GluN2B N‐methyl‐D‐aspartic acid receptor subunit mediates atorvastatin‐Induced neuroprotection after focal cerebral ischemia

Statins are potent cholesterol biosynthesis inhibitors that exert protective effects in humans and in experimental models of stroke. The mechanisms involved in these protective actions are not completely understood. This study evaluates whether atorvastatin (ATV) treatment affects the GluN1 and GluN2B subunits of the N‐methyl‐D‐aspartic acid receptor in the somatosensory cerebral cortex at short and long periods following ischemia. Sham and ischemic male Wistar rats received 10 mg/kg of ATV or placebo by gavage every 24 hr for 3 consecutive days. The first dose was administered 6 hr after ischemia–reperfusion or the sham operation. ATV treatment resulted in faster recovery of neurological scores than placebo, prevented the appearance of pyknotic neurons, and restored microtubule‐associated protein 2 and neuronal nuclei staining to control values in the somatosensory cerebral cortex and the hippocampus at 72 hr and 15 days postischemia. Furthermore, ATV prevented spatial learning and memory deficits caused by cerebral ischemia. Cerebral ischemia reduced the number of GluN1/PSD‐95 and GluN2B/PSD‐95 colocalization clusters in cortical pyramidal neurons and reduced the levels of brain‐derived neurotrophic factor (BDNF) in the cerebral cortex. These effects of the ischemic insult were prevented by ATV, which also induced GluN2B/PSD‐95 colocalization in neuronal processes and an association of GluN2B with TrkB. The GluN2B pharmacological inhibitor ifenprodil prevented the increase in BDNF levels and the motor and cognitive function recovery caused by ATV in ischemic rats. These findings indicate that GluN2B is involved in the neuroprotective mechanism elicited by ATV to promote motor and cognitive recovery after focal cerebral ischemia. © 2014 Wiley Periodicals, Inc.     

3‐[(2,4‐dimethoxy)benzylidene]‐anabaseine dihydrochloride protects against 6‐hydroxydopamine‐induced parkinsonian neurodegeneration through α7 nicotinic acetylcholine receptor stimulation in rats

To explore a novel therapy against Parkinson's disease through enhancement of α7 nicotinic acetylcholine receptor (nAChR), we evaluated the neuroprotective effects of 3‐[(2,4‐dimethoxy)benzylidene]‐anabaseine dihydrochloride (DMXBA; GTS‐21), a functionally selective α7 nAChR agonist, in a rat 6‐hydroxydopamine (6‐OHDA)‐induced hemiparkinsonian model. Microinjection of 6‐OHDA into the nigrostriatal pathway of rats destroys dopaminergic neurons selectively. DMXBA dose dependently inhibited methamphetamine‐stimulated rotational behavior and dopaminergic neuronal loss induced by 6‐OHDA. The protective effects were abolished by methyllycaconitine citrate salt hydrate, an α7 nAChR antagonist. Immunohistochemical study confirmed abundant α7 nAChR expression in the cytoplasm of dopaminergic neurons. These results indicate that DMXBA prevented 6‐OHDA‐induced dopaminergic neuronal loss through stimulating α7 nAChR in dopaminergic neurons. Injection of 6‐OHDA elevated immunoreactivities to glial markers such as ionized calcium binding adaptor molecule 1, CD68, and glial fibrillary acidic protein in the substantia nigra pars compacta of rats. In contrast, these immunoreactivities were markedly inhibited by comicroinjection of DMXBA. Microglia also expressed α7 nAChR in both resting and activated states. Hence, we hypothesize that DMXBA simultaneously affects microglia and dopaminergic neurons and that both actions lead to dopaminergic neuroprotection. The findings that DMXBA attenuates 6‐OHDA‐induced dopaminergic neurodegeneration and glial activation in a rat model of Parkinson's disease raisethe possibility that DMXBA could be a novel therapeutic compound to prevent Parkinson's disease development. © 2012 Wiley Periodicals, Inc.     

