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Global Gene Expression Profile of the Hippocampus in a Rat Model of Vascular Dementia
Abstract
Vascular dementia (VD) has been one of the most serious public health problems worldwide. It is well known that cerebral hypoperfusion is the key pathophysiological basis of VD, but it remains unclear how global genes in hippocampus respond to cerebral ischemia-reperfusion. In this study, we aimed to reveal the global gene expression profile in the hippocampus of VD using a rat model. VD was induced by repeated occlusion of common carotid arteries followed by reperfusion. The rats with VD were characterized by deficit of memory and cognitive function and by the histopathological changes in the hippocampus, such as a reduction in the number and the size of neurons accompanied by an increase in intercellular space. Microarray analysis of global genes displayed up-regulation of 7 probesets with genes with fold change more than 1.5 (P < 0.05) and down-regulation of 13 probesets with genes with fold change less than 0.667 (P < 0.05) in the hippocampus. Gene Ontology (GO) and pathway analysis showed that the up-regulated genes are mainly involved in oxygen binding and transport, autoimmune response and inflammation, and that the down-regulated genes are related to glucose metabolism, autoimmune response and inflammation, and other biological process, related to memory and cognitive function. Thus, the abnormally expressed genes are closely related to oxygen transport, glucose metabolism, and autoimmune response. The current findings display global gene expression profile of the hippocampus in a rat model of VD, providing new insights into the molecular pathogenesis of VD.
... Microarray analysis. Microarray analysis was conducted following a previously described procedure (14). In brief, total RNA was converted into first-strand complementary DNA (cDNA) for 2 h at 42˚C and then second-strand cDNA for 1 h at 16˚C and 10 min at 65˚C using the GeneChip™ 3'IVT PLUS Reagent kit. ...
... RT-qPCR assays. RT-qPCR was used to confirm that 14 representative genes from the microarray analysis as previously described with minor modifications (14). The genes were mainly involved in the regulation of cell proliferation/migration/differentiation, cell cycle, apoptosis, MAPK activity, autophagy and inflammatory response. ...
... Vascular dementia is a state of impairment in the memory functioning secondary to problems related to blood supply to the brain. Ischemia-reperfusioninduced cerebral injury is one of more commonly employed models to induce vascular dementia in animals (Wu et al. 2015;Wan et al. 2015). In the present study, a state of cerebral ischemia reperfusion was induced by occlusion of both carotid arteries. ...
The present study explored the role of endothelin-1, H2S, and Nrf2 in remote preconditioning (RIPC)-induced beneficial effects in ischemia–reperfusion (I/R)-induced vascular dementia. Mice were subjected to 20 min of global ischemia by occluding both carotid arteries to develop vascular dementia, which was assessed using Morris water maze test on 7th day. RIPC was given by subjecting hind limb to four cycles of ischemia (5 min) and reperfusion (5 min) and it significantly restored I/R-induced locomotor impairment, neurological severity score, cerebral infarction, apoptosis markers along with deficits in learning and memory. Biochemically, there was increase in the plasma levels of endothelin-1 along with increase in the brain levels of H2S and its biosynthetic enzymes viz., cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CLS). There was also an increase in the expression of Nrf2 and glutathione reductase in the brain in response to RIPC. Pretreatment with bosentan (dual blocker of ETA and ETB receptors), amino-oxyacetic acid (CBS synthase inhibitor), and DL-propargylglycine (CLS inhibitor) significantly attenuated RIPC-mediated beneficial effects and biochemical alterations. The effects of bosentan on behavioral and biochemical parameters were more significant than individual treatments with CBS or CLS inhibitors. Moreover, CBS and CLS inhibitors did not alter the endothelin-1 levels possibly suggesting that endothelin-1 may act as upstream mediator of H2S. It is concluded that RIPC may stimulate the release endothelin-1, which may activate CBS and CLS to increase the levels of H2S and latter may increase the expression of Nrf2 to decrease oxidative stress and prevent vascular dementia.
