How Ketamine Affects Livers of Pregnant Mice and Developing Mice?

It is well known that ketamine abuse can induce liver damage in adult addicts, but the effects of ketamine abuse in pregnant mothers on their offspring have received less attention. In this study, we investigated the effects of 5-day ketamine injections (30 mg/kg) to pregnant Institute for Cancer Research (ICR) mice during early gestation or mid-gestation on the aspartate aminotransferase (AST) and alkaline phosphatase (ALP) activities of the mothers and the offspring. We also looked into whether administering ketamine treatment to the mothers had any effects on the extent of fibrosis, cell proliferation and cell death in the livers of the newborns. No significant biochemical differences were found between treatment and control groups in the mothers. In the offspring, ketamine treatment mildly suppressed the gradual increase of hepatic AST activity in neonates during liver maturation. Measurements of hepatic ALP activity and lactic acid dehydrogenase (LDH) immunoreactivity revealed that ketamine treatment may lead to increased cell death. Proliferation of liver cells of the newborns was also retarded as shown by reduced proliferative cell nuclear antigen (PCNA) immunoreactivity in the ketamine groups. No obvious fibrosis was evident. Thus, we demonstrated that ketamine administration to pregnant mice suppressed hepatic development and also induced liver cell death of the offspring.

The modulation of BDNF expression and signalling dissects the antidepressant from the reinforcing properties of ketamine: Effects of single infusion vs. chronic self-administration in rats.

Ketamine is a drug of abuse with a unique profile, which besides its inherent mechanism of action as a non-competitive antagonist of the NMDA glutamate receptor, displays both antidepressant and reinforcing properties. The major aim of our study was to find a molecular signature of ketamine that may help in discriminating between its reinforcing and antidepressant effects. To this end, we focused our attention on BDNF, a neurotrophin that has been shown to play a role in both antidepressant and reinforcing properties of several drugs. Rats were exposed to self-administer intravenous (IV) ketamine (S/A) for 43 days or to receive a single IV ketamine 0.5mg/kg, or vehicle infusion. Although the dose we employed is lower than that reported by the literature, it however yields Cmax values that correspond to those achieved in humans after antidepressant treatment. Our results show that while the single infusion of ketamine increased the neurotrophin expression in the hippocampus while reducing it in the ventral striatum, a feature shared with other antidepressants, the repeated self-administration reduced mBDNF expression and its downstream signalling in both ventral striatum and hippocampus. Further, we here show that phosphorylation of Akt is oppositely regulated by ketamine, pointing to this pathway as central to the different actions of the drug. Taken together, we here point to BDNF and its downstream signalling pathway as a finely tuned mechanism whose modulation might subserve the different features of ketamine.

ERRα augments HIF-1 signalling by directly interacting with HIF-1α in normoxic and hypoxic prostate cancer cells.

Adaptation of cancer cells to a hypoxic microenvironment is important for their facilitated malignant growth and advanced development. One major mechanism mediating the hypoxic response involves up-regulation of hypoxia-inducible factor 1 (HIF-1) expression, which controls reprogramming of energy metabolism and angiogenesis. Oestrogen-related receptor-α (ERRα) is a pivotal regulator of cellular energy metabolism and many biosynthetic pathways, and has also been proposed to be an important factor promoting the Warburg effect in advanced cancer. We and others have previously shown that ERRα expression is increased in prostate cancer and is also a prognostic marker. Here we show that ERRα is oncogenic in prostate cancer and also a key hypoxic growth regulator. ERRα-over-expressing prostate cancer cells were more resistant to hypoxia and showed enhanced HIF-1α protein expression and HIF-1 signalling. These effects could also be observed in ERRα-over-expressing cells grown under normoxia, suggesting that ERRα could function to pre-adapt cancer cells to meet hypoxia stress. Immunoprecipitation and FRET assays indicated that ERRα could physically interact with HIF-1α via its AF-2 domain. A ubiquitination assay showed that this ERRα-HIF-1α interaction could inhibit ubiquitination of HIF-1α and thus reduce its degradation. Such ERRα-HIF-1α interaction could be attenuated by XCT790, an ERRα-specific inverse agonist, resulting in reduced HIF-1α levels. In summary, we show that ERRα can promote the hypoxic growth adaptation of prostate cancer cells via a protective interaction with HIF-1α, suggesting ERRα as a potential therapeutic target for cancer treatment.

