Alterations of amygdala-prefrontal cortical coupling and attention deficit/hyperactivity disorder-like behaviors induced by neonatal habenula lesion: normalization by Ecklonia stolonifera extract and its active compound fucosterol.

Alterations of monoamine transmission in mesocorticolimbic regions have been suggested in the pathophysiology of attention deficit/hyperactivity disorder (ADHD). The habenula is an important brain area in regulation of monoamine transmission. In this study, we investigated behavioral and electrophysiological alterations induced by neonatal habenula lesion (NHL) in rats. In NHL rats, age-dependent behavioral alterations relevant to the ADHD symptoms, such as hyperlocomotion, impulsivity, and attention deficit, were observed. Local field potentials (LFPs) in mesocorticolimbic regions of anesthetized rats were examined with in vivo electrophysiological recordings. Abnormally enhanced synchronization of slow (delta) and fast (gamma) LFP oscillations between the amygdala (AMY) and prefrontal cortex (PFC) was found in juvenile, but not in adult, NHL rats. We further examined the effects of an extract and the active compound from the perennial large brown algae Ecklonia stolonifera (ES), which have previously been demonstrated to modulate monoamine transmission, on these NHL-induced alterations. One week of ES extract treatments normalized the NHL-induced behavioral alterations, whereas the active compound fucosterol improved attention deficit and impulsivity, but not hyperlocomotion, in NHL rats. Consistent with the behavioral effects, ES extract treatments also normalized augmented AMY-PFC coupling. These results suggest that altered limbic-cortical information processing may be involved in ADHD-like behavioral alterations induced by NHL, which could be ameliorated by the natural substance, such as ES that affects monoamine transmission.

The effects of Engelhardtia chrysolepis Hance on long-term memory and potential dopamine involvement in mice.

Engelhardtia chrysolepis Hance (ECH) is a perennial plant used in traditional medicine. A major active ingredient of ECH is astilbin (ASB), which has recently been shown to have neuroprotective effects as well as to affect catecholamine neurotransmissions in brain areas such as the prefrontal cortex. In this study, we investigated the effects of ECH and ASB on long-term memory in mice using a battery of behavioral tests. Acute ECH treatments dose-dependently facilitated nonspatial, but not spatial, memory. ECH treatments also upregulated expression of tyrosine hydroxylase, the enzyme mediating catecholamine synthesis, in neuroblastoma cell culture. Acute ASB treatments similarly improved nonspatial memory, whereas chronic ASB treatments improved both nonspatial and spatial memory. In accordance with such behavioral effects, the increased ratio of tissue concentrations of dopamine metabolites over dopamine in striatal regions was observed in mice with chronic ASB treatments. These results suggest that ECH and its active ingredient ASB may facilitate long-term memory by modulating catecholamine transmission.

Oligomeric proanthocyanidins improve memory and enhance phosphorylation of vascular endothelial growth factor receptor-2 in senescence-accelerated mouse prone/8.

Senescence-accelerated mouse prone/8 (SAMP8), a murine model of accelerated senescence, shows age-related deficits in learning and memory. We investigated the effect of oligomeric proanthocyanidins (oligomers) on memory impairment using the SAMP8 model involving the oral administration of oligomers for 5 weeks. To analyse memory improvement in SAMP8, we performed Morris water maze, object location and object recognition tests. The oral administration of oligomers improved spatial and object recognition impairment in SAMP8. Expressions of phosphorylated neurofilament-H (P-NF-H, axon marker), microtubule-associated proteins (MAP) 2a and 2b (MAP2; dendrite marker) and synaptophysin were increased in the brains of SAMP8-administered oligomers. In particular, the expression of P-NF-H was significantly elevated in the hippocampal CA1. This indicates that oligomers result in an increase in the densities of axons, dendrites and synapses. To investigate the protective mechanisms of oligomers against brain dysfunction with ageing, we carried out a receptor tyrosine kinase phosphorylation antibody array, and clarified that the administration of oligomers led to an increase in the phosphorylation of vascular endothelial growth factor receptor (VEGFR)-2, suggesting the neuroprotective role of oligomers. The phosphorylation of VEGFR-2 was more greatly increased in the hypothalamus and choroid plexus than in other brain regions of SAMP8. Memory in oligomer-treated mice was impaired by SU1498, a VEGFR-2-specific antagonist. Elucidating the relationship between memory impairment with ageing and VEGFR-2 signalling may provide new suggestions for protection against memory deficit in the ageing brain.

Persimmon oligomeric proanthocyanidins extend life span of senescence-accelerated mice.

The anti-aging activities of persimmon oligomeric proanthocyanidins (POPs), reported to improve life span and behavioral characteristics associated with the aging process, were investigated using the senescence-accelerated mouse (SAM) P8, which is a good model for studies on aging-related behavioral changes as well as life span. We demonstrated that the administration of POPs extended the life span of SAMP8. In addition, POPs elevated Sirt1 expression, which is recognized as an essential factor for life span extension in the brain. On the other hand, the administration of POPs did not induce stereotypical behaviors such as rearing, jumping, and hanging from the lid of a cage, whereas food restriction increased these frequencies without a significant change in motor function. The present study suggests a promising role of POPs as anti-aging agents to extend life span, although further studies elucidating their anti-aging mechanisms acting are needed.

Ameliorative effects of proanthocyanidin on oxidative stress and inflammation in streptozotocin-induced diabetic rats.