... Hippocampal formation, which plays a key role in the consolidation and retrieval of episodic and spatial memory, is among the brain structures most vulnerable to cerebral ischemia [4], and impaired hippocampal function is an important factor in the cognitive dysfunction of Alzheimer's disease (AD). Vascular dementia (VD) is (after AD) the next most common cause of cognitive dysfunction and is associated with hippocampal damage [5][6][7][8][9][10][11][12]. ...
The hippocampus is a key structure for encoding and processing memory and for spatial orientation, which are among the cognitive functions most sensitive to cerebral ischemia, hypoxia, and vascular dementia (VD). Since hippocampal formation is one of the principle forebrain targets for arginine-vasopressin (AVP) innervations arising in the hypothalamic paraventricular nucleus (PVN), we explored the contributions of AVP to VD pathogenesis. To this end, we randomly assigned pathogen-free, male Wistar rats to one of seven groups in a VD model and tested AVP treatment effects on spatial learning and memory using the Morris water maze. We also measured the superoxide dismutase (SOD) activity and malondialdehyde (MDA) concentration in brain samples and monitored the expression of AVP-positive neurons in the hippocampus by immunohistochemistry. The VD model with repeated cerebral ischemia-reperfusion injury evoked impairment of cognitive function and reduced cerebral concentrations of the antioxidation markers. Lesioning the rat PVN showed a similar effect on learning and memory and reduced antioxidation markers in the brain tissue. However, AVP injection into the PVN improved cognitive performance in VD rats, while enhancing/rectifying the changes in antioxidation markers. We conclude that our VD model may decrease AVP secretion in the PVN and subsequently reduce antioxidant capacity in the hippocampus, leading to impaired cognitive function.
... During reperfusion, blood flow is reintroduced to the tissue, triggering a series of events including oxidative stress, energy failure, inflammation, excitatory amino acids toxicity, the activation of various cell-signaling pathways, apoptosis, and neuronal death [5,6]. Meanwhile, the ischemia-reperfusion process usually lead to increase or decrease of a number of genes, such as insulin-like growth factor-1 (IGF-1) [7], heat shock protein (HSP27) [8], protein tyrosine kinase type 2 beta (Ptk2b) [9], high mobility group box 1 (HMGB1) [10], and pyruvate dehydrogenase kinase 4 (PDK4) [11]. We hypothesize that the process of reperfusion induces the abnormal expression of a large number of genes. ...
It is well-established that reperfusion following cerebral ischemic injury gives rise to secondary injury accompanied by structural and functional damage. However, it remains unclear how global genes changes in cerebral ischemia-reperfusion injury (IRI). This study investigated global gene expression in the hippocampi of Wistar rats following transient cerebral IRI using an RNA-sequencing strategy. The results revealed ≥2-fold up-regulation of 156 genes and ≥2-fold down-regulation of 26 genes at 24 h post-reperfusion. Fifteen differentially expressed genes were selected to confirm the RNA-sequencing results. Gene expression levels were dynamic, with the peak expression level of each gene occurring at different time points postreperfusion. Gene Ontology (GO) analysis classified the differentially expressed genes as mainly involved in inflammation, stress and immune response, glucose metabolism, proapoptosis, antiapoptosis, and biological processes. KEGG pathway analysis suggested that IRI activated different signaling pathways, including focal adhesion, regulation of actin cytoskeleton, cytokine-cytokine receptor interaction, MAPK signaling, and Jak-STAT signaling. This study describes global gene expression profiles in the hippocampi of Wistar rats using the middle cerebral artery occlusion (MCAO) model. These findings provide new insights into the molecular pathogenesis of IRI and potential drug targets for the prevention and treatment of IRI in the future.