The neuroprotection of Rattin against amyloid β peptide in spatial memory and synaptic plasticity of rats

Rattin, a specific derivative of humanin in rats, shares the ability with HN to protect neurons against amyloid β (Aβ) peptide‐induced cellular toxicity. However, it is still unclear whether Rattin can protect against Aβ‐induced deficits in cognition and synaptic plasticity in rats. In the present study, we observed the effects of Rattin and Aβ31–35 on the spatial reference memory and in vivo hippocampal Long‐term potentiation of rats by using Morris water maze test and hippocampal field potential recording. Furthermore, the probable molecular mechanism underlying the neuroprotective roles of Rattin was investigated. We showed that intra‐hippocampal injection of Rattin effectively prevented the Aβ31–35‐induced spatial memory deficits and hippocampal LTP suppression in rats; the Aβ31–35‐induced activation of Caspase‐3 and inhibition of STAT3 in the hippocampus were also prevented by Rattin treatment. These findings indicate that Rattin treatment can protect spatial memory and synaptic plasticity of rats against Aβ31–35‐induced impairments, and the underlying protective mechanism of Rattin may be involved in STAT3 and Caspases‐3 pathways. Therefore, application of Rattin or activation of its signaling pathways in the brain might be beneficial to the prevention of Aβ‐related cognitive deficits. © 2013 Wiley Periodicals, Inc.     

γ‐aminobutyric acid‐mediated neurotransmission in cerebellar–hypothalamic circuit attenuates gastric mucosal injury induced by ischemia‐reperfusion

Background Excessive greater splanchnic nerve (GSN) activation contributes to the progression of gastric ischemia‐reperfusion (GI‐R) injury. This study was designed to investigate the protective mechanism of cerebellar fastigial nucleus (FN) stimulation against GI‐R injury. Methods The GI‐R injury model was induced in rats by clamping the celiac artery for 30 min, and then reperfusion for 30 min, 1, 3, 6, or 24 h, respectively. Key Results Microinjection of l ‐Glu (3, 6, 12 μg) into the FN dose‐dependently attenuated GI‐R injury and GSN activity. In addition, there was an enhancement of gastric mucosal blood flow in GI‐R rats. Pretreatment with the glutamic acid decarboxylase antagonist into the FN, the GABA_A receptor antagonist into the lateral hypothalamic area or lesion of superior cerebellar peduncle all reversed the protective effects of the FN stimulation. Furthermore, the FN stimulation reduced the TUNEL‐positive gastric mucosal cell and Bax‐positive gastric mucosal cell in GI‐R rats. Conclusions & Inferences These results indicate that the protective effects of the FN stimulation against GI‐R injury may be mediated by attenuation of the excessive GSN activation, gastric mucosal cell apoptosis, and Bax expression in GI‐R rats.     

Pranlukast, a cysteinyl leukotriene receptor-1 antagonist, protects against chronic ischemic brain injury and inhibits the glial scar formation in mice

We have recently reported the neuroprotective effect of pranlukast (ONO-1078), a cysteinyl leukotriene receptor-1 (CysLT1) antagonist, on cerebral ischemia in rats and mice. In this study, we further determined whether the effect of pranlukast is long lasting and related to the formation of a glial scar in cerebral ischemic mice. Focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO). After ischemia, pranlukast (0.1 mg/kg) was injected intraperitoneally for 5 consecutive days. Neurological deficits and sensorimotor function were determined during 70 days after ischemia. Brain lesion and glial scar formation were detected at the end of the experiment. Pranlukast did not reduce mortality, but significantly improved neurological deficits and promoted sensorimotor recovery during 70 days. At the end of the experiment, pranlukast significantly reduced lesion volume, and increased neuron densities in the cortex and hippocampal CA1 region in the ischemic hemispheres. Importantly, pranlukast also remarkably reduced the thickness of a scar wall in the ischemic hemispheres. These findings indicate that pranlukast has a long-lasting protective effect on focal cerebral ischemia in mice, and inhibit the ischemia-induced glial scar formation, providing further evidence of the therapeutic potential of pranlukast in the treatment of ischemic stroke.     

