Toxic effect of acrylamide on the development of hippocampal neurons of weaning rats

Although numerous studies have examined the neurotoxicity of acrylamide in adult animals,the effects on neuronal development in the embryonic and lactational periods are largely unknown.Thus,we examined the toxicity of acrylamide on neuronal development in the hippocampus of fetal rats during pregnancy.Sprague-Dawley rats were mated with male rats at a 1：1 ratio.Rats were administered 0,5,10 or 20 mg/kg acrylamide intragastrically from embryonic days 6–21.The gait scores were examined in pregnant rats in each group to analyze maternal toxicity.Eight weaning rats from each group were also euthanized on postnatal day 21 for follow-up studies.Nissl staining was used to observe histological change in the hippocampus.Immunohistochemistry was conducted to observe the condition of neurites,including dendrites and axons.Western blot assay was used to measure the expression levels of the specific nerve axon membrane protein,growth associated protein 43,and the presynaptic vesicle membrane specific protein,synaptophysin.The gait scores of gravid rats significantly increased,suggesting that acrylamide induced maternal motor dysfunction.The number of neurons,as well as expression of growth associated protein 43 and synaptophysin,was reduced with increasing acrylamide dose in postnatal day 21 weaning rats.These data suggest that acrylamide exerts dose-dependent toxic effects on the growth and development of hippocampal neurons of weaning rats.

Myricetin protects hippocampal CA3 pyramidal neurons and improves learning and memory impairments in rats with Alzheimer's disease

There is currently no treatment for effectively slowing the progression of Alzheimer＇s disease, so early prevention is very important. Numerous studies have shown that flavonoids can improve memory impairment. The present study investigated the effects of myricetin, a member of the flavonoids, on intracerebroventricular streptozotocin induced neuronal loss and memory impairment in rat models of Alzheimer＇s disease. Myricetin at 5 or 10 mg/kg was intraperitoneally injected into rats over 21 days. Control rats were treated with 10 m L/kg saline. Behavioral test（the shuttle box test） was performed on day 22 to examine learning and memory in rats. Immediately after that, hematoxylin-eosin staining was performed to observe the morphological change in hippocampal CA3 pyramidal neurons. Myricetin greatly increased the number of hippocampal CA3 pyramidal neurons and improved learning and memory impairments in rats with Alzheimer＇s disease. These findings suggest that myricetin is beneficial for treatment of Alzheimer＇s disease.

Neuroprotective effects of ischemic preconditioning on hippocampal CA1 pyramidal neurons through maintaining calbindin D28k immunoreactivity following subsequent transient cerebral ischemia

Ischemic preconditioning elicited by a non-fatal brief occlusion of blood flow has been applied for an experimental therapeutic strategy against a subsequent fatal ischemic insult. In this study, we investigated the neuroprotective effects of ischemic preconditioning（2-minute transient cerebral ischemia） on calbindin D28k immunoreactivity in the gerbil hippocampal CA1 area following a subsequent fatal transient ischemic insult（5-minute transient cerebral ischemia）. A large number of pyramidal neurons in the hippocampal CA1 area died 4 days after 5-minute transient cerebral ischemia. Ischemic preconditioning reduced the death of pyramidal neurons in the hippocampal CA1 area. Calbindin D28k immunoreactivity was greatly attenuated at 2 days after 5-minute transient cerebral ischemia and it was hardly detected at 5 days post-ischemia. Ischemic preconditioning maintained calbindin D28 k immunoreactivity after transient cerebral ischemia. These findings suggest that ischemic preconditioning can attenuate transient cerebral ischemia-caused damage to the pyramidal neurons in the hippocampal CA1 area through maintaining calbindin D28k immunoreactivity.

Minocycline Attenuates Microglial Response and Reduces Neuronal Death after Cardiac Arrest and Cardiopulmonary Resuscitation in Mice