Differential hypoglycaemic, anorectic, autonomic and emetic effects of the glucagon-like peptide receptor agonist, exendin-4, in the conscious telemetered ferret.

BACKGROUND: Rodents are incapable of emesis and consequently the emetic potential of glucagon-like peptide-1 receptor (GLP-1R) agonists in studies designed to assess a potential blood glucose lowering action of the compound was missed. Therefore, we investigated if the ferret, a carnivore with demonstrated translation capability in emesis research, would identify the emetic potential of the GLP-1R agonist, exendin-4, and any associated effects on gastric motor function, appetite and cardiovascular homeostasis. METHODS: The biological activity of the GLP-1R ligands was investigated in vivo using a glucose tolerance test in pentobarbitone-anesthetised ferrets and in vitro using organ bath studies. Radiotelemetry was used to investigate the effect of exendin-4 on gastric myoelectric activity (GMA) and cardiovascular function in conscious ferrets; behaviour was also simultaneously assessed. Western blot was used to characterize GLP-1R distribution in the gastrointestinal and brain tissues. RESULTS: In anesthetised ferrets, exendin-4 (30 nmol/kg, s.c.) reduced experimentally elevated blood glucose levels by 36.3%, whereas the GLP-1R antagonist, exendin (9-39) (300 nmol/kg, s.c.) antagonised the effect and increased AUC0-120 by 31.0% when injected alone (P < 0.05). In animals with radiotelemetry devices, exendin-4 (100 nmol/kg, s.c.) induced emesis in 1/9 ferrets, but inhibited food intake and decreased heart rate variability (HRV) in all animals (P < 0.05). In the animals not exhibiting emesis, there was no effect on GMA, mean arterial blood pressure, heart rate, or core body temperature. In the ferret exhibiting emesis, there was a shift in the GMA towards bradygastria with a decrease in power, and a concomitant decrease in HRV. Western blot revealed GLP-1R throughout the gastrointestinal tract but exendin-4 (up to 300 nM) and exendin (9-39), failed to contract or relax isolated ferret gut tissues. GLP-1R were found in all major brain regions and the levels were comparable those in the vagus nerve. CONCLUSIONS: Peripherally administered exendin-4 reduced blood glucose and inhibited feeding with a low emetic potential similar to that in humans (11% vs 12.8%). A disrupted GMA only occurred in the animal exhibiting emesis raising the possibility that disruption of the GMA may influence the probability of emesis occurring in response to treatment with GLP-1R agonists.

Chronic ketamine exposure induces permanent impairment of brain functions in adolescent cynomolgus monkeys.

Ketamine, a non-competitive N-methyl-D-aspartic acid receptor antagonist, has emerged as an increasingly popular drug among young drug abusers worldwide. Available evidence suggests that ketamine produces acute impairments of working, episodic and semantic memory along with psychotogenic and dissociative effects when a single dose is given to healthy volunteers. However, understanding of the possible chronic effects of ketamine on behavior, cognitive anomalies and neurochemical homeostasis is still incomplete. Although previous human studies demonstrate that ketamine could impair a range of cognitive skills, investigation using non-human models would permit more precise exploration of the neurochemical mechanisms which may underlie the detrimental effects. The current study examined the abnormalities in behavior (move, walk, jump and climb) and apoptosis of the prefrontal cortex using terminal deoxynucleotidyl transferase-mediated biotinylated dUTP nick end labeling (TUNEL) and apoptotic markers, including Bax, Bcl-2 and caspase-3 in adolescent male cynomolgus monkeys (Macaca fascicularis) after 1 or 6 months of sub-anesthetic ketamine administration (1 mg/kg, i.v.). Results showed that ketamine decreased locomotor activity and increased cell death in the prefrontal cortex of monkeys with 6 months of ketamine treatment when compared with the control monkeys. Such decreases were not found in the 1-month ketamine-treated group. Our study suggested that ketamine administration of recreational dose in monkeys might produce permanent and irreversible deficits in brain functions due to neurotoxic effects, involving the activation of apoptotic pathways in the prefrontal cortex.

