Goreisan regulates cerebral blood flow according to barometric pressure fluctuations in female C57BL/6J mice.

Goreisan is a Kampo medicine used to treat headaches associated with climate change. Here, by using an implantable complementary metal-oxide-semiconductor (CMOS) device, we evaluated the effects of Goreisan and loxoprofen on cerebral blood flow (CBF) dynamics associated with barometric pressure fluctuations in freely moving mice. In the vehicle group, decreasing barometric pressure increased CBF that was prevented by Goreisan and loxoprofen. Notably, Goreisan, but not loxoprofen, reduced CBF after returning to atmospheric pressure. These results indicate that, unlike the mechanism of action of antipyretic analgesics, Goreisan normalizes CBF abnormalities associated with barometric pressure fluctuations by actively reducing CBF increase.

Therapeutic effect of allicin in a mouse model of intracerebral hemorrhage.

Natural compounds with sulfur moiety produce various biological actions that may be beneficial for the therapies of several devastative disorders of the central nervous system. Here we investigated potential therapeutic effect of allicin, an organosulfur compound derived from garlic, in a mouse model of intracerebral hemorrhage (ICH) based on intrastriatal collagenase injection. Daily intraperitoneal administration of allicin (50 mg/kg) from 3 h after induction of ICH afforded neuroprotective effects, as evidenced by the increase of surviving neurons in the hematoma, reduction of axonal transport impairment, and prevention of axon tract injury. In addition, allicin inhibited accumulation of activated microglia/macrophages around the hematoma and infiltration of neutrophils within the hematoma. Allicin also suppressed ICH-induced mRNA upregulation of pro-inflammatory factors such as interleukin 6 and C-X-C motif ligand 2 in the brain, suggesting its anti-inflammatory effect. Moreover, ICH-induced increase of malondialdehyde as well as decrease of total glutathione in the brain was attenuated by allicin. Finally, allicin-treated mice showed better recovery of sensorimotor functions after ICH than vehicle-treated mice. These results indicate that allicin produces a therapeutic effect on ICH pathology via alleviation of neuronal damage, inflammatory responses and oxidative stress in the brain.

Matcha Tea Powder's Antidepressant-like Effect through the Activation of the Dopaminergic System in Mice Is Dependent on Social Isolation Stress.

Matcha tea powder is believed to have various physiological benefits; however, its detailed mechanism of action has been poorly understood. Here, we investigated whether the mental state of mice, due to social isolation stress, affects the antidepressant-like effect of Matcha tea powder by using the tail suspension test. Oral administration of Matcha tea powder reduced the duration of immobility in the stress-susceptible C57BL/6J strain, but not in BALB/c strain. In C57BL/6J mice, SCH23390, a dopamine D1 receptor blocker, prevented Matcha tea powder from exerting its antidepressant-like effect. Matcha tea powder also increased the number of c-Fos-positive cells in the prefrontal cortex (PFC) region and the nucleus accumbens (NAc) region in C57BL/6J mice, but not in BALB/c mice. In contrast, Matcha tea powder did not change the number of c-Fos-positive cells in the ventral tegmental area (VTA) region. Notably, C57BL/6J mice with a shorter immobility time had a higher number of c-Fos-positive cells in the PFC, NAc, and VTA regions. However, no such correlation was observed in the stress-tolerant BALB/c mice. These results suggest that Matcha tea powder exerts an antidepressant-like effect through the activation of the dopaminergic system including the PFC-NAc-VTA circuit and that mental states are important factors affecting the physiological benefits of Matcha tea powder.

Antileukemic Activity of Twig Components of Caucasian Beech in Turkey.

Despite the development of a range of anti-cancer agents, cancer diagnoses are still increasing in number, remaining a leading cause of death. Anticancer drug treatment is particularly important for leukemia. We screened Turkish plants and found the unique antileukemic activity of twig components in Turkish Caucasian beech, selectively inducing apoptosis in leukemia cells. This effect is unique among some kinds of beeches, presumably related to oxidative stress. This study would lead to effective use of discarded material, i.e., twig of beech, and a new anti-leukemic drug based on large tree.

Anti-neuroinflammatory activities of extract and polymethoxyflavonoids from immature fruit peels of Citrus 'Hebesu'.

Chronic neuroinflammation is reported to be associated in the progression of many neurodegenerative diseases and there is an increasing interest for the natural products as neuroprotective and anti-neuroinflammatory agents. In present research, we evaluated the potential inhibitory effects of extract, fractions, and isolated compounds from Citrus 'Hebesu' on lipopolysaccharide (LPS)-induced inflammatory responses using BV-2 murine microglial cells. The dried methanol extract (CH) was suspended in water and partitioned with hexane and ethyl acetate to give hexane soluble (CHH), ethyl acetate soluble (CHE), and water soluble (CHW) fractions. The extract (CH) and fractions CHH and CHE inhibited the expression of mRNA encoding pro-inflammatory cytokine interleukin (IL)-1ß. CHE and CHH were further purified by various column chromatographic methods to obtain hesperidin (1), tangeretin (2), 5-hydroxy-6,7,8,3',4'-pentamethoxyflavone (3), 3,5,6,7,8,3',4'-heptamethoxyflavone (4), nobiletin (5), 3,4,5-trimethoxy-trans-cinnamic alcohol (6), and meranzin hydrate (7). Among them, three polymethoxyflavonoids, 3, 4, and 5 significantly inhibited the expression of IL-1ß mRNA. PRACTICAL APPLICATIONS: Citrus 'Hebesu' is a local cultivar in Hyuga City, Miyazaki prefecture, Japan and its immature fruits are consumed with different food recipes. Till now, there is no detailed study on the chemical constituents and anti-neuroinflammatory activity of this cultivar. In this study, seven compounds were isolated from the peels of immature fruits. Methanol extract, hexane, and ethyl acetate fractions and three polymethoxyflavonoids showed a significant inhibitory activity against expression of IL-1ß mRNA. Consumption of peels of Citrus 'Hebesu' might play important role in the prevention and treatment of neurodegenerative diseases, however, detailed mechanism based in vivo studies are necessary in future for providing more scientific evidences.

