The effect of alprostadil on perihematomal tissue of experimental intracerebral hemorrhage in rats

Objective To investigate the effect of alprostadil on perihematomal tissue of experimental intracerebral hemorrhage (ICH) in rats. Methods The ICH was induced by stereotaxic infusion of autologous arterial blood into the right basal ganglion. Forelimb placing test and corner turn test were used as behavioral tests. The rats were tested at 3, 5, 7 and 14 d after ICH. Nissl staining was performed to observe the neuronal morphological changes in perihematomal tissue. Immunofluorescence staining was used to determine the number and distribution of tumor necrosis factor ⁃ α (TNF ⁃ α) and interleukin⁃6 (IL⁃6) positive cells in perihematomal tissue at 3, 5, 7 and 14 d. Results Alprostadil⁃treated group showed significant improvement in behavioral tests at 5, 7 and 14 d compared with the control group (P < 0.05 or P < 0.01), but there was no significant difference at 3 d (P = 0.788, 1.000). Nissl staining showed that after cerebral hemorrhage there were obvious inflammatory infiltration, tissue necrosis presented as a "compressed zone" in the perihematomal tissue, and cells around the zone were swollen and had no apparent profile. After alprostadil treatment inflammatory cell infiltration and swollen neurons were reduced in different degrees. Along with the duration of treatment, neuron gradually increased in cortical area beside the medial fissure ipsilateral to the hemorrhagic side, and achieved approximately to normal level at the end of the therapy (P = 0.650). TNF ⁃ α and IL ⁃6 positive cells were mainly distributed around the hematoma, while there were few positive cells at the distal and contralateral site. After administration of alprostadil TNF⁃α positive cells decreased and IL⁃6 positive cells increased in perihematomal region, and all nearly reached to normal level as the control group at 7 d (P = 0.035, 0.023) and 14 d (P = 0.024, 0.020). Conclusion Alprostadil can improve neurological function of cerebral hemorrhagic rats. The mechanisms may be related to the suppression of acute inflammation and relief of secondary neuron injury around hematomal tissue. DOI：10.3969/j.issn.1672-6731.2011.03.01

NOS1AP O-GlcNAc Modification Involved in Neuron Apoptosis Induced by Excitotoxicity

O-Linked N-acetylglucosamine, or O-GlcNAc, is a dynamic post-translational modification that cycles on and off serine and threonine residues of nucleocytoplasmic and mitochondrial proteins. In addition to cancer and inflammation diseases, O-GlcNAc modification appears to play a critical role during cell apoptosis and stress response, although the precise mechanisms are still not very clear. Here we found that nitric oxide synthase adaptor (NOS1AP), which plays an important part in glutamate-induced neuronal apoptosis, carries the modification of O-GlcNAc. Mass spectrometry analysis identified Ser47, Ser183, Ser204, Ser269, Ser271 as O-GlcNAc sites. Higher O-GlcNAc of NOS1AP was detected during glutamate-induced neuronal apoptosis. Furthermore, with O-GlcNAc sites of NOS1AP mutated, the interaction of NOS1AP and neuronal nitric oxide syntheses (nNOS) decreases. Finally, during glutamate-induced neuronal apoptosis, decreasing the O-GlcNAc modification of NOS1AP results in more severe neuronal apoptosis. All these results suggest that O-GlcNAc modification of NOS1AP exerts protective effects during glutamate-induced neuronal apoptosis

Berberine Ameliorates Diabetes-Associated Cognitive Decline through Modulation of Aberrant Inflammation Response and Insulin Signaling Pathway in DM Rats