Dose-dependent anti-inflammatory and neuroprotective effects of an ανß3 integrin-binding peptide.

Previous studies have shown that prevention of leukocyte infiltration by targeting integrins involved in transendothelial migration may suppress the clinical and pathological features of neuroinflammatory disease. This study was designed to investigate the effects of C16, an ανß3 integrin-binding peptide, in an acute experimental allergic encephalomyelitis (EAE) rat model. Multiple histological and immunohistochemical staining, electron microscopy observation, ELISA assay, Western blot, and magnetic resonance imaging (MRI) were employed to assess the degree of inflammation, axonal loss, neuronal apoptosis, white matter demyelination, and extent of gliosis in the brain and spinal cord of differently treated EAE models. The results showed that C16 treatment could inhibit extensive leukocyte and macrophage accumulation and infiltration and reduce cytokine tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) expression levels. A significantly lower clinical score at the peak time of disease was also demonstrated in the C16 treated group. Moreover, astrogliosis, demyelination, neuronal death, and axonal loss were all alleviated in C16 treated EAE animals, which may be attributed to the improvement of microenvironment. The data suggests that C16 peptide may act as a protective agent by attenuating inflammatory progression and thus affecting the expression of some proinflammatory cytokines during neuroinflammatory disease.

Effects of DL-3-n-butylphthalide on vascular dementia and angiogenesis.

3-n-Butylphthalide (NBP) is a compound extracted from Chinese celery and is used as an anti-hypertensive herbal medicine for treating stroke patients. The aim of this study is to demonstrate the effects and mechanisms of this compound through in vitro and in vivo experiments. Culture experiments were performed by adding hydrogen peroxide (H(2)O(2)) to SH-SY5Y cells. From the MTT assay result, enhanced cell survival was observed with DL-NBP treatment, regardless of whether they are added before, simultaneously with or after the addition of H(2)O(2). For the in vivo experiment, Spontaneously Hypertensive rats and Wistar Kyoto control rats with chronic cerebral ischemia, which were induced by bilateral transection of the common carotid arteries, were given DL-NBP. Their performances in the place navigation test and spatial probe test in the Morris Water Maze have significantly improved compared with the DL-NBP untreated animals, indicating an improvement in spatial learning and memory in the ischemic-animals. In addition, in the chick embryonic chorioallantoic membrane assay, angiogenesis was more vigorous under the effects of DL-NBP, together with increased expression of growth factors, VEGF, VEGF-receptor and bFGF. All these suggested that one of the mechanisms of DL-NBP might be ameliorating vascular dementia and promoting angiogenesis.

Triptolide down-regulates COX-2 expression and PGE2 release by suppressing the activity of NF-κB and MAP kinases in lipopolysaccharide-treated PC12 cells.

As an active compound extracted from the Chinese herb Tripterygium wilfordii, triptolide (TP) was demonstrated to have potent antiinflammatory and immunosuppressive properties in previous studies. Recently, it has been shown that TP prevented the loss of dopaminergic neurons in the substantia nigra of rats in a model of Parkinson's disease, but little is known about the precise neuroprotective mechanism of TP. This study was designed to elucidate whether the neuroprotective effect of TP is partially based on its direct inhibition of inflammatory molecules by investigating the effects of TP on the expression of cyclooxygenase (COX)-2 and prostaglandin E2 (PGE2) related to the nuclear factor (NF)-κB pathway in lipopolysaccharide (LPS)-stimulated PC12 cells. The activation of related upstream molecules such as NF-κB, P38, extracellular signal-regulated kinase (ERK)1/2, and beta-alanyl-alpha-ketoglutarate transaminase (AKT), in PC12 cells were investigated by real time polymerase chain reaction (PCR), western blotting and enzyme-linked immunosorbent assay (ELISA). Our results showed that TP directly inhibited the expression of both mRNA and protein of COX-2 (p < 0.01), decreased PGE2 production (p < 0.01) in a dose-dependent manner, down-regulated NF-κB activity (p < 0.01), and significantly inhibited the phosphorylation of p38, ERK1/2 (p42/p44) and AKT in PC12 cells after LPS challenge. This suggests that the neuroprotective effects of TP may be partially mediated by direct inhibition of the expression of COX-2, activation of NF-κB, and phosphorylation of p38, ERK1/2 (p42/p44) and AKT proteins of neuronal cells.

