Objective To investigate the effects of specific TrkB receptor agonist 7,8-dihydroxyflavone (7,8-DHF) on spatial cognitive function and synaptic structure in schizophrenia rat model. Methods SD infant rats were divided into normal control group and model group according to the random number table method on the 6th day after birth. During the postnatal day 7 to 11, rats in the normal control group received subcutaneous injection of 0.9% sodium chloride solution (1 mL·kg-1) twice daily, and the rats in the model group were injected with dizocilpine (0.1 mg·kg-1). Beginning on the postnatal day 60, model rats were randomly divided into 7,8-DHF group and model control group, which were given intraperitoneal injection of 7,8-DHF (5 mg·kg-1) and DMSO once daily for 14 consecutive days, respectively. The rats of normal control group were given equal volume injections of DMSO. Morris water maze task, Golgi staining and Western blotting were adopted to examine spatial cognitive function, hippocampal dendritic spine density, protein expression and activity, respectively. Results The result in the open field test showed that the total travelled distance within 5 min was (12.20±1.62) m in the normal control group, (11.73±1.36) m in the model control group and (12.94±1.09) m in the 7,8-DHF group. The escape latency and travelled distance in the model control group were significantly higher than those in the normal control group (P<0.05), and the escape latency and travelled distance in rats of 7,8-DHF group were significantly shortened as compared with those in the model control group (P<0.05). There was no significant difference in the swimming speed among the three groups (P>0.05). The hippocampal dendritic spine density was (14.2±2.3)/10 μm in the normal control group, (8.0±1.9)/10 μm in the model control group, and (13.5±1.7)/10 μm in the 7,8-DHF group, the differences between the three groups were significant (all P<0.05); the phosphorylation level of GluR1 protein was (100.0±5.0) in the normal control group, (47.9±10.8) in the model control group, and (97.5±9.3) in the 7,8-DHF group, and the differences among the three groups were significant (all P<0.05). Conclusion 7,8-DHF treatment could improve the spatial cognitive function in rat model of schizophrenia and the mechanisms might be related with the increases of hippocampal dendritic spine density and phosphorylated levels of GluR1.
图2
Western blotting 检测3组大鼠海马组织GluR1、p-GluR1和β-actin蛋白 A.正常对照组;B.模型对照组;C.7,8-DHF组
Fig.2
Western blotting analysis on GluR1, p-GluR1 and β-actin in hippocampal tissues from three groups of rats A.normal control group;B.model control group;C.7,8-DHF group
PILLAIA.Brain-derived neurotropic factor/TrkB signaling in the pathogenesis and novel pharmacotherapy of schizophrenia[J].Neurosignals,2008,16(2/3):183-193.
The role of neurotropins, predominantly brain-derived neurotropic factor (BDNF), has been implicated in the pathophysiology as well as treatment outcome of schizophrenia. Both human and rodent studies indicate that the beneficial effects of antipsychotic drugs are mediated, at least in part, through BDNF and its receptor, TrkB. This review will discuss the available data on the levels of BDNF and TrkB in subjects with schizophrenia and in animals with and without conventional antipsychotics. The data concerning the impact of the antipsychotic drugs on BDNF/TrkB signaling will also be discussed. More importantly, this review will provide future perspective on BDNF/TrkB signaling as a novel molecular target to correct the pathogenesis and improve the long-term clinical outcome by treatments with conventional and adjunctive drugs.
DURANYN,MICHELT,ZOCHLINGR,et al.Brainderiv-ed neurotrophic factor and neurotrophin 3 in schizophrenic psychoses[J].Schizophr Res,2001,52(1/2):79-86.
Abstract Disturbed neural development has been postulated as a crucial factor in the pathophysiology of schizophrenic psychoses. The neurobiochemical basis for such changes of cytoarchitecture and changed neural plasticity could involve an alteration in the regulation of neurotrophic factors. In order to test this hypothesis, BDNF and NT-3 levels in post-mortem brain tissue from schizophrenic patients were determined by ELISA. There was a significant increase in BDNF concentrations in cortical areas and a significant decrease of this neurotrophin in hippocampus of patients when compared with controls. NT-3 concentrations of frontal and parietal cortical areas were significantly lower in patients than in controls. These findings lend further evidence to the neurotrophin hypothesis of schizophrenic psychoses which proposes that alterations in expression of neurotrophic factors could be responsible for neural maldevelopment and disturbed neural plasticity, thus being an important event in the etiopathogenesis of schizophrenic psychoses.