NG2 and NG2‐positive cells delineate focal cerebral infarct demarcation in rats

Focal cerebral ischemia induces cellular responses that may result in secondary tissue damage. We recently demonstrated multi‐facetted spatial and temporal patterns of neuroinflammation by multimodal imaging. In the present study, we especially focus on the separation of vital and necrotic tissue, which enabled us to define a demarcation zone. Focal cerebral ischemia was induced via macrosphere embolization of the middle cerebral artery in Wistar rats. Subsequent cellular processes were investigated immunohistochemically from 3 to 56 days after onset of ischemia. We detected several infarct subareas: a necrotic infarct core and its margin adjacent to a nerve/glial antigen 2 (NG2)+ zone delineating it from a vital peri‐infarct zone. Initially transition from necrotic to vital tissue was gradual; later on necrosis was precisely separated from vital tissue by a narrow NG2+ belt that was devoid of astrocytes, oligodendrocytes or neurons. Within this demarcation zone NG2+ cells associate with ionized calcium binding adaptor molecule 1 (Iba1) but not with GFAP, neuronal nuclear antigen (NeuN) or 2′, 3′‐cyclic nucleotide 3′‐phosphodiesterase (CNPase). During further infarct maturation NG2 seemed to be positioned in the extracellular matrix (ECM) of the demarcation zone, whereas Iba1+ cells invaded the necrotic infarct core and GFAP+ cells built a gliotic containing belt between the lesion and NeuN+ unaffected tissue. Overall, our data suggested that NG2 proteoglycan expression and secretion hallmarked demarcation as a process that actively separated necrosis from vital tissue and therefore decisively impacts secondary neurodegeneration after ischemic stroke.     

Suppression of hypoxia‐inducible factor‐1α and its downstream genes reduces acute hyperglycemia‐enhanced hemorrhagic transformation in a rat model of cerebral ischemia

We evaluated a role of hypoxia‐inducible factor‐1α (HIF‐1α) and its downstream genes in acute hyperglycemia‐induced hemorrhagic transformation in a rat model of focal cerebral ischemia. Male Sprague‐Dawley rats weighing 280–300 g (n = 105) were divided into sham, 90 min middle cerebral artery occlusion (MCAO), MCAO plus HIF‐1α inhibitors, 2‐methoxyestradiol (2ME2) or 3‐(5′‐hydroxymethyl‐2′‐furyl)‐1‐benzylindazole (YC‐1), groups. Rats received an injection of 50% dextrose (6 ml/kg intraperitoneally) at 15 min before MCAO. HIF‐1α inhibitors were administered at the onset of reperfusion. The animals were examined for neurological deficits and sacrificed at 6, 12, 24, and 72 hr following MCAO. The cerebral tissues were collected for histology, zymography, and Western blot analysis. The expression of HIF‐1α was increased in ischemic brain tissues after MCAO and reduced by HIF‐1α inhibitors. In addition, 2ME2 reduced the expression of vascular endothelial growth factor (VEGF) and the elevation of active matrix metalloproteinase‐2 and ?9 (MMP‐2/MMP‐9) in the ipsilateral hemisphere. Both 2ME2 and YC‐1 reduced infarct volume and ameliorated neurological deficits. However, only 2ME2 attenuated hemorrhagic transformation in the ischemic territory. In conclusion, the inhibition of HIF‐1α and its downstream genes attenuates hemorrhagic conversion of cerebral infarction and ameliorates neurological deficits after focal cerebral ischemia. © 2010 Wiley‐Liss, Inc.     

Water maze experience and prenatal choline supplementation differentially promote long‐term hippocampal recovery from seizures in adulthood