Comparative Review of Effects of Pien Tze Huang and AnGong NiuHuang Pill and their Potential on Treatment of Central Nervous System Diseases.

The ancient composite formulae Angong Niuhuang pill and Pien Tze Huang, which were used a few hundred years ago to treat febrile disease and inflammation, respectively, are found to exert effects benefiting other neurological diseases and conditions. This short review introduces the main constituents of the two formulae, looking into both the cumulative synergetic and possible individual effects of each herb or animal apcoien. In essence, the main effects of Angong Niuhuang pill include anti-inflammation, antioxidation, anti-cell death, anticonvulsion, antiedema, antipyretic, antithrombotic, antimicrobial (bacteria, viruses, fungi), neuroprotective effects, and cardiovascular protection. The main effects of Pien Tze Huang include anti-inflammation, antioxidation, anti-cell death, antithrombotic, antimicrobial, neuroprotective effects, and cardiovascular protection. Comparing both composites, similarities in the effects and part of the components are found, showing some pharmacological evidence. This review casts light on research on the effects of neuroprotective and cardiovascular protective mechanisms as well as treatment mechanisms for cerebral accidents from the integrative medicine perspective.

ß-sitosterol inhibits high cholesterol-induced platelet ß-amyloid release.

Recently, increasing evidence has linked high cholesterol to the pathogenesis of Alzheimer's disease (AD), suggesting that cholesterol may be a target for developing new compounds to prevent or treat AD. Plant sterols, a group of sterols enriched in plant oils, nuts, and avocados, have the structure very similar to that of cholesterol, and have been widely used to reduce blood cholesterol. Due to their cholesterol-lowering property, plant sterols such as ß-sitosterol may also influence cholesterol-depending functions including its role in AD development. Using human platelets, a type of peripheral blood cells containing the most circulating amyloid precursor protein (APP), this study investigated the effect of ß-sitosterol on high cholesterol-induced secretion of ß amyloid protein (Aß). It was found that ß-sitosterol effectively inhibited high cholesterol-driven platelet Aß release. In addition, ß-sitosterol prevented high cholesterol-induced increase of activities of ß- and γ-secretase, two APP cleaving enzymes to generate Aß. Additional experiments showed that high cholesterol up-regulated lipid raft cholesterol. This effect of cholesterol could be suppressed by ß-sitosterol. These findings suggest that ß-sitosterol is able to inhibit high cholesterol-induced Aß release probably through maintenance of membrane cholesterol homeostasis. Given that dietary plant sterols have the potential of penetrating the blood-brain barrier (BBB), these data suggest that plant sterols such as ß-sitosterol may be useful in AD prevention.

Profiles of serotonin receptors in the developing human thalamus.

The critical importance of the thalamus and its serotonergic innervation with respect to neuropsychiatric syndromes is increasingly recognized. This study investigates the localization of serotonin (5-hydroxytryptamine; 5-HT) receptors by immunohistochemistry in the thalamic nuclei of human fetuses aged 21 to 32 weeks of gestation. Results indicate that, already at 21 weeks of gestation, two 5-HT receptors are present in the dorsomedial nucleus of the developing thalamus: 5-HT2A receptors are localized in neurons and 5-HT2C receptors in fibers. By 31 and 32 weeks of gestation, 5-HT1A and 5-HT4 receptors are also detected in neuronal fibers of the same nucleus. At this later developmental stage, the percentage of 5-HT2A labeled neurons has significantly increased in the dorsomedial nucleus, and 5-HT2C positive neurons are observed in the centromedian and lateroventral thalamic nuclei as well. In contrast, neither neuronal cells nor fibers display any immunoreactivity for 5-HT3 or 5-HT6 receptors at any of the ages examined. Our observation that 5-HT1A, 5-HT2A, 5-HT2C and 5-HT4 receptors are present in the human thalamus prenatally indicates that 5-HT may play a role during fetal development. Disrupted development of the thalamic serotonergic system during this gestational period may contribute to the pathophysiology of neuropsychiatric disorders.