... Previous studies have elucidated that the pathogenesis of vascular cognitive impairment is due to delayed neuronal death in the hippocampus CA1 area, and repetitive cerebral I/R is an important cause of vascular cognitive impairment [30]. In the hippocampus, the CA1, CA2/3 and DG areas are basic area involved in long-term memory formation [31]. ...
Chronic intermittent hypobaric hypoxia (CIHH) has protective effects on heart and brain against ischemia injury through mobilizing endogenous adaptive mechanisms. However, whether CIHH prevents against cognitive impairment was not elucidated. The present study aimed to investigate the effect and mechanism of CIHH treatment on ischemia/reperfusion (IR)-induced cognitive dysfunction. Mice were randomly divided into 8 groups: Control, Sham, CIHH (simulating 5000 m high-altitude for 28 days, 6 h per day), IR (three 16-min occlusions of bilateral common carotid arteries interrupted by two 10-min intervals), CIHH + IR, PD98059 (inhibitor of MEK1/2) + CIHH + IR, PD98059 + Sham and PD98059 + IR group. Morris water maze and step-down passive avoidance tests were performed to evaluate the capability of learning and memory 1 month after ischemia. Thionine dyeing was to examine histological manifestations of pyramidal neurons in hippocampus CA1 region. Western blotting assay was for measurement of the protein expressions in ERK1/2-CREB-BDNF signaling pathway. There were a shorter escape latency and a longer percentage of time retaining in the target quadrant in Morris water maze test, fewer times of errors in the step-down avoidance test and a higher neuronal density of the hippocampal CA1 subfield in CIHH + IR group than in IR group. CIHH upregulated the expressions of BDNF, phosphorylated CREB, ERK1/2 and TrkB with or without ischemia. The protective effects of CIHH were abolished by PD98059 administration 15 min before ischemia. CIHH ameliorated ischemia-induced cognitive dysfunction through activation of ERK1/2-CREB-BDNF signaling pathway.
Background:
Electroacupuncture (EA) has been shown to reduce cognitive impairment in vascular dementia (VaD) patients. However, the mechanism of action remains unknown.
Objective:
The c-Jun N-terminal kinase (JNK) signaling pathway plays an important role in apoptosis. Herein, we focused on whether EA can inhibit apoptosis and alleviate cognitive impairment by regulating the JNK signaling pathway using a mouse model of VaD induced by modified bilateral common carotid artery occlusion (BCCAo).
Methods:
In experiment I, 60 mice were randomly divided into a Sham group, BCCAo group, BCCAo + EA group, BCCAo + Sham-EA group, BCCAo + SP group (receiving the selective JNK inhibitor SP600125) and BCCAo + SP + EA group. Morris water maze tests, TdT-mediated dUTP-biotin nick end labeling (TUNEL) staining and flow cytometry were used to evaluate the effect of the EA intervention on VaD. In experiment II, 30 mice were randomly divided into a Sham group, BCCAo group, BCCAo + EA group, BCCAo + SP group and BCCAo + SP + EA group. Western blotting and real-time reverse transcription polymerase chain reaction were used to detect protein and mRNA expression of key factors in the JNK signaling pathway in the hippocampus.
Results:
EA, SP600125 and EA + SP600125 significantly inhibited hippocampal apoptosis and improved cognitive impairment in VaD model mice. There were no significant differences between the BCCAo group and the BCCAo + Sham-EA group. EA, EA + SP600125 and SP600125 inhibited the phosphorylation of JNK and caspase-3. EA and EA + SP600125 promoted protein and mRNA expression of B-cell lymphoma 2 (Bcl-2) in the hippocampus of VaD mice and inhibited protein and mRNA expression of activator protein (AP)-1, p53 and Bax.
Conclusion:
EA can reverse cognitive deficits and inhibit hippocampal neuronal apoptosis in VaD model mice, at least partially through inhibition of the JNK signaling pathway and regulation of apoptosis signals.