Propranolol prevents cerebral blood flow changes and pain-related behaviors in migraine model mice.

Propranolol, a ß-adrenergic receptor blocker, is one of the most commonly used prophylactic drugs for migraines. Cortical spreading depression (CSD) is the propagation wave of neuronal excitation along with cerebral blood flow (CBF) changes over the cerebral cortex and has been implicated in the pathological process of migraine auras and its pain response. However, the effect of propranolol on CSD-related CBF changes and behavioral responses remains poorly understood. In this study, we measured CSD-related CBF responses using a micro-device with a green light emitting diode (LED) and micro-complementary-metal-oxide-semiconductor (CMOS) image sensor and evaluated pain-related reduced locomotor activity in mice. An injection of KCl into the visual cortex led to CSD-related CBF changes; however, propranolol prevented the increase in CBF as well as delayed the propagation velocity in KCl-induced CSD. Furthermore, an injection of KCl reduced locomotor activity and induced freezing behavior in awake and freely moving mice, which were prevented by propranolol treatment. These results suggest that the modulation of CSD-related CBF responses by the blockade of ß-adrenergic receptor contributes to its prophylactic effects on migraines.

Cystamine-mediated inhibition of protein disulfide isomerase triggers aggregation of misfolded orexin-A in the Golgi apparatus and prevents extracellular secretion of orexin-A.

Orexins (orexin-A and orexin-B) are neuropeptides that are reduced in narcolepsy, a sleep disorder that is characterized by excessive daytime sleepiness, sudden sleep attacks and cataplexy. However, it remains unclear how orexins in the brain and orexin neurons are reduced in narcolepsy. Orexin-A has two closely located intramolecular disulfide bonds and is prone to misfolding due to the formation of incorrect disulfide bonds. Protein disulfide isomerase (PDI) possesses disulfide interchange activity. PDI can modify misfolded orexin-A to its native form by rearrangement of two disulfide bonds. We have previously demonstrated that sleep deprivation and a high fat diet increase nitric oxide in the brain. This increase triggers S-nitrosation and inactivation of PDI, leading to aggregation of orexin-A and reduction of orexin neurons. However, the relationship between PDI inactivation and loss of orexin neurons has not yet been fully elucidated. In the present study, we used a PDI inhibitor, cystamine, to elucidate the precise molecular mechanism by which PDI inhibition reduces the number of orexin neurons. In rat hypothalamic slice cultures, cystamine induced selective depletion of orexin-A, but not orexin-B and melanin-concentrating hormone. Moreover, cystamine triggered aggregation of orexin-A, but not orexin-B in the Golgi apparatus of hypothalamic slice cultures and in vivo mouse brains. However, cystamine did not induce endoplasmic reticulum (ER) stress, and an ER stress inducer did not trigger aggregation of orexin-A in slice cultures. Finally, we demonstrated that cystamine significantly decreased extracellular secretion of orexin-A in AD293 cells overexpressing prepro-orexin. These findings suggest that cystamine-induced PDI inhibition induces selective depletion, aggregation in the Golgi apparatus and impaired secretion of orexin-A. These effects may represent an initial step in the pathogenesis of narcolepsy.

High fat diet induces specific pathological changes in hypothalamic orexin neurons in mice.

Loss of orexin neurons in the hypothalamus is a prominent feature of narcolepsy and several other neurological conditions. We have recently demonstrated that sleep deprivation stimulates local nitric oxide (NO) production by neuronal NO synthase in the lateral hypothalamus, which leads to selective degeneration of orexin neurons accompanied by formation of orexin-immunoreactive aggregates. Here we analyzed whether lifestyle-related conditions other than sleep deprivation could trigger similar pathological changes in orexin neurons. Four-week-old male C57BL/6 mice were fed with high fat diet (HFD) for 8 weeks. Immunohistochemical analysis revealed that the number of orexin-immunopositive neurons was significantly decreased by HFD intake, whereas the number of melanin-concentrating hormone-immunopositive neurons was unchanged. In addition, HFD promoted formation of intracellular orexin-immunoreactive aggregates in a subset of orexin neurons. We also confirmed that expression of inducible NO synthase (iNOS) in the hypothalamus was upregulated in response to HFD intake. Notably, loss of orexin-immunopositive neurons and formation of orexin-immunoreactive aggregates were not observed in iNOS knockout mice fed with HFD. These results indicate that inappropriate dietary conditions could trigger specific neuropathological events in orexin neurons in an iNOS-dependent manner.