Review of evidence suggesting that the fascia network could be the anatomical basis for acupoints and meridians in the human body.

The anatomical basis for the concept of meridians in traditional Chinese medicine (TCM) has not been resolved. This paper reviews the evidence supporting a relationship between acupuncture points/meridians and fascia. The reviewed evidence supports the view that the human body's fascia network may be the physical substrate represented by the meridians of TCM. Specifically, this hypothesis is supported by anatomical observations of body scan data demonstrating that the fascia network resembles the theoretical meridian system in salient ways, as well as physiological, histological, and clinical observations. This view represents a theoretical basis and means for applying modern biomedical research to examining TCM principles and therapies, and it favors a holistic approach to diagnosis and treatment.

Comparative proteomic analysis of mesenchymal stem cells derived from human bone marrow, umbilical cord and placenta: implication in the migration.

Umbilical cord (UC) and placenta (P) have been suggested as alternatives to bone marrow (BM) as sources of mesenchymal stem cells (MSC) for cell therapy, with both UC- and P-MSC possess immunophenotypic and functional characteristics similar to BM-MSC. However, under defined conditions, the migration capacity of BM- and P-MSC was found to be 5.9- and 3.2-folds higher than that of UC-MSC, respectively. By the use of 2-DE and combined MS and MS/MS analysis, six differentially expressed proteins were identified among these MSC samples, with five of them known to be involved in cell migration as migration enhancing or inhibiting proteins. Interestingly, the expression levels of those proteins reflect perfectly the migration capacity of corresponding MSC, which is also proved by in vitro overexpression and silencing techniques. Our study indicates that a bunch of migration-related proteins are pivotal in governing the migration capacity of MSC.

Reaction of the Liver upon Long-Term Treatment of Fluoxetine and Atorvastatin Compared with Alcohol in a Mouse Model.

BACKGROUND: Alcoholism is known to cause liver toxicity and is extensively researched. On the other hand, stress, depression, and obesity are interrelated conditions with alcoholism, and their medications would affect the liver itself. In this study, we investigated the effects of the drugs fluoxetine and atorvastatin on the liver and compared with those of alcohol in a mouse model. METHODS: Comparisons of animals treated with the three drugs were carried out: serum aspartate transaminase (AST), alanine transaminase (ALT), and albumin were measured; liver tumor necrosis factor alpha (TNF alpha) and transforming growth factor beta (TGF beta-1) levels were evaluated; proliferative cells were detected via immunohistochemistry (IHC) targeting on proliferating cell nuclear antigen (PCNA) and minichromosome maintenance complex component 2 (MCM2); for apoptosis, IHC targeting on activated caspase-3 and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) were employed; and histopathology was also documented in all groups. RESULTS: For ALT, AST, albumin, and liver TNF alpha, only the ethanol group surged to significantly higher levels. For TGF beta-1, both ethanol and atorvastatin groups reached a significantly higher level. PCNA and MCM2 showed increased proliferation in the livers of all three groups, with the ethanol group having the highest number of positive cells followed by atorvastatin and then the fluoxetine group. As for cell death, both ethanol and fluoxetine groups showed significantly more apoptosis than control in TUNEL and activated caspase-3, while in the atorvastatin group, activated caspase-3 positive cells increased significantly, but the increase in TUNEL-positive cells did not reach statistical significance.

Gene expression of synaptosomal-associated protein 25 (SNAP-25) in the prefrontal cortex of the spontaneously hypertensive rat (SHR).