The possible role of minocycline in microglial activation and neuronal death after cardiac arrest（CA） and cardiopulmonary resuscitation（CPR） in mice was investigated in this study. The mice were given potassium chloride to stop the heart beating for 8 min to achieve CA, and they were subsequently resuscitated with epinephrine and chest compressions. Forty adult C57BL/6 male mice were divided into 4 groups（n=10 each）： sham-operated group, CA/CPR group, CA/CPR＋minocycline group, and CA/CPR＋vehicle group. Animals in the latter two groups were intraperitoneally injected with minocycline（50 mg/kg） or vehicle（normal saline） 30 min after recovery of spontaneous circulation（ROSC）. Twenty-four h after CA/CPR, the brains were removed for histological evaluation of the hippocampus. Microglial activation was evaluated by detecting the expression of ionized calcium-binding adapter molecule-1（Iba1） by immunohistochemistry. Neuronal death was analyzed by hematoxylin and eosin（H＆E） staining and the levels of tumor necrosis factor-alpha（TNF-α） in the hippocampus were measured by enzyme-linked immunosorbent assay（ELISA）. The results showed that the neuronal death was aggravated, most microglia were activated and TNF-α levels were enhanced in the hippocampus CA1 region of mice subjected to CA/CPR as compared with those in the sham-operated group（P〈0.05）. Administration with minocycline 30 min after ROSC could significantly decrease the microglial response, TNF-α levels and neuronal death（P〈0.05）. It was concluded that early administration with minocycline has a strong therapeutic potential for CA/CPR-induced brain injury.

Resveratrol effects on neural connectivity during aging

Aging has been considered a natural process of any living being.The rate of aging depends on many factors,including genetic and environmental factors.For this reason,many researchers in this field suggest that aging is an epigenetic process.Nowadays,the age groups have undergone a change.

The dynamics of adult neurogenesis in human hippocampus

The phenomenon of adult neurogenesis is now an accepted occurrence in mammals and also in humans.At least two discrete places house stem cells for generation of neurons in adult brain. These are olfactory system and the hippocampus. In animals, newly generated neurons have been directly or indirectly demonstrated to generate a significant amount of new neurons to have a functional role. However, the data in humans on the extent of this process is still scanty and such as difficult to comprehend its functional role in humans. This paper explores the available data on as extent of adult hippocampal neurogenesis in humans and makes comparison to animal data.

Denervated hippocampus provides a favorable microenvironment for neuronal differentiation of endogenous neural stem cells

Fimbria-fornix transection induces both exogenous and endogenous neural stem cells to differentiate into neurons in the hippocampus.This indicates that the denervated hippocampus provides an environment for neuronal differentiation of neural stem cells.However,the pathways and mechanisms in this process are still unclear.Seven days after fimbria fornix transection,our reverse transcription polymerase chain reaction,western blot assay,and enzyme linked immunosorbent assay results show a significant increase in ciliary neurotrophic factor m RNA and protein expression in the denervated hippocampus.Moreover,neural stem cells derived from hippocampi of fetal（embryonic day 17） Sprague-Dawley rats were treated with ciliary neurotrophic factor for 7 days,with an increased number of microtubule associated protein-2-positive cells and decreased number of glial fibrillary acidic protein-positive cells detected.Our results show that ciliary neurotrophic factor expression is up-regulated in the denervated hippocampus,which may promote neuronal differentiation of neural stem cells in the denervated hippocampus.

A protease-activated receptor 1 antagonist protects against global cerebral ischemia/reperfusion injury after asphyxial cardiac arrest in rabbits

Cerebral ischemia/reperfusion injury is partially mediated by thrombin, which causes brain damage through protease-activated receptor 1（PAR1）. However, the role and mechanisms underlying the effects of PAR1 activation require further elucidation. Therefore, the present study investigated the effects of the PAR1 antagonist SCH79797 in a rabbit model of global cerebral ischemia induced by cardiac arrest. SCH79797 was intravenously administered 10 minutes after the model was established. Forty-eight hours later, compared with those administered saline, rabbits receiving SCH79797 showed markedly decreased neuronal damage as assessed by serum neuron specific enolase levels and less neurological dysfunction as determined using cerebral performance category scores. Additionally, in the hippocampus, cell apoptosis, polymorphonuclear cell infiltration, and c-Jun levels were decreased, whereas extracellular signal-regulated kinase phosphorylation levels were increased. All of these changes were inhibited by the intravenous administration of the phosphoinositide 3-kinase/Akt pathway inhibitor LY29004（3 mg/kg） 10 minutes before the SCH79797 intervention. These findings suggest that SCH79797 mitigates brain injury via anti-inflammatory and anti-apoptotic effects, possibly by modulating the extracellular signal-regulated kinase, c-Jun N-terminal kinase/c-Jun and phosphoinositide 3-kinase/Akt pathways.