An association between anticardiolipin antibodies and dementia has been reported in several recent
studies; however, its physiopathological mechanism remains controversial. The aim of this study was to evaluate the association of vascular dementia and anticardiolipin antibodies. Material/Methods: A random prospective investigation of 17 male and 13 female patients with vascular dementia was made with regard to anticardiolipin antibodies. Their ages ranged from 56 to 77 years (average: 67.2 years). The criteria of NINDS-AIREN were used to defi ne the vascular dementia. A control group of 25 female and 9 male patients was formed with ages ranging from 62 to 80 years (mean: 68 years). Evaluation of the anticardiolipin antibodies was performed by means of Enzyme-Linked Immunoabsorbent Assay (ELISA) for the quantitative measurement of IgG and IgM antibodies against cardiolipins in serum. Statistical analysis was done using the Fisher’s exact test, where p<0.05 was considered signifi cant. Results: Elevated levels of anticardiolipin antibodies were detected in 56.6% of the patients with vascular dementia and 26.4% of the control group (p<0.02). Conclusions: There was a signifi cant difference in the prevalence of high levels of anticardiolipin antibodies between the group of patients with vascular dementia and the control group. This proves that anticardiolipin antibodies present a risk factor for vascular dementia.
Stroke is most important cause of death and disability in adults. The hippocampus CA1 and sub-ventricular zone neurons are vulnerable to ischemia that can impair memory and learning. Although neurogenesis normally occurs in the dentate gyrus (DG) of the hippocampus and sub-ventricular zone (SVZ) following brain damage, this response is unable to compensate for severe damage. This study researches both neurogenesis and the neuroprotective effects of TGF-α on the hippocampus and SVZ following ischemia-reperfusion.
In this experimental study, male Wistar rats were divided into the following groups: surgical and vehicle shams, ischemia and treatment groups. Ischemia was induced by common carotid occlusion for 30 minutes followed by reperfusion and TGF-α was injected into the right lateral ventricle. Spatial memory was assessed using Morris Water Maze (MWM). Nestin and Bcl-2 family protein expressions were studied by immunohistochemical and Western blot methods, respectively. Finally, data were analyzed using SPSS 16 software and one-way analysis of variance (ANOVA).
TGF-α injection significantly increased nestin expression in both the dentate gyrus and SVZ. Transforming Growth Factor -α (TGF-α) treatment caused a significant decrease in Bax expression and increase in Bcl-2 anti-apoptotic protein expression in the hippocampus. Our results showed a significant increase in the number of pyramidal neurons. Memory also improved significantly following TGF-α treatment.
Our findings proved that TGF-α reduced ischemic injury and played a neuroprotective role in the pathogenesis of ischemia.
Background & objectives:
The population of elderly is growing globally and so are the physical illnesses and psychiatric morbidity. This study was planned to assess the prevalence and patterns of psychiatric morbidity amongst rural older adults in Lucknow, north India.
Methods:
A survey was conducted in subjects aged 60 yr and above to identify the cases of psychiatric morbidity in rural population from randomly selected two revenue blocks of Lucknow district, Uttar Pradesh, India. All subjects were screened through Hindi Mental Status Examination (HMSE) and Survey Psychiatric Assessment Schedule (SPAS) to identify for the suspected cases of cognitive and the psychiatric disorders, respectively. The subjects screened positive on HMSE and SPAS were assessed in detail on Cambridge Mental Disorder of the Elderly Examination-Revised (CAMDEX-R) and Schedule for Clinical Assessment in Neuropsychiatry (SCAN), to diagnose cognitive disorders and psychiatric disorders (other than the cognitive), respectively on the basis of International Classification of Diseases-10 (ICD-10) diagnostic guidelines.