Dopamine is believed to play an important role in the etiology of attention-deficit/hyperactivity disorder (ADHD). In our previous study, we showed that gene expression of dopamine D4 receptor decreased in the spontaneously hypertensive rat (SHR) in the prefrontal cortex (PFC). In the present study, we explored the potential causes of dysfunction in the dopamine system in ADHD. It is the first time that neuronal activities in both juvenile SHR and WKY rats have been measured by functional MRI (fMRI). Our results showed that in PFC the Blood Oxygenation Level Dependent (BOLD) signal response in SHR was much higher than WKY under stressful situations. We tested the effects of acute and repeated administration of amphetamine on behavioral changes in SHR combined with the expression of the neuronal activity marker, c-fos, in the PFC. Meanwhile dopamine-related gene expression was measured in the PFC after repeated administration of amphetamine. We found that potential neuronal damage occurred through deficit of D2-like receptor protective functions in the PFC of the SHR. We also measured the expression of synaptosomal-associated protein 25 (SNAP-25) in SHR in PFC. The results showed decreased expression of SNAP-25 mRNA in the PFC of SHR; this defect disappeared after repeated injection of D-AMP.

Bilobalide prevents apoptosis through activation of the PI3K/Akt pathway in SH-SY5Y cells.

Bilobalide, a sesquiterpene trilactone constituent of Ginkgo biloba leaf extracts, has been proposed to exert protective and trophic effects on neurons. However, mechanisms underlying the protective effects of bilobalide remain unclear. Using human SH-SY5Y neuroblastoma cells and primary hippocampal neurons, this study investigated the neuroprotective effects of bilobalide. We mimicked aging-associated neuronal impairments by applying external factors (beta amyloid protein (Abeta) 1-42, H(2)O(2) and serum deprivation) consequently inducing cell apoptosis. As markers for apoptosis, cell viability, DNA fragmentation, mitochondrial membrane potential and levels of cleaved caspase 3 were measured. We found that, bilobalide prevented Abeta 1-42-, H(2)O(2)- and serum deprivation-induced apoptosis. To better understand the neuroprotective effects of bilobalide, we also tested the ability of bilobalide to modulate pro-survival signaling pathways such as protein kinase C (PKC), extracellular-regulated kinase 1/2 (ERK1/2) and phosphatidylinositol 3-kinase (PI3K)/Akt pathways. It was found that, bilobalide dose-dependently increased PI3K activity and levels of phosphorylated Akt (p-Akt Ser473 and Thr308), which could be maintained up to at least 2 h after bilobalide withdrawal in cells treated with or without Abeta 1-42, H(2)O(2) or serum-free medium. In addition, application of PI3K/Akt inhibitor LY294002 could abrogate both the protective effects of bilobalide against Abeta 1-42-, H(2)O(2)- and serum deprivation-induced apoptotic cell damage and bilobalide-induced increase in PI3K activity and levels of p-Akt (Ser473 and Thr308). In contrast, application of PKC inhibitor staurosporine (STS) did not affect the protective effects of bilobalide. Moreover, no change in levels of phosphorylated ERK1/2 (p-ERK1/2) was observed in bilobalide-treated cells. These results further suggested that the PI3K/Akt pathway might be involved in the protective effects of bilobalide. Since modern technology allows production of purified bilobalide with high bioavailability, bilobalide may be useful in developing therapy for diseases involving age-associated neurodegeneration.

Ginkgo biloba extract EGb761 protects against mitochondrial dysfunction in platelets and hippocampi in ovariectomized rats.

Using ovariectomized middle-aged rats to mimic the post-menopausal pathophysiological changes in women, we have previously demonstrated that estrogen withdrawal and age-related decrease in the functional reserve of mitochondria might co-operate to induce persistent mitochondrial dysfunction, which may be critical in inducing degenerative processes in the brain later in post-menopausal women. The standardized Ginkgo biloba extract EGb761 has long been considered a natural antioxidant. More recently it has also proposed to have direct protective effects on the mitochondria. In this work, effects of EGb761 on mitochondrial function in platelets and hippocampi of ovariectomized and sham-operated rats were investigated. It was found that EGb761 protected against the decrease of cytochrome c oxidase (COX) activity, mitochondrial ATP (adenosine-5'-triphosphate) content and mitochondrial glutathione (GSH) content in both platelets and hippocampi of ovariectomized rats, suggesting its peripheral and central effects against estrogen withdrawal-induced degeneration. In contrast, in sham-operated rats, EGb761 increased mitochondrial GSH content in platelets but failed to show similar effect on hippocampi, suggesting that EGb761 may help to enhance the functional reserve of mitochondria, but this effect was limited to the outside of the central nervous system. EGb761 displayed similar effects on platelets and hippocampi of ovariectomized rats but showed differential effects on platelets and hippocampi of sham-operated rats, possibly because estrogen withdrawal induced an increase of blood brain barrier (BBB) permeability. Therefore, while EGb761's effect may be limited to the outside of the nervous system under normal physiological conditions, EGb761 may be a potential protective agent against central neurodegeneration in post-menopausal women.