Specific effects of c-Jun NH2-terminal kinaseinteracting protein 1 in neuronal axons

c-Jun NH2-terminal kinase（JNK）-interacting protein 3 plays an important role in brain-derived neurotrophic factor/tropomyosin-related kinase B（Trk B） anterograde axonal transport. It remains unclear whether JNK-interacting protein 1 mediates similar effects, or whether JNK-interacting protein 1 affects the regulation of Trk B anterograde axonal transport. In this study, we isolated rat embryonic hippocampus and cultured hippocampal neurons in vitro. Coimmunoprecipitation results demonstrated that JNK-interacting protein 1 formed Trk B complexes in vitro and in vivo. Immunocytochemistry results showed that when JNK-interacting protein 1 was highly expressed, the distribution of Trk B gradually increased in axon terminals. However, the distribution of Trk B reduced in axon terminals after knocking out JNK-interacting protein 1. In addition, there were differences in distribution of Trk B after JNK-interacting protein 1 was knocked out compared with not. However, knockout of JNK-interacting protein 1 did not affect the distribution of Trk B in dendrites. These findings confirm that JNK-interacting protein 1 can interact with Trk B in neuronal cells, and can regulate the transport of Trk B in axons, but not in dendrites.

Effect of ischemic preconditioning on antioxidant status in the gerbil hippocampal CA1 region after transient forebrain ischemia

Ischemic preconditioning（IPC） is a condition of sublethal transient global ischemia and exhibits neuroprotective effects against subsequent lethal ischemic insult.We,in this study,examined the neuroprotective effects of IPC and its effects on immunoreactive changes of antioxidant enzymes including superoxide dismutase（SOD） 1 and SOD2,catalase（CAT） and glutathione peroxidase（GPX） in the gerbil hippocampal CA1 region after transient forebrain ischemia.Pyramidal neurons of the stratum pyramidale（SP） in the hippocampal CA1 region of animals died 5 days after lethal transient ischemia without IPC（8.6%（ratio of remanent neurons） of the sham-operated group）;however,IPC prevented the pyramidal neurons from subsequent lethal ischemic injury（92.3%（ratio of remanent neurons） of the sham-operated group）.SOD1,SOD2,CAT and GPX immunoreactivities in the sham-operated animals were easily detected in pyramidal neurons in the stratum pyramidale（SP） of the hippocampal CA1 region,while all of these immunoreactivities were rarely detected in the stratum pyramidale at 5 days after lethal transient ischemia without IPC.Meanwhile,their immunoreactivities in the sham-operated animals with IPC were similar to（SOD1,SOD2 and CAT） or higher（GPX） than those in the sham-operated animals without IPC.Furthermore,their immunoreactivities in the stratum pyramidale of the ischemia-operated animals with IPC were steadily maintained after lethal ischemia/reperfusion.Results of western blot analysis for SOD1,SOD2,CAT and GPX were similar to immunohistochemical data.In conclusion,IPC maintained or increased the expression of antioxidant enzymes in the stratum pyramidale of the hippocampal CA1 region after subsequent lethal transient forebrain ischemia and IPC exhibited neuroprotective effects in the hippocampal CA1 region against transient forebrain ischemia.

Intracerebral interplay and neurotransmitter systems involvement in animal models of neurodegenerative disorders:EEG approach expectations

An imbalance between activities of different structures and neurotransmitter systems in the brain is suggested to be the main cause of its abnormal functioning in neurodegenerative pathologies.Electroencephalogram（EEG）registered from areas specifically linked with a disease in combination with pharmacological testing of involved mediatory systems allows discovery of its progression and mechanism（s）. This, in turn, potentiates development of perspective approaches for early diagnostic and effective treatment of neurodegenerative disorders.

Monocarboxylate transporter 4 plays a significant role in the neuroprotective mechanism of ischemic preconditioning in transient cerebral ischemia

Monocarboxylate transporters（MCTs）, which carry monocarboxylates such as lactate across biological membranes, have been associated with cerebral ischemia/reperfusion process. In this study, we studied the effect of ischemic preconditioning（IPC） on MCT4 immunoreactivity after 5 minutes of transient cerebral ischemia in the gerbil. Animals were randomly designated to four groups（sham-operated group, ischemia only group, IPC ＋ sham-operated group and IPC ＋ ischemia group）. A serious loss of neuron was found in the stratum pyramidale of the hippocampal CA1 region（CA1）, not CA2/3, of the ischemia-only group at 5 days post-ischemia; however, in the IPC ＋ ischemia groups, neurons in the stratum pyramidale of the CA1 were well protected. Weak MCT4 immunoreactivity was found in the stratum pyramidale of the CA1 in the sham-operated group. MCT4 immunoreactivity in the stratum pyramidale began to decrease at 2 days post-ischemia and was hardly detected at 5 days post-ischemia; at this time point, MCT4 immunoreactivity was newly expressed in astrocytes. In the IPC ＋ sham-operated group, MCT4 immunoreactivity in the stratum pyramidale of the CA1 was increased compared with the sham-operated group, and, in the IPC ＋ ischemia group, MCT4 immunoreactivity was also increased in the stratum pyramidale compared with the ischemia only group. Briefly, present findings show that IPC apparently protected CA1 pyramidal neurons and increased or maintained MCT4 expression in the stratum pyramidale of the CA1 after transient cerebral ischemia. Our findings suggest that MCT4 appears to play a significant role in the neuroprotective mechanism of IPC in the gerbil with transient cerebral ischemia.