EHRENREICHH,HINZE-SELCHD,STAWICKIS,et al.Improvement of cognitive functions in chronic schizophrenic patients by recombinant human erythropoietin[J].Mol Psychiatry,2007,12(2):206-220.
Schizophrenia is increasingly recognized as a neurodevelopmental disease with an additional degenerative component, comprising cognitive decline and loss of cortical gray matter. We hypothesized that a neuroprotective/neurotrophic add-on strategy, recombinant human erythropoietin (rhEPO) in addition to stable antipsychotic medication, may be able to improve cognitive function even in chronic schizophrenic patients. Therefore, we designed a double-blind, placebo-controlled, randomized, multicenter, proof-of-principle (phase II) study. This study had a total duration of 2 years and an individual duration of 12 weeks with an additional safety visit at 16 weeks. Chronic schizophrenic men (N=39) with defined cognitive deficit (>or=1 s.d. below normal in the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)), stable medication and disease state, were treated for 3 months with a weekly short (15 min) intravenous infusion of 40,000 IU rhEPO (N=20) or placebo (N=19). Main outcome measure was schizophrenia-relevant cognitive function at week 12. The neuropsychological test set (RBANS subtests delayed memory, language-semantic fluency, attention and Wisconsin Card Sorting Test (WCST-64) - perseverative errors) was applied over 2 days at baseline, 2 weeks, 4 weeks and 12 weeks of study participation. Both placebo and rhEPO patients improved in all evaluated categories. Patients receiving rhEPO showed a significant improvement over placebo patients in schizophrenia-related cognitive performance (RBANS subtests, WCST-64), but no effects on psychopathology or social functioning. Also, a significant decline in serum levels of S100B, a glial damage marker, occurred upon rhEPO. The fact that rhEPO is the first compound to exert a selective and lasting beneficial effect on cognition should encourage new treatment strategies for schizophrenia.
DUX,HILL RA.7,8-Dihydroxyflavone as a proneurotrop-hic treatment for neurodevelopmental disorders[J].Neurochem Int,2015,89:170-180.
Neurodevelopmental disorders are a group of conditions that arises from impairments of the central nervous system during its development. The causes of the various disorders are heterogeneous and the symptoms likewise are multifarious. Most of these disorders currently have very little available treatment that is effective in combating the plethora of serious symptoms. Brain-derived neurotrophic factor (BDNF) is a fundamental neurotrophin with vital functions during brain development. Pre-clinical studies have shown that increasing BDNF signalling may be a potent way to prevent, arrest or even reverse abnormal neurodevelopmental events arising from a variety of genetic or environmental causes. However, many difficulties make BDNF problematic to administer in an efficient manner. The recent discovery of a small BDNF-mimetic, the naturally occurring flavonoid 7,8-dihydroxyflavone (7,8-DHF), may provide an avenue to allow efficient and safe activation of the BDNF pathway in tackling the symptoms of neurodevelopmental disorders. Here, evidence will be provided to support the potential of 7,8-DHF as a novel treatment for several neurodevelopmental disorders where the BDNF signalling pathway is implicated in the pathophysiology and where benefits are therefore most likely to be derived from its implementation.
STEFANI MR,MOGHADDAMB.Transient N-methyl-D-aspartate receptor blockade in early development causes lasting cognitive deficits relevant to schizophrenia[J].Biol Psychiatry,2005,57(4):433-436.
These results suggest that a brief disruption of NMDA receptors during a sensitive period of cortical development is sufficient to produce selective cognitive deficits that are relevant to schizophrenia.
WANG CM,YANG YJ,ZHANG JT,et al.Regulation of emotional memory by hydrogen sulfide:role of GluN2B-containing NMDA receptor in the amygdala[J].J Neurochem,2015,132(1):124-134.