Status epilepticus (SE) in adulthood dramatically alters the hippocampus and produces spatial learning and memory deficits. Some factors, like environmental enrichment and exercise, may promote functional recovery from SE. Prenatal choline supplementation (SUP) also protects against spatial memory deficits observed shortly after SE in adulthood, and we have previously reported that SUP attenuates the neuropathological response to SE in the adult hippocampus just 16 days after SE. It is unknown whether SUP can ameliorate longer‐term cognitive and neuropathological consequences of SE, whether repeatedly engaging the injured hippocampus in a cognitive task might facilitate recovery from SE, and whether our prophylactic prenatal dietary treatment would enable the injured hippocampus to more effectively benefit from cognitive rehabilitation. To address these issues, adult offspring from rat dams that received either a control (CON) or SUP diet on embryonic days 12–17 first received training on a place learning water maze task (WM) and were then administered saline or kainic acid (KA) to induce SE. Rats then either remained in their home cage, or received three additional WM sessions at 3, 6.5, and 10 weeks after SE to test spatial learning and memory retention. Eleven weeks after SE, the brains were analyzed for several hippocampal markers known to be altered by SE. SUP attenuated SE‐induced spatial learning deficits and completely rescued spatial memory retention by 10 weeks post‐SE. Repeated WM experience prevented SE‐induced declines in glutamic acid decarboxylase (GAD) and dentate gyrus neurogenesis, and attenuated increased glial fibrilary acidic protein (GFAP) levels. Remarkably, SUP alone was similarly protective to an even greater extent, and SUP rats that were water maze trained after SE showed reduced hilar migration of newborn neurons. These findings suggest that prophylactic SUP is protective against the long‐term cognitive and neuropathological effects of KA‐induced SE, and that rehabilitative cognitive enrichment may be partially beneficial. © 2010 Wiley‐Liss, Inc.     

MicroRNA‐365 modulates astrocyte conversion into neuron in adult rat brain after stroke by targeting Pax6

Reactive astrocytes induced by ischemia can transdifferentiate into mature neurons. This neurogenic potential of astrocytes may have therapeutic value for brain injury. Epigenetic modifications are widely known to involve in developmental and adult neurogenesis. PAX6, a neurogenic fate determinant, contributes to the astrocyte‐to‐neuron conversion. However, it is unclear whether microRNAs (miRs) modulate PAX6‐mediated astrocyte‐to‐neuron conversion. In the present study we used bioinformatic approaches to predict miRs potentially targeting Pax6, and transient middle cerebral artery occlusion (MCAO) to model cerebral ischemic injury in adult rats. These rats were given striatal injection of glial fibrillary acidic protein targeted enhanced green fluorescence protein lentiviral vectors (Lv‐GFAP‐EGFP) to permit cell fate mapping for tracing astrocytes‐derived neurons. We verified that miR‐365 directly targets to the 3′‐UTR of Pax6 by luciferase assay. We found that miR‐365 expression was significantly increased in the ischemic brain. Intraventricular injection of miR‐365 antagomir effectively increased astrocytic PAX6 expression and the number of new mature neurons derived from astrocytes in the ischemic striatum, and reduced neurological deficits as well as cerebral infarct volume. Conversely, miR‐365 agomir reduced PAX6 expression and neurogenesis, and worsened brain injury. Moreover, exogenous overexpression of PAX6 enhanced the astrocyte‐to‐neuron conversion and abolished the effects of miR‐365. Our results demonstrate that increase of miR‐365 in the ischemic brain inhibits astrocyte‐to‐neuron conversion by targeting Pax6, whereas knockdown of miR‐365 enhances PAX6‐mediated neurogenesis from astrocytes and attenuates neuronal injury in the brain after ischemic stroke. Our findings provide a foundation for developing novel therapeutic strategies for brain injury.     

Neuroprotection against permanent focal cerebral ischemia by ginkgolides A and B is associated with obstruction of the mitochondrial apoptotic pathway via inhibition of c‐Jun N‐terminal kinase in rats

