japanese Individuals: A 2-Year Randomized and Controlled Trial.

Brown rice contains many ingredients that might protect against cognitive decline and Alzheimer's disease. However, brown rice is very hard, difficult to cook, and is poorly digested; thus, it is difficult to eat long-term. To solve these problems, ultra-high hydrostatic pressurizing brown rice (UHHPBR) was prepared. We investigated the effects of dietary UHHPBR administration for 24 mo on cognitive function and mental health in the elderly. Healthy elderly participants (n=52) were randomized into UHHPBR and polished white rice (WR) groups. The UHHPBR group consumed 100 g of UHHPBR per day for 24 mo and the WR group consumed white rice. At baseline, and after 12 and 24 mo, cognitive functions were assessed using the Revised Hasegawa's Dementia Scale, Mini-Mental State Examination, Frontal Assessment Battery (FAB), and the Cognitive Assessment for Dementia, iPad version (CADi). Mental health condition was also assessed using the Apathy Scale and the Zung Self-Rating Depression Scale, and serum biochemical parameters were determined. From baseline to month 24, the mean change in the FAB-sub item 1 scores was higher in the UHHPBR group compared to the WR group. Furthermore, apathy scores decreased, as well as the time required to answer all questions of the CADi, and plasma epinephrine levels increased. These results indicate that a 2-y oral consumption of UHHPBR increases information processing speed (as a measure of cognitive function) and improves apathy in the elderly, suggesting a protective effect of UHHPBR administration against age-related decline in brain cognition and motivation.

Long-Term Ultra-High Hydrostatic Pressurized Brown Rice Intake Prevents Bone Mineral Density Decline in Elderly Japanese Individuals.

Bone embrittlement with aging, namely osteoporosis, is characterized by low bone mass and deterioration of bone tissue, and can lead to increased risk of fracture. The development of functional foods that can prevent geriatric diseases is in progress. Our focus was on brown rice because of its properties. An interventional study using of ultra-high hydrostatic pressurized brown rice (UHHPBR) for human has not yet been conducted. In this study, we investigated whether long-term dietary intake of UHHPBR prevents aging-related decline of bone mineral density in elderly Japanese individuals. Elderly participants (n=40; mean 73.1 y) in Iinan-cho, Shimane, Japan, were randomly divided into two groups. The UHHPBR-intake group (n=20) consumed 100 g of UHHPBR and 100 g of white rice (WR) per day for 12 mo, while the WR-intake group (n=20) consumed 200 g of WR per day. Pre- and 12-mo post-intervention, bone mineral density was evaluated by quantitative ultrasound. After 12 mo of intervention, the UHHPBR group's bone mineral density was significantly higher than the WR group's bone mineral density. Moreover, chronic intake of UHHPBR had no adverse side effects on participants. Long-term oral UHHPBR intake may have beneficial effects on bone mineral density decline and may attenuate osteoporosis in the elderly.

Theobromine Improves Working Memory by Activating the CaMKII/CREB/BDNF Pathway in Rats.

Theobromine (TB) is a primary methylxanthine found in cacao beans. cAMP-response element-binding protein (CREB) is a transcription factor, which is involved in different brain processes that bring about cellular changes in response to discrete sets of instructions, including the induction of brain-derived neurotropic factor (BDNF). Ca2+/calmodulin-dependent protein kinase II (CaMKII) has been strongly implicated in the memory formation of different species as a key regulator of gene expression. Here we investigated whether TB acts on the CaMKII/CREB/BDNF pathway in a way that might improve the cognitive and learning function in rats. Male Wistar rats (5 weeks old) were divided into two groups. For 73 days, the control rats (CN rats) were fed a normal diet, while the TB-fed rats (TB rats) received the same food, but with a 0.05% TB supplement. To assess the effects of TB on cognitive and learning ability in rats: The radial arm maze task, novel object recognition test, and Y-maze test were used. Then, the brain was removed and the medial prefrontal cortex (mPFC) was isolated for Western Blot, real-time PCR and enzyme-linked immunosorbent assay. Phosphorylated CaMKII (p-CaMKII), phosphorylated CREB (p-CREB), and BDNF level in the mPFC were measured. In all the behavior tests, working memory seemed to be improved by TB ingestion. In addition, p-CaMKII and p-CREB levels were significantly elevated in the mPFC of TB rats in comparison to those of CN rats. We also found that cortical BDNF protein and mRNA levels in TB rats were significantly greater than those in CN rats. These results suggest that orally supplemented TB upregulates the CaMKII/CREB/BDNF pathway in the mPFC, which may then improve working memory in rats.

Effect of chronic administration of arachidonic acid on the performance of learning and memory in aged rats.

BACKGROUND: Arachidonic acid (AA, C20:4, ω-6) is a ω-6 polyunsaturated fatty acid (PUFA) and plays diverse roles in cell signaling. Numerous reports on the effects of ω-3 PUFAs, such as docosahexaenoic acid (DHA, C22:6, ω-3) and eicosapentaenoic acid (EPA, C20:5, ω-3) on learning and memory impairments of rats are available, however, the role of AA on brain cognition is largely unknown. OBJECTIVE: In this study, our aim was to investigate the effect of oral administration of AA on spatial memory-related learning ability in aged (100 weeks) male rats. DESIGN: One group was per orally administered 240 mg/kg per day AA oil and the other group was administered the similar volume of control oil. Five weeks after the start of the administration, rats were tested with the partially baited eight-arm radial maze to evaluate two types of spatial memory-related learning ability displayed by reference memory errors (RMEs) and working memory errors (WMEs). Also, the time required to complete the task was recorded. The levels of lipid peroxide (LPO) and reactive oxygen species (ROS) were measured, as an indicator oxidative stress in the plasma and brain corticohippocampal brain tissues. RESULTS: The scores of RMEs and WMEs, which are analogous to long-term and short-term memory, respectively, were not affected, however, the trial time was shorter in the AA-administered rats than that of the controls. AA also significantly increased the degree of oxidative stress both in the plasma and corticohippocampal brain tissues. CONCLUSIONS: Our results suggest that though AA deposition in the corticohippocampal tissues of senescent rats caused a faster performance activity, which is reminiscent to hyperactive behavior of animals, the spatial learning ability-related memory of the rats, however, was not improved.