As an endogenous gaseous molecule, hydrogen sulfide (H2S) has attracted extensive attention because of its multiple biological effects. However, the effect of H2S on amygdala-mediated emotional memory has not been elucidated. Here, by employing Pavlovian fear conditioning, an animal model widely used to explore the neural substrates of emotion, we determined whether H2S could regulate emotional memory. It was shown that the H2S levels in the amygdala of rats were significantly elevated after cued fear conditioning. Both intraamygdala and systemic administrations of H2S markedly enhanced amygdala-dependent cued fear memory in rats. Moreover, it was found that H2S selectively increased the surface expression and currents of NMDA-type glutamate receptor subunit 2B (GluN2B)-containing NMDA receptors (NMDARs) in lateral amygdala of rats, whereas blockade of GluN2B-containing NMDARs in lateral amygdala eliminated the effects of H2S to enhance amygdalar long-term potentiation and cued fear memory. These results demonstrate that H2S can regulate amygdala-dependent emotional memory by promoting the function of GluN2B-containing NMDARs in amygdala, suggesting that H2S-associated signaling may hold potential as a new target for the treatment of emotional disorders.
LIUY,CHENJ,SONGT,et al.Contribution of K+-Cl- cotrans-porter 2 in MK-801-induced impairment of long term potentiation[J].Behav Brain Res,2009,201(2):300-304.
Previous studies have indicated that GABAergic disinhibition contributes to cognitive deficits mediated by NMDA receptor hypofunction in schizophrenia model of rats. However, the underlying mechanism of GABAergic disinhibition in schizophrenia remains elusive. In this study, we found that the maintenance of long term potentiation (LTP) was impaired in the hippocampus of rats with MK-801-induced cognitive impairments. The impairment of LTP maintenance was significantly reversed by picrotoxinin, a specific GABA(A) receptor-chloride channel blocker and furosemide, a K+-Cl- cotransporter 2 (KCC2) blocker, respectively. Furthermore, immunoblotting results indicated KCC2 expression in hippocampal CA1 of MK-801-treated rats was lower than that of normal rats before LTP induction. Additionally, LTP-accompanied downregulation of KCC2 was prevented in MK-801-treated rats during LTP induction. Our results suggested that KCC2 expression in hippocampal CA1 of MK-801-treated rats was not further decreased by LTP induction because of its low expression caused by MK-801 treatment. Accordingly, GABAergic inhibition was not further decreased during LTP induction due to the depressed basal GABAergic tone in MK-801-treated rats, Therefore, GABAergic disinhibition in MK-801-treated rats restricts the further downregulation of KCC2 during LTP induction and contributes to the stable GABAergic inhibition and the impaired LTP expression. Our results thus reveal the mechanism that GABAergic disinhibition contributes to cognitive deficits.
CHENT,YANG YJ,LI YK,et al.Chronic administration tetrahydroxystilbene glucoside promotes hippocampal memory and synaptic plasticity and activates ERKs,CaMKII and SIRT1/miR-134 in vivo[J].J Ethnopharmacol,2016,190:74-82.
Chronic administration of TSG promotes hippocampal memory in normal mice, suggesting that supplementary of TSG might serve as an enhancement of memory.
HARRIS LW,SHARPT,GARTLONJ,et al.Longterm be-havioural,molecular and morphological effects of neonatal NMDA receptor antagonism[J].Eur J Neurosci,2003,18(6):1706-1710.
Brief N-methyl-D-aspartate (NMDA) receptor blockade in neonatal rats has been reported to increase neuronal apoptosis. We replicated this finding using MK-801 (0.5 mg/kg) administered twice on postnatal day 7, and then studied the long-term consequences. In adulthood, treated rats showed reduced volume and neuronal number within the hippocampus, and altered hippocampal NMDA receptor (NR1 subunit) expression. Synaptophysin mRNA was decreased in the thalamus (laterodorsal nucleus). Adult MK-801-treated females had prepulse inhibition deficits and increased locomotor activity. The data show that a transient and limited glutamatergic intervention during development can have chronic behavioural, structural and molecular effects. The effects are reminiscent of alterations reported in schizophrenia and, as such, are consistent with hypotheses advocating a role for NMDA receptor hypofunction, and aberrant apoptosis, in the neurodevelopmental pathogenesis of the disorder.
HARVEY PD,KEEFE RS.Studies of cognitive change in patients with schizophrenia following novel antipsychotic treatment[J].Am J Psychiatry,2001,158(2):176-184.