We have previously reported that ginkgolides containing ginkgolides A and B (GKAB) reduce infarct size in a rat model of focal ischemia. c‐Jun N‐terminal kinase (JNK), also known as stress‐activated kinase (SAPK), is a critical stress‐responsive kinase activated by various brain insults. Previous studies have demonstrated a brief increase in p‐SAPK/JNK levels after focal ischemic brain injuries. In this study, we sought to investigate whether the neuroprotective effects of GKAB in rat models of permanent focal cerebral ischemia are associated with the JNK signaling pathway. Sprague‐Dawley rats were subjected to permanent middle cerebral artery occlusion by intraluminal suture blockade. GKAB was injected intravenously immediately after ischemia onset. Here we demonstrate in rats that GKAB reduces neuronal apoptosis and blocks the increase of p‐SAPK/JNK levels and nuclear translocation after cerebral ischemia in a dose‐dependent manner. Furthermore, we report that cerebral ischemia increases ischemia‐induced induction of reactive oxygen species, and this effect was blocked by GKAB. In addition, we show that BimL is induced and attenuated by GKAB. GKAB also repressed the ischemia‐induced increase in the expression of Bax and reversed the decline in expression of Bcl‐2. Likewise, there was a reduction in the release or activation of several mitochondrial proapoptotic molecules, including cytochrome c, caspases 3 and 9, and PARP. Taken together, our findings strongly suggest that GKAB‐mediated neuroprotective effects against focal ischemia act through the inhibition of p‐SAPK/JNK activation, in which the obstruction of the mitochondrial apoptotic pathway via the JNK signaling pathway is a key downstream mechanism of GKAB. © 2013 Wiley Periodicals, Inc.     

2‐Phenylethynyl‐butyltellurium attenuates amyloid‐β peptide(25–35)‐induced learning and memory impairments in mice

Our previous study demonstrated that 2‐phenylethynyl‐butyltellurium (PEBT), an organotellurium compound, enhances memory in mice. In this study, the effects of PEBT on cognitive impairment induced by Aβ_25–35 were assessed by Morris water maze and step‐down inhibitory avoidance tasks. Mice received a single intracerebroventricular injection of Aβ_25–35 (3 nmol/3 μl/per site) and a daily oral administration of PEBT (1 mg/kg, for 10 days). PEBT significantly improved Aβ‐induced learning deficits on the training session in the Morris water maze. At the probe trial session, PEBT significantly decreased the escape latency and increased the number of crossings in the platform local compared with the Aβ‐treated group. PEBT significantly improved Aβ‐induced memory impairment in the step‐down inhibitory avoidance task. General locomotor activity was similar in all groups. This study showed that PEBT ameliorated the impairments of spatial and nonspatial long‐term memory evaluated on Morris water maze and step‐down inhibitory avoidance tasks, respectively. The results suggest that PEBT could be considered a candidate for the prevention of memory deficits such as those observed in Alzheimer's disease. © 2013 Wiley Periodicals, Inc.     

Achyranthes bidentata polypeptides confer neuroprotection through inhibition of reactive oxygen species production,Bax expression,and mitochondrial dysfunction induced by overstimulation of N‐methyl‐D‐aspartate receptors

Achyranthes bidentata polypeptides (ABPP), the important constituents separated from the aqueous extract of Achyranthes bidentata, have been shown to attenuate N‐methyl‐D‐aspartate (NMDA)‐induced cell apoptosis in cultured hippocampal neurons through differential modulation of NR2A‐ and NR2B‐containing NMDA receptors. The present study sought to investigate the possible mechanism underlying the neuroprotective effect of ABPP on NMDA‐induced cell death. Western blot analysis and colorimetric enzymatic assay demonstrated that ABPP pretreatment inhibited NMDA‐induced increase of Bax protein expression or caspase‐3 activity in cultured hippocampal neurons. Fluorescence measurements after staining with 2,7‐dichlorofluorescin diacetate and rhodamine 123 showed that ABPP treatment also reversed NMDA‐induced intracellular radical oxygen species (ROS) elevation and mitochondrial membrane potential depression in cultured hippocampal neurons. Furthermore, the in vivo effects of ABPP on cerebral neuronal damage during focal ischemia‐reperfusion were also investigated. In rat middle cerebral artery occlusion (MCAO) model, ABPP attenuated the increase in the neurological deficit and cerebral infarction induced by focal ischemia‐reperfusion, showing in vivo neuroprotective effects. The results collectively suggest that ABPP might exert neuroprotective actions through inhibiting Bax protein expression, caspase‐3 activity, ROS production, and mitochondrial dysfunction that are all caused by overstimulation of NMDA receptors. © 2009 Wiley‐Liss, Inc.     