nNOS expression of hippocampal neurons in aged rats after brain ischemia/reperfusion and its role in DND development

Objective: To study the role of neuronal nitric oxide synthase (nNOS) in aged rats hippocampal delayed neuronal death (DND) following brain ischemia. Methods: Models of incomplete brain ischemia were induced by clipping common carotid artery. A total of 46 aged SD rats were divided into 8 groups: normal control group (Group A, n=5), sham operation group (Group B, n=5), reperfusion 1, 6, 12, 24, 48, and 96 hours groups after brain ischemia for 30 minutes (Group C, D, E, F, G, and H, n=6/group). The expression of nNOS was examined by immunohistochemistry and neuronal ultrastructural changes were observed by the transmission electron microscopy (TEM) at different time points after reperfusion. Results: Immunohistochemistry showed that nNOS expression in the hippocampal neurons was high in Group E, low expression in Group D, moderate expression in Group F and G. There was nearly no expression of nNOS in Group A, B, C, and H. Ultrastructure of hippocampal neurons was damaged more severely in reperfusion over 24 hours groups. Conclusions: Nitric oxide (NO) may be one of the important factors in inducing DND after ischemia/reperfusion.

Protective effects of astragalus extract against intermittent hypoxia-induced hippocampal neurons impairment in rats

Background Intermittent hypoxia is the main pathophysiological cause of the obstructive sleep apnea syndrome. Astragalus shows improvement of spatial learning and memory abilities under intermittent hypoxia. Our study aimed to investigate the protective effect of astragalus against intermittent hypoxia induced-hippocampal neurons impairment in rats and lay the theoretical foundation for the sleep apnea improvement in cognitive function by astragalus. Methods Male Wistar rats were divided into 4 groups： blank control group, normoxia group, intermittent hypoxia group and astragalus treated intermittent hypoxia group. After 6-week treatment, apoptosis of neurons was evaluated by terminal deoxynucleotidyl-transferase-mediated dUTP nick end-labeling （TUNEL） assay. Furthermore, the expression of HIF-la was detected by real-time reverse transcription polymerase chain reaction （RT-PCR） at the mRNA level as well as by immunohistochemistry （IHC） and Western blotting at the protein level. Results HPLC analysis indicated that astragaloside IV, astragaloside II and astragaloside I were the main compounds in astragals extract. Astragalus extract reduced the apoptosis of hippocampal neurons （P 〈0.05） and decreased the expression of HIF-la at both the mRNA and protein levels in hippocampus compared with non-treated groups （P 〈0.05）. Conclusion Astragalus protects aqainst intermittent hypoxia-induced hippocampal neurons impairment in rats.

Effects of 5-hydroxymethyl Furfural Extracted from Rehmannia Glutinosa Libosch on the Expression of Signaling Molecules Relevant to Learning and Memory among Hippocampal Neurons Exposed to High Concentration of Corticosterone

Objective：To determine the effects of 5-hydroxymethyl furfural（5-HMF）,an extract of Rehmannia glutinosa Libosch,on several down-regulated signaling molecules involved in learning and memory in hippocampal neurons.Methods：After cultured for 7 days,primary hippocampal neurons were divided into 5 groups：normal,corticosterone model,RU38486,5-HMF,and donepezil group.Neuron survival rates were calculated 24 h later using SYT013-P1 double-fluorescence staining and an 3-（4,5-Dimethylthiazol-2-yl）-2,5-diphenyltetrazolium bromide（MTT）assay.β-galactosidase activity was also assayed.Protein expressed by the glucocorticoid receptor（GCR）,brainderived neurotrophic factor（BDNF）,and N-methyl-D-aspartate receptor 2B（NR2B）,as well as phosphorylationcyclic adenosine monophosphate（cAMP）response element binding protein（p-CREB）,phosphorylation-extracellular signal-regulated kinase（p-ERK）,and phosphorylation-synapsin（p-synapsin）were quantified with Western blot.Results：Hippocampal neuron survival rates and the above-mentioned proteins were dramatically decreased（P〈0.05）,β-galactosidase activity was significantly increased in the model group,but the effect was reversed by5-HMF,RU38486,and to a lesser extent by donepezil（P〈0.05）.Conclusion：5-HMF extracts from the Chinese herb Rehmannia glutinosa Libosch could protect hippocampal neurons from glucocorticoid injury and from down-regulated signaling molecules in the GCR-BDNF-NR2B-p-ERK-p-CREB-p-synapsin signal transduction pathway.