Results:
The overall prevalence of psychiatric morbidity in rural older adults was found to be 23.7 per cent (95% CI=21.89-25.53). Mood (affective) disorders were the commonest (7.6%, 95% CI=6.51-8.80), followed by mild cognitive impairment (4.6%, 95% CI=3.72-5.53), mental and behavioural disorders due to substance use (4.0%, 95% CI=3.17-4.87) and dementia (2.8%) [Alzheimer's disease (2.4%, 95% CI=1.81-3.16) and vascular (0.4%, 95% CI=0.16-0.73)].
Interpretation & conclusions:
Overall prevalence of psychiatric morbidity amongst rural elderly in this study was found to be less in comparison to those reported in earlier studies from India. However, prevalence pattern of different disorders was found to be similar. Therefore, it appears that a stringent methodology, refined case criteria for diagnosis and assessment by trained professionals restrict false diagnosis.
The Chinese population has been aging rapidly and the country's economy has experienced exponential growth during the past three decades. The goal of this study was to estimate the changes in the prevalence of dementia, Alzheimer's disease (AD), and vascular dementia (VaD) among elderly Chinese individuals and to analyze differences between urban and rural areas.
For the years 2008 to 2009, we performed a population-based cross-sectional survey with a multistage cluster sampling design. Residents aged 65 years and older were drawn from 30 urban (n = 6096) and 45 rural (n = 4180) communities across China. Participants were assessed with a series of clinical examinations and neuropsychological measures. Dementia, AD, and VaD were diagnosed according to established criteria via standard diagnostic procedures.
The prevalence of dementia, AD, and VaD among individuals aged 65 years and older were 5.14% (95% CI, 4.71-5.57), 3.21% (95% CI, 2.87-3.55), and 1.50% (95% CI, 1.26-1.74), respectively. The prevalence of dementia was significantly higher in rural areas than in urban ones (6.05% vs. 4.40%, P < .001). The same regional difference was also seen for AD (4.25% vs. 2.44%, P < .001) but not for VaD (1.28% vs. 1.61%, P = .166). The difference in AD was not evident when the sample was stratified by educational level. Moreover, the risk factors for AD and VaD differed for urban and rural populations.
A notably higher prevalence of dementia and AD was found in rural areas than in urban ones, and education might be an important reason for the urban-rural differences.
Dementia is a major cause of morbidity in the western society. Pharmacological therapies to delay the progression of cognitive impairments are modestly successful. Consequently, new therapies are urgently required to improve cognitive deficits associated with dementia. We evaluated the effects of physical and cognitive activity on learning and memory in a rat model of vascular dementia (VasD). Male Sprague-Dawley rats (6 months old) were exposed to either regular chow or a diet rich in saturated fats and sucrose and chronic bilateral common carotid artery occlusion or sham surgery. First, this model of VasD was validated using a 2 × 2 experimental design (surgery × diet) and standard cognitive outcomes. Next, using identical surgical procedures, we exposed animals to a paradigm of cognitive rehabilitation or a sedentary condition. At 16 weeks post surgery, VasD animals demonstrated significant learning and memory deficits in the Morris water maze, independent of diet. Rehabilitation significantly attenuated these cognitive deficits at this time point as well as at 24 weeks. Further, rehabilitation normalized hippocampal CA1 soma size (area and volume) to that of control animals, independent of cell number. Importantly, these findings demonstrate beneficial neuroplasticity in early middle-aged rats that promoted cognitive recovery, an area rarely explored in preclinical studies.Journal of Cerebral Blood Flow & Metabolism advance online publication, 20 February 2013; doi:10.1038/jcbfm.2013.21.
Theories on the functions of the hippocampal system are based largely on two fundamental discoveries: the amnestic consequences of removing the hippocampus and associated structures in the famous patient H.M. and the observation that spiking activity of hippocampal neurons is associated with the spatial position of the rat. In the footsteps of these discoveries, many attempts were made to reconcile these seemingly disparate functions. Here we propose that mechanisms of memory and planning have evolved from mechanisms of navigation in the physical world and hypothesize that the neuronal algorithms underlying navigation in real and mental space are fundamentally the same. We review experimental data in support of this hypothesis and discuss how specific firing patterns and oscillatory dynamics in the entorhinal cortex and hippocampus can support both navigation and memory.