Mild hypothermia mitigates post‐ischemic neuronal death following focal cerebral ischemia in rat brain: Immunohistochemical study of Fas,caspase‐3 and TUNEL

Mild hypothermia is considered to have a protective effect during ischemic neuronal cell death. The present study provides experimental evidence for this beneficial role of mild hypothermia using reversible middle cerebral artery occlusion (MCAo) in a Sprague–Dawley (SD) rat model. MCAo was induced in rats for 1 h followed by reperfusion at different periods. Hematoxylin–eosin (HE) staining in normothermic (NT) 37°C and hypothermic (HT) 33°C groups of rats confirmed cerebral infarcts. The mean per cent infarct area was significantly reduced in the HT group of rats. Immunohistochemical analysis was done using anti‐Fas and caspase‐3 antibodies. The immunohistochemical expression of Fas and caspase‐3 was demonstrable as early as 5 h after reperfusion, but the expression pattern maximized at 24 h after reperfusion. The expression of Fas and caspase‐3 proteins showed a clear decrease in the HT group over the NT group. In situ detection of DNA fragmentation was done using the terminal deoxy‐nucleotidyl transferase‐mediated dUTP‐biotin nick end‐ labeling method (TUNEL). TUNEL‐positive cells were first observed at 5 h after reperfusion and progressively increased by 24 h. A higher number of TUNEL‐positive cells was found in the NT group, but they were significantly decreased in the HT group. Further, DNA fragmentation was confirmed by size fractionation in agarose gel. These findings demonstrate a positive relation between the expression of Fas, caspase‐3 and TUNEL‐positive cells. Mild expression of Fas and caspase‐3 proteins and a reduced number of TUNEL‐positive cells in the HT group is clear evidence for the protective role of hypothermia in ischemia‐induced cell death.     

(+)‐Methamphetamine‐induced monoamine reductions and impaired egocentric learning in adrenalectomized rats is independent of hyperthermia

Methamphetamine (MA) is widely abused and implicated in residual cognitive deficits. In rats, increases in plasma corticosterone and egocentric learning deficits are observed after a 1‐day binge regimen of MA (10 mg/kg × 4 at 2‐h intervals). The purpose of this experiment was to determine if adrenal inactivation during and following MA exposure would attenuate the egocentric learning deficits in the Cincinnati water maze (CWM). In the first experiment, the effects of adrenalectomy (ADX) or sham surgery (SHAM) on MA‐induced neurotoxicity at 72 h were determined. SHAM‐MA animals showed typical patterns of hyperthermia, whereas ADX‐MA animals were normothermic. Both SHAM‐MA‐ and ADX‐MA‐treated animals showed increased neostriatal glial fibrillary acidic protein and decreased monoamines in the neostriatum, hippocampus, and entorhinal cortex. In the second experiment, SHAM‐MA‐ and ADX‐MA‐treated groups showed equivalently impaired CWM performance 2 weeks post‐treatment (increased latencies, errors, and start returns) compared to SHAM‐saline (SAL) and ADX‐SAL groups with no effects on novel object recognition, elevated zero maze, or acoustic startle/prepulse inhibition. Post‐testing, monoamine levels remained decreased in both MA‐treated groups in all three brain regions, but were not as large as those observed at 72‐h post‐treatment. The data demonstrate that MA‐induced learning deficits can be dissociated from drug‐induced increases in plasma corticosterone or hyperthermia, but co‐occur with dopamine and serotonin reductions. Synapse 64:773–785, 2010. © 2010 Wiley‐Liss, Inc.     

The phosphodiesterase type 2 inhibitor BAY 60‐7550 reverses functional impairments induced by brain ischemia by decreasing hippocampal neurodegeneration and enhancing hippocampal neuronal plasticity