Ginkgo biloba extract EGb761 protects against aging-associated mitochondrial dysfunction in platelets and hippocampi of SAMP8 mice.

Standardized Ginkgo biloba extract, EGb761, has been shown to possess polyvalent properties, such as anti-oxidation, anti-apoptosis and anti-inflammation. Recently, it has also been proposed to have direct protective effects on mitochondria. The effects of EGb761 make it a potential anti-aging drug. Despite that, the 'anti-aging' effect of EGb761, particularly its effect on the central nervous system, is still inconclusive. Using two age groups (3-week-old and 40-week-old) of SAMP8 mice (a senescence-accelerated strain of mice), the effects of EGb761 on mitochondrial function in platelets and hippocampi were investigated in this study. It was found that mitochondrial functions, evaluated as cytochrome c oxidase (COX) activity, mitochondrial ATP (adenosine-5'-triphosphate) content and mitochondrial glutathione (GSH) content, decreased with age. EGb761 protected against mitochondrial dysfunction in platelets of young and old mice, suggesting a peripheral effect of this herb in the prevention and treatment of age-associated degeneration. In contrast, in hippocampi, protective effects of EGb761 were observed only in the old mice, probably due to an age-associated increase in the permeability of the blood brain barrier (BBB). Therefore, while EGb761 has a potential anti-aging effect, its central effect can be affected by in vivo factors such as the BBB permeability. A better understanding of the in vivo pharmacological actions of EGb761 may contribute to a better understanding of the effectiveness and complexity of this drug.

Ethanol extract of Fructus Ligustri Lucidi promotes osteogenesis of mesenchymal stem cells.

Fructus Ligustri Lucidi (FLL) has been used in traditional Chinese medicine for over 1000 years. The ethanol extract of FLL (EFLL) has been shown to be a potential candidate in the prevention and treatment of osteoporosis. The present study aimed to determine whether EFLL carries out the effect by promoting osteogenesis in mesenchymal stem cells (MSCs). The osteogenic differentiation of MSCs was evaluated by their alkaline phosphatase (ALP) activities and mineralization. Expression of genes was detected by RT-PCR. We found that EFLL significantly stimulated the ALP activities and shortened the time needed for the mineralization of MSCs during osteogenic differentiation. The expression of several osteoblast differentiation regulators was also upregulated by EFLL during this process. Our study demonstrated that the EFLL is capable of enhancing osteogenic differentiation of MSCs. It might be useful for treating diseases with inadequate bone formation, including osteoporosis.

Analysis of neuronal nitric oxide synthase expression and increasing astrogliosis in the brain of senescence-accelerated-prone 8 mice.

The senescence-accelerated mouse (SAM) is an autogenic senile murine model characterized by early cognitive impairment and age-related deterioration of learning and memory. The present study investigated the alternations of neuronal nitric oxide synthase (nNOS) expression in frontal cortex and hippocampus in the aging process of SAM-prone 8 (SAMP8) and SAM-resistant 1 (SAMR1) mice. The results demonstrated that the expression of nNOS was upregulated in the frontal cortex, but downregulated in the hippocampus in SAMP8. Further, age-related increases of astrogliosis were seen in the cortex and hippocampi of aged SAMP8 and SAMR1, as revealed by the expression of the astrocyte specific marker, glial fibrillary acidic protein (GFAP). Indeed, astrogliosis in aged SAMP8 was significantly greater than that of aged SAMR1. Our results suggest the possibility of a correlation between the downregulation of nitric oxide (NO) in the hippocampus and reported learning and memory deficits in SAMP8. However, the toxic effects of NO and age-related increases of astrogliosis, may have contributed to abnormal alterations in metabolism and neurochemical mechanisms in aged SAMP8.