Heart disease is the major leading cause of death and disability in the world. Mainly affecting the elderly population, heart disease and its main outcome, cardiovascular disease, have become an important risk factor in the development of cognitive decline and Alzheimer's disease (AD). This paper examines the evidence linking chronic brain hypoperfusion induced by a variety of cardiovascular deficits in the development of cognitive impairment preceding AD. The evidence indicates a strong association between AD and cardiovascular risk factors, including ApoE(4), atrial fibrillation, thrombotic events, hypertension, hypotension, heart failure, high serum markers of inflammation, coronary artery disease, low cardiac index, and valvular pathology. In elderly people whose cerebral perfusion is already diminished by their advanced age, additional reduction of cerebral blood flow stemming from abnormalities in the heart-brain vascular loop ostensibly increases the probability of developing AD. Evidence also suggests that a neuronal energy crisis brought on by relentless brain hypoperfusion may be responsible for protein synthesis abnormalities that later result in the classic neurodegenerative lesions involving the formation of amyloid-beta plaques and neurofibrillary tangles. Insight into how cardiovascular risk factors can induce progressive cognitive impairment offers an enhanced understanding of the multifactorial pathophysiology characterizing AD and ways at preventing or managing the cardiovascular precursors of this dementia.
To study the effect of nimodipine on hippocampal regional cerebral blood flow (rCBF) and proinflammatory cytokines in rats with experimental vascular dementia.
Male Sprague Dawley rats were randomly divided into four groups (n = 15/group): sham operated controls (group A); focal cerebral ischaemia (group B); vascular dementia (group C); and vascular dementia treated with 20 mg/kg nimodipine daily (group D). The Morris water maze test evaluated learning and memory, and magnetic resonance perfusion-weighted imaging was used to measure rCBF. Hippocampal levels of nuclear factor-κB (NF-κB), tumour necrosis factor-α (TNF-α) and interleukin 1β (IL-1β) were measured.
Compared with group C, rats in group D demonstrated significantly improved learning ability and significantly increased hippocampal rCBF. The levels of NF-κB, TNF-α and IL-1β were significantly lower in group D than in group C. Hippocampal nerve cell morphology was abnormal in group C but near normal in group D.
Nimodipine improved the symptoms of cognitive impairment, increased rCBF, reduced hippocampal cytokine levels and alleviated neuronal injury in the hippocampus of rats with experimental vascular dementia.
Cerebrovascular disease is the second leading cause of cognitive impairment in the elderly, either alone or in combination with Alzheimer's disease (AD). Vascular dementia (VaD) is heterogeneous in terms of both clinical phenotype and pathogenetic mechanisms. It may result from multiple cortical infarctions due to cerebral large vessel pathologies or to subcortical ischemic changes such as leukoaraiosis or lacunar infarction due to cerebral small artery disease. Clinical symptoms and signs vary depending on the location and size of the stroke lesion, and no single neuropsychological profile characteristic of VaD has been defined, although dysexecutive function is common. A slightly higher mortality rate and slower progression are reported in VaD compared with AD. VaD is potentially preventable by rigorous identification and treatment of cardiovascular disease risk factors, and modest symptomatic improvement with cholinesterase inhibitors has been reported.