Cognitive and affective impairments are the most characterized consequences following cerebral ischemia. BAY 60‐7550, a selective phosphodiesterase type 2 inhibitor (PDE2‐I), presents memory‐enhancing and anxiolytic‐like properties. The behavioral effects of BAY 60‐7550 have been associated with its ability to prevent hydrolysis of both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) thereby interfering with neuronal plasticity. Here, we hypothesize that PDE2‐I treatment could promote functional recovery after brain ischemia. Mice C57Bl/6 were submitted to bilateral common carotid artery occlusion (BCCAO), an experimental model of transient brain ischemia, for 20 min. During 21 days after reperfusion, the animals were tested in a battery of behavioral tests including the elevated zero maze (EZM), object location task (OLT) and forced swim test (FST). The effects of BAY 60‐7550 were evaluated on neuronal nuclei (NeuN), caspase‐9, cAMP response element‐binding protein (CREB), phosphorylated CREB (pCREB) and brain‐derived neurotrophic factor (BDNF) expression in the hippocampus. BCCAO increased anxiety levels, impaired hippocampus‐dependent cognitive function and induced despair‐like behavior in mice. Hippocampal neurodegeneration was evidenced by a decrease in NeuN and increase incaspase‐9 protein levels in BCCAO mice. Ischemic mice also showed low BDNF protein levels in the hippocampus. Repeated treatment with BAY 60‐7550 attenuated the behavioral impairments induced by BCCAO in mice. Concomitantly, BAY 60‐7550 enhanced expression of pCREB and BDNF protein levels in the hippocampus of ischemic mice. The present findings suggest that chronic inhibition of PDE2 provides functional recovery in BCCAO mice possibly by augmenting hippocampal neuronal plasticity.     

Soybean isoflavone ameliorates β‐amyloid 1‐42‐induced learning and memory deficit in rats by protecting synaptic structure and function

This research aims to investigate whether soybean isoflavone (SIF) could alleviate the learning and memory deficit induced by β‐amyloid peptides 1‐42 (Aβ1‐42) by protecting the synapses of rats. Adult male Wistar rats were randomly allocated to the following groups: (1) control group; (2) Aβ1‐42 group; (3) SIF group; (4) SIF + Aβ1‐42 group (SIF pretreatment group) according to body weight. The 80 mg/kg/day of SIF was administered orally by gavage to the rats in SIF and SIF+Aβ1‐42 groups. Aβ1‐42 was injected into the lateral cerebral ventricle of rats in Aβ1‐42 and SIF+Aβ1‐42 groups. The ability of learning and memory, ultramicrostructure of hippocampal synapses, and expression of synaptic related proteins were investigated. The Morris water maze results showed the escape latency and total distance were decreased in the rats of SIF pretreatment group compared to the rats in Aβ1‐42 group. Furthermore, SIF pretreatment could alleviate the synaptic structural damage and antagonize the down‐regulation expressions of below proteins induced by Aβ1‐42: (1) mRNA and protein of the synaptophysin and postsynaptic density protein 95 (PSD‐95); (2) protein of calmodulin (CaM), Ca²⁺/calmodulin‐dependent protein kinase II (CaMK II), and cAMP response element binding protein (CREB); (3) phosphorylation levels of CaMK II and CREB (pCAMK II, pCREB). These results suggested that SIF pretreatment could ameliorate the impairment of learning and memory ability in rats induced by Aβ1‐42, and its mechanism might be associated with the protection of synaptic plasticity by improving the synaptic structure and regulating the synaptic related proteins. Synapse 67:856–864, 2013 . © 2013 Wiley Periodicals, Inc.     

Acyl ghrelin improves cognition,synaptic plasticity deficits and neuroinflammation following amyloid β (Aβ1‐40) administration in mice

Ghrelin is a metabolic hormone that has neuroprotective actions in a number of neurological conditions, including Parkinson's disease (PD), stroke and traumatic brain injury. Acyl ghrelin treatment in vivo and in vitro also shows protective capacity in Alzheimer's disease (AD). In the present study, we used ghrelin knockout (KO) and their wild‐type littermates to test whether or not endogenous ghrelin is protective in a mouse model of AD, in which human amyloid β peptide 1‐40 (Aβ_1‐40) was injected into the lateral ventricles i.c.v. Recognition memory, using the novel object recognition task, was significantly impaired in ghrelin KO mice and after i.c.v. Aβ_1‐40 treatment. These deficits could be prevented by acyl ghrelin injections for 7 days. Spatial orientation, as assessed by the Y‐maze task, was also significantly impaired in ghrelin KO mice and after i.c.v. Aβ_1‐40 treatment. These deficits could be prevented by acyl ghrelin injections for 7 days. Ghrelin KO mice had deficits in olfactory discrimination; however, neither i.c.v. Aβ_1‐40 treatment, nor acyl ghrelin injections affected olfactory discrimination. We used stereology to show that ghrelin KO and Aβ_1‐40 increased the total number of glial fibrillary acidic protein expressing astrocytes and ionised calcium‐binding adapter expressing microglial in the rostral hippocampus. Finally, Aβ_1‐40 blocked long‐term potentiation induced by high‐frequency stimulation and this effect could be acutely blocked with co‐administration of acyl ghrelin. Collectively, our studies demonstrate that ghrelin deletion affects memory performance and also that acyl ghrelin treatment may delay the onset of early events of AD. This supports the idea that acyl ghrelin treatment may be therapeutically beneficial with respect to restricting disease progression in AD.     