Protective effect of cardiomyopeptidin on cultured rat hippocampal neurons injured by anoxia reoxygenation

Cardiomyopeptidin (CMP), a small molecular polypeptide, is a new drug extracted from pig myocardium. Recently, evidence of its protective effect on myocardium injured by ischemia or anoxia has appeared.^(1,2) Neurons are also vulnerable to ischemia/anoxia. The aim of this study was to evaluate the neuroprotection of CMP in an anoxic model, which was the cultured hippocampal neurons in vitro, and to determine the relationship between CMP and expression of Bcl-2.

Zinc modulates hippocampus CA1 neurons excitability and glutamatergic synaptic transmission

Zinc ion is key physiological importance in mammalian tissues. It is a major structural component of many proteins and acts as co-factors for the activity of many enzymes that

Neuronal cdc-2 like kinase in developing kindling rat hippocampus

Objective To test the hypothesis that neuronal cdc2 like kinase (Cdk5/p35 nck5a ) plays an important role in neuronal maturation and sprouting Methods Changes kinase activity, expression levels and subcellular localizations of Cdk5 and p35 nck5a in the rat hippocampus were studied during kindling progression by Western blot analysis, immunohistochemitry, immunoprecipitation and kinase assay Results Kinase activity in kindling rats was significantly higher than that in normal adult rats The kinase activity at stage 3 was most prominent among all stages of kindling progression The changes in kinase activity coincided with those of p35 nck5a expression in kindling rats In contrast, the expression of Cdk5 was constant throughout the progression of kindling stages However, subcellular localization of Cdk5 dramatically changed in the hippocampal neurons of kindling rats Cdk5 was translocated from axon to soma when kinase activity was high p35 nck5a was always localized in the soma throughout kindling progression Conclusions Neuronal cdc2 like kinase plays an important role in synaptic reorganization, and the translocation of Cdk5 to the soma from the axon may be a novel regulatory mechanism to control kinase activity

Effects of Electroacupuncture on Hippocampal and Cortical Apoptosis in A Mouse Model of Cerebral Ischemia-reperfusion Injury

Objective: To observe the effects of electroacupuncture on hippocampal and cortical apoptosis in a mouse model of cerebral ischemia-reperfusion injury. Methods: Mouse models established by repeated cerebral ischemia-reperfusion, followed by electroacupuncture at Shenshu, Geshu, and Baihui points. The control group mice were intragastrically administered Hydergine. On day 1 and 7 post-treatment, hippocampal and cortical apoptosis was detected by terminal-deoxynucleotidyl transferase mediated dUTP nick-end labeling (TUNEL), and apoptosis images in the hippocampal CA1 zone and cortical area were analyzed. Results: In the model group, apoptotic cells were detected one day after treatment and some cellular fibers were disarrayed. By day 7 post-treatment, there was an increase in the number of apoptotic cells in the hippocampal CA1 region. In addition, there were apoptotic cells in the cortical area, the cortical layers were thinner with localized neuronal loss and sieve-like lymphocyte infiltration, as well as glial cell proliferation and visible infarct lesions. However, in the Hydergine and electroacupuncture groups, there was a small number of apoptotic cells. At 7 days post-treatment in the model group, field number, numerical density on area, and surface density were increased. However, in the Hydergine and electroacupuncture groups these parameters were decreased (P<0.01), with a significant difference between the two treatment groups (P<0.01). Conclusion: Electroacupuncture treatment inhibited apoptosis and provided neuroprotection.

Harnessing GABAergic Transmission for Slow Oscillations

Oscillatory neuronal activity is the fundamental signature of neural networks.In the EEG literature,the oscillations are described as belonging to different frequency bands that are commonly used in clinical monitoring.