OBJECTIVE: Novel antipsychotic medications have been reported to have beneficial effects on cognitive functioning in patients with schizophrenia. However, these effects have been assessed in studies with considerable variation in methodology. A large number of investigator-initiated and industry-sponsored clinical trials are currently underway to determine the effect of various novel antipsychotics on cognitive deficits in patients with schizophrenia. The ability to discriminate between high- and low-quality studies will be required to understand the true implications of these studies and their relevance to clinical practice. METHOD: This article addresses several aspects of research on cognitive enhancement in schizophrenia, emphasizing how the assessment of cognitive function in clinical trials requires certain standards of study design to lead to interpretable results. RESULTS: Novel antipsychotic medications appear to have preliminary promise for the enhancement of cognitive functioning. However, the methodology for assessing the treatment of cognitive deficits is still being developed. CONCLUSIONS: Researchers and clinicians alike need to approach publications in this area with a watchful eye toward methodological weaknesses that limit the interpretability of findings.
FRANTSEVA MV,FITZGERALD PB,CHENR,et al.Evidence for impaired long-term potentiation in schizophrenia and its relationship to motor skill learning[J].Cereb Cortex,2008,18(5):990-996.
Several lines of evidence suggest that schizophrenia (SCZ) is associated with disrupted plasticity in the cortex. However, there is little direct neurophysiological evidence of aberrant long-term potentiation (LTP)-like plasticity in SCZ and little human evidence to establish a link between LTP to learning and memory. LTP was evaluated using a neurophysiological paradigm referred to as paired associative stimulation (PAS). PAS involves pairing of median nerve electric stimulation with transcranial magnetic stimulation (TMS) over the contralateral motor cortex (for abductor pollicis brevis muscle activation) delivered at 25-ms interstimulus interval. This pairing was delivered at a frequency of 0.1 Hz for 30 min. LTP was reflected by the change in motor evoked potentials (MEPs) before and after PAS. In addition, motor skill learning was assessed using the rotary pursuit task. Compared with healthy subjects, patients with SCZ demonstrated significant MEP facilitation deficits following PAS and impaired rotary-pursuit motor learning. Across all subjects there was a significant association between LTP and motor skill learning. These data provide evidence for disrupted LTP in SCZ, whereas the association between LTP with motor skill learning suggests that the deficits in learning and memory in SCZ may be mediated through disordered LTP.
ZHANGC,FANGY,XUL.Glutamate receptor 1 phospho-rylation at serine 845 contributes to the therapeutic effect of olanzapine on schizophrenia-like cognitive impairments[J].Schizophr Res,2014,159(2/3):376-384.
Schizophrenia patients exhibit a wide range of impairments in cognitive functions. Clinically, atypical antipsychotic drugs (AAPs) such as olanzapine (OLZ) have a therapeutic effect on memory function among schizophrenia patients rather than typical antipsychotics, e.g., haloperidol. To date, however, little is known about the neuroplasticity mechanism underlying the effect of AAPs on the impairment of cognitive functions. Here, we treated schizophrenia rat models with a systematic injection of MK-801 (0.1mg/kg) and chose the drug OLZ as a tool to investigate the mechanisms of AAPs when used to alter cognitive function. The results showed that the systematic administration of MK-801 results in the impairment of spatial learning and memory as well as spatial working memory in a Morris water maze task. OLZ but not HAL improved these MK-801-induced cognitive dysfunctions. After MK-801 application, the hippocampal LTP was profoundly impaired. In conjunction with the results of the behavioral test, the administration of OLZ but not of HAL resulted in a significant reversal effect on the impaired LTP induced via MK-801 application. Furthermore, we found that OLZ but not HAL can upregulate the phosphorylation of GluR1 Ser845. These data suggest that the therapeutic effect of OLZ on cognitive dysfunctions may be due to its contribution to synaptic plasticity via the ability to upregulate the state of GluR1 Ser845 phosphorylation. We therefore suggest that the upregulated state of GluR1 Ser845 phosphorylation may be a promising target for developing novel therapeutics for treating schizophrenia.
Chronic administration tetrahydroxystilbene glucoside promotes hippocampal memory and synaptic plasticity and activates ERKs,CaMKII and SIRT1/miR-134 in vivo
, 余斌, 康光宇, 闫琨, 杨远坚