Flupirtine reduces functional deficits and neuronal damage after global ischemia in rats

Global cerebral ischemia leads to selective neuronal damage in the CA1 sector of the hippocampus and in the dorsolateral striatum. In addition, it results in deficits in spatial learning and memory as shown by an increase in escape latency and swim distance during the escape trials and a reduction of time spent in the quadrant of the former platform position during the probe trial of the water maze. Flupirtine is a non-opioid, centrally acting analgesic which has been shown to be neuroprotective against N-methyl-

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-aspartate (NMDA)-mediated toxicity in vitro. The purpose of the present study was to investigate the potential protective effect of flupirtine in vivo with both behavioural and histological measures of global cerebral ischemia. Global ischemia was induced by four-vessel-occlusion (4VO) for 20 min in rats. Flupirtine was administered at a dose of 5 mg/kg i.p. either 20 min before and 50 min after occlusion (pre-treatment) or directly and 70 min after occlusion (post-treatment). 1 week after surgery, spatial learning and memory was tested in the Morris water maze. Pre-treatment with flupirtine reduced the increase in escape latency and in swim distance induced by 4VO. It also diminished the deficit in spatial memory as revealed by an increase in time spent in the quadrant of the former platform position during the probe trial which was reduced by 4VO. Post-treatment with flupirtine had no effect on the deficits in spatial learning and memory induced by 4VO. Neuronal damage in the CA1 sector of the hippocampus and in the striatum produced by 4VO was significantly attenuated with pre-treatment of flupirtine whereas post-treatment did not affect this neuronal damage. The present data demonstrate that pre-treatment with flupirtine exerts a protective effect on hippocampal and striatal neuronal damage and on deficits in spatial learning induced by 4VO. © 1997 Elsevier Science B.V. All rights reserved.     

Melatonin protects against amyloid‐β‐induced impairments of hippocampal LTP and spatial learning in rats

Alzheimer's disease (AD), the most prevalent neurodegenerative disease in the elderly, leads to progressive loss of memory and cognitive deficits. Amyloid‐β protein (Aβ) in the brain is thought to be the main cause of memory loss in AD. Melatonin, an indole hormone secreted by the pineal gland, has been reported to produce neuroprotective effects. We examined whether melatonin could protect Aβ‐induced impairments of hippocampal synaptic plasticity, neuronal cooperative activity, and learning and memory. Rats received bilateral intrahippocampal injection of Aβ1‐42 or Aβ31‐35 followed by intraperitoneal application of melatonin for 10 days, and the effects of chronic melatonin treatment on in vivo hippocampal long‐term potentiation (LTP) and theta rhythm and Morris water maze performance were examined. We showed that intrahippocampal injection of Aβ1‐42 or Aβ31‐35 impaired hippocampal LTP in vivo, while chronic melatonin treatment reversed Aβ1‐42‐ or Aβ31‐35‐induced impairments in LTP induction. Intrahippocampal injection of Aβ31‐35 impaired spatial learning and decreased the power of theta rhythm in the CA1 region induced by tail pinch, and these synaptic, circuit, and learning deficits were rescued by chronic melatonin treatment. These results provide evidence for the neuroprotective action of melatonin against Aβ insults and suggest a strategy for alleviating cognition deficits of AD. Synapse 67:626–636, 2013 . © 2013 Wiley Periodicals, Inc.