The last comparison of prevalence figures of dementia across European studies was 10 years ago. Using studies conducted in the 1990s, the authors compare the age- and sex-specific prevalence of dementia, AD, and vascular dementia (VaD) across European population-based studies of persons 65 years and older. Data from these studies were also pooled to obtain stable estimates of age- and sex-specific prevalence. A total of 2346 cases of mild to severe dementia were identified in 11 cohorts. Age-standardized prevalence was 6.4% for dementia (all causes), 4.4% for AD, and 1.6% for VaD. The prevalence of dementia increased continuously with age and was 0.8% in the group age 65 to 69 years and 28.5% at age 90 years and older. The corresponding figures for AD (53.7% of cases) were 0.6% and 22.2%, and for VaD (15.8% of cases), 0.3% and 5.2%. Variation of AD prevalence across studies was greatest for men. In the VaD subtype, a large variation across studies was observed, as well as a difference in prevalence between men and women that was age dependent. Dementia is more prevalent in women, and AD is the main contributor to the steep increase of prevalence with age.
The hippocampal CA1 neurons are selectively vulnerable to global ischemia, and neuronal death occurs in a delayed manner. The threshold of global ischemia duration that induces neuronal death has been studied, but the relationship between ischemia duration and glial death in the hippocampal CA1 area has not been fully studied. We examined neuronal/glial viability and morphological changes in the CA1 subregion after different durations of global ischemia. Global ischemia was induced in Sprague-Dawley rats by 10, 5, and 3 min of bilateral common carotid artery occlusion and hypotension. At 1-56 days after ischemia, the morphological reactions of neurons, astrocytes, oligodendrocytes, and microglia were immunohistochemically evaluated. Most of the hippocampal CA1 pyramidal neurons underwent delayed death at 3 days after 10/5 min of ischemia, but not after 3 min of ischemia. The number of astrocytes gradually declined after 10/5 min of ischemia, and viable astrocytes showed characteristic staged morphological reactions. Oligodendrocytes also showed morphological changes in their processes after 10/5 min of ischemia. Microglia transformed into a reactive form at 5 days only after 10/5 min of ischemia. These data suggest that some morphological changes in glial cells were not dependent on neuronal cell death, but their own reactions to the different severity of ischemia.
Activation of glycolytic genes by HIF-1 is considered critical for metabolic adaptation to hypoxia through increased conversion of glucose to pyruvate and subsequently to lactate. We found that HIF-1 also actively suppresses metabolism through the tricarboxylic acid cycle (TCA) by directly trans-activating the gene encoding pyruvate dehydrogenase kinase 1 (PDK1). PDK1 inactivates the TCA cycle enzyme, pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA. Forced PDK1 expression in hypoxic HIF-1alpha null cells increases ATP levels, attenuates hypoxic ROS generation, and rescues these cells from hypoxia-induced apoptosis. These studies reveal a hypoxia-induced metabolic switch that shunts glucose metabolites from the mitochondria to glycolysis to maintain ATP production and to prevent toxic ROS production.
Early growth response (egr) genes encode transcription factors that are induced by stimuli that cause synaptic plasticity. Here we show that the expression of one member of this family, egr-2, is induced in the orbital frontal cortex (OFC) and medial prefrontal cortex (mPFC) of mice performing an attention-set-shifting task (ASST). The ASST is a series of two-choice perceptual discriminations between different odors and textures. Within the OFC and mPFC, different subregions exhibited egr-2 induction in response to different test-related features. In the medial OFC and the anterior cingulate subregion of the mPFC, egr-2 induction occurred in response to exposure to the novel odor stimulus. In the ventrolateral OFC and the pre- and infralimbic mPFC, additional egr-2 induction occurred during the associative learning phase of the ASST. In the infralimbic mPFC, further egr-2 induction occurred when mice performed set-shifting and reversal learning phases of the ASST. Mice with enhanced set-shifting performance exhibited decreased egr-2 induction in the mPFC indicating that the magnitude of egr-2 induction correlates with the magnitude of attentional demand. This decrease was largest in the infralimbic mPFC suggesting further that egr-2 induction in this region plays a role in the attentional control during set-shifting. In contrast to egr-2, neither egr-1 nor egr-3 expression was altered in ASST-tested mice, and no egr-2 induction occurred in mice that performed a spatial working memory task. These findings suggest a specific role of egr-2-mediated transcriptional