Recent evidence strongly suggests that oxidative stress due to redox imbalance is causally associated with inflammatory processes and various diseases including diabetes. We examined the effects of proanthocyanidin from persimmon peel, using both oligomers and polymers, against oxidative stress with elucidation of the underlying mechanisms in streptozotocin-induced diabetic rats. The elevation of lipid peroxidation in the kidney and serum under the diabetic condition was decreased by the administration of proanthocyanidin. The suppression of reactive oxygen species generation and elevation of the reduced glutathione/oxidized glutathione ratio were observed in the groups administered proanthocyanidin. These results support the protective role of proanthocyanidin from oxidative stress induced by diabetes. Moreover, proanthocyanidin, especially its oligomeric form, affected the inflammatory process with regulation of related protein expression, inducible nitric oxide synthase, cyclooxygenase-2, and upstream regulators, nuclear factor kappaB, and inhibitor-binding protein kappaB-alpha. Proanthocyanidin ameliorated the diabetic condition by decreases of serum glucose, glycosylated protein, serum urea nitrogen, urinary protein, and renal advanced glycation endproducts. In particular, oligomeric proanthocyanidin exerted a stronger protective activity than the polymeric form. This suggests that the polymerization of proanthocyanidin has an effect on its protective effect against diabetes. The present study supports the beneficial effect of proanthocyanidin against diabetes and oxidative stress-related inflammatory processes.

Inhibitory activities of proanthocyanidins from persimmon against oxidative stress and digestive enzymes related to diabetes.

The present study was carried out to evaluate the promising potential of polymers and oligomers from proanthocyanidins of persimmon peel as antioxidants and therapeutic agents for diabetes. Both polymers and oligomers showed the scavenging effect of 2,2-diphenyl-l-picrylhydrazyl, with IC50 values of 4.35 and 2.41 microg/mL, respectively, and they also showed a protective activity against protein oxidation induced by 2,2'-azobis (2-amidinopropane) dihydrochloride. In particular, oligomers exerted a stronger activity against free radicals than polymers. In addition, to investigate their protective potential against diabetes-related pathological conditions, their inhibitory activities on digestive enzymes and advanced glycation endproduct (AGE) formation were evaluated. Polymers showed a strong inhibitory activity against alpha-amylase, while oligomers had a relatively weak effect. This suggests that the inhibition of alpha-amylase activity would probably depend on the degree of polymerization. On the other hand, against alpha-glucosidase activity and AGE formation, oligomers exerted a stronger protective effect than polymers. The present study suggests that polymers and oligomers from proanthocyanidins of persimmon peel could play a role as antidiabetic agents with antioxidative effects. Moreover, oligomers rather than polymers from proanthocyanidins of persimmon peel may be expected to be a more promising antioxidative and antidiabetic agent in relation to utilization in biological systems.

Protective effects of broccoli (Brassica oleracea) against oxidative damage in vitro and in vivo.

The antioxidative effect and protective potential against diabetes of the broccoli flower were investigated both in vitro and in a diabetic rat model. Among fractions of MeOH, CH2Cl2, BuOH, and H2O, the BuOH fraction exerted the strongest inhibitory activities on 1,1-diphenyl-2-picrylhydrazyl radical, radical-induced protein oxidation, and nitric oxide generation by sodium nitroprusside. The in vitro results suggest that the BuOH fraction from the broccoli flower has a protective potential against oxidative stress. The rat model with diabetes induced by streptozotocin was employed to evaluate the protective effect of the BuOH fraction in vivo. Diabetic rats showed reduced body weight gain and heavier kidney and liver weights than normal rats, while oral administration of the BuOH fraction at an oral dose of 100 or 200 mg/kg body weight/d for 20 d attenuated the physiological changes induced by diabetes. In addition, oral administration of the BuOH fraction to diabetic rats led to significant decreases in serum glucose and glycosylated protein, while it resulted in the increase of serum albumin, implying that the BuOH fraction improves the abnormal metabolism of glucose and protein that leads to oxidative stress. Moreover, it significantly reduced thiobarbituric acid-reactive substance levels in serum, hepatic and renal mitochondria. This suggests that the BuOH fraction would alleviate the oxidative stress associated with diabetes through the inhibition of lipid peroxidation. The present study demonstrates that the BuOH fraction has an antioxidative effect in vitro and it protects against oxidative stress induced by diabetes in an in vivo model.

Protective effects of broccoli (Brassica oleracea) and its active components against radical-induced oxidative damage.

The radical scavenging effect and protective potential from oxidative damage by radical generator, 2,2'-azobis (2-amidinopropane) dihydrochloride (AAPH), in renal epithelial LLC-PK1 cell of broccoli (Brassica oleracea) were investigated and identified the active components under the bioassay-linked fractionation method. The MeOH extract, and fractions of CH2Cl2, BuOH and H2O from broccoli showed the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging effect in a dose-dependent manner. In addition, they exerted the protective effect against LLC-PK1 cellular damage induced by AAPH dose-dependently. In particular, the BuOH fraction was evaluated as the most active fraction, indicating that the BuOH fraction contains the active components with antioxidative capacity. Employing a bioassay-linked fractionation method, the active principles were isolated and characterized as 1,2-disinapoylgentiobiose and 1-sinapoyl-2-feruloylgentiobiose from the BuOH fraction. These two compounds from broccoli displayed potent antioxidant effects against the DPPH radical, showing the IC50 values of 5.18 and 7.52 microg/mL, respectively. Moreover, the compounds significantly and dose-dependently recovered cell viability lowered by AAPH treatment, suggesting the protective roles from cellular oxidative damage. The present study suggests that broccoli has excellent antioxidative potential and the hydroxycinamic acid esters from broccoli, 1,2-disinapoylgentiobiose and 1-sinapoyl-2-feruloylgentiobiose, are considered as the active components with antioxidative effect.