Background: Memory-impairment was one of the common characteristics in patients with diabetes mellitus. The release of chronic inflammation mediators and insulin resistance in diabetic brain gave rise to the generation of toxic factor Aβ42 which was the marker of Alzheimer’s disease. In addition, the impairment of memory in diabetes mellitus was also correlated predominantly with uptake/metabolism of glucose in medial prefrontal cortex (mPFC). Previously, anti-inflammation and hypoglycemic effects of berberine (BBr) have been described in peripheral tissues. For better understanding the effects of BBr on cognitive action in diabetics, we investigated the functions of BBr involved in anti-inflammation and ameliorating insulin resistance in prefrontal cortex of diabetic rats.Methods: Intragastric administration of BBr (187.5 mg/Kg/d) was used in diabetic rats. Fear-condition assay was applied for cognitive assessment, and relative protein expressions were detected by western-blot. The glucose uptake in prefrontal cortex of diabetic rats was tested by Positron-Emission Tomography imaging. The levels of inflammation mediators were determined by commercial ELISA kits.Results: The inflammation mediator release and insulin resistance in the mPFC of diabetic rats was inhibited by BBr. The activation of PI3K/Akt/mTOR and MAPK signaling pathway, as well as two novel isoforms PKCη and PKC and the translocation of NF-κB in neuron were also down-regulated by BBr; furthermore, the neuron specific glucose transporter GLUT3 was remarkably augmented by 2–3 times when compared with diabetic group; meanwhile, BBr also promoted glucose uptake in the brain. Additionally BBr decreased the expressions of amyloid precursor protein and BACE-1, and the production of oligomeric Aβ42. Finally, it accelerates the reinforcement of the information and ameliorates cognitive impairment.Conclusion: BBr inhibited the activation of inflammation pathway and insulin resistance in the mPFC of diabetic rats. Finally, it improved the lesion of cognition in diabetic rats

SSTR2 associated with neuronal apoptosis after intracerebral hemorrhage in adult rats

<p>SSTR2 is a member of superfamily of SST receptor (SSTR), and widely expressed in the brain; however, the knowledge of its functions in area adjacent to hematoma after intracerebral hemorrhage (ICH) is still limited.</p> <p>The role of SSTR2 in the processes of ICH was explored by conducting an ICH rat model. Western blot and immunohistochemistry were employed to examine the level of SSTR2 in area adjacent to hematoma after ICH. Immunofluorescent staining was used to observe the spatial correlation of SSTR2 with cellular types adjacent to hematoma after ICH. RNA interference specific to SSTR2 was adopted in PC12 cells to clarify the causal correlation between SSTR2 and neuronal activities.</p> <p>Increased expression of SSTR2 was observed and restricted to the neurons adjacent to hematoma following ICH. Immunofluorescent staining showed that SSTR2 was significant increased in neurons, but not astrocytes or microglia. Increasing SSTR2 level was found to be accompanied by the up-regulation of activated caspase-3 and the down-expression of p-Akt in a time-dependent manner. What’s more, using SSTR2 RNA interference (SSTR2-RNAi) in PC12 cells, we indicated that SSTR2 might have a pro-apoptotic role in neurons.</p> <p>We speculated that SSTR2 might exert its pro-apoptotic function in neurons through inhibiting Akt activity following ICH.</p

Revised stratigraphy and chronology for Homo floresiensis at Liang Bua in Indonesia

Homo floresiensis, a primitive hominin species discovered in Late Pleistocene sediments at Liang Bua (Flores, Indonesia)1,2,3, has generated wide interest and scientific debate. A major reason this taxon is controversial is because the H. floresiensis-bearing deposits, which include associated stone artefacts2,3,4 and remains of other extinct endemic fauna5,6, were dated to between about 95 and 12 thousand calendar years (kyr) ago2,3,7. These ages suggested that H. floresiensis survived until long after modern humans reached Australia by ~50 kyr ago8,9,10. Here we report new stratigraphic and chronological evidence from Liang Bua that does not support the ages inferred previously for the H. floresiensis holotype (LB1), ~18 thousand calibrated radiocarbon years before present (kyr cal. BP), or the time of last appearance of this species (about 17 or 13–11 kyr cal. BP)1,2,3,7,11. Instead, the skeletal remains of H. floresiensis and the deposits containing them are dated to between about 100 and 60 kyr ago, whereas stone artefacts attributable to this species range from about 190 to 50 kyr in age. Whether H. floresiensis survived after 50 kyr ago—potentially encountering modern humans on Flores or other hominins dispersing through southeast Asia, such as Denisovans12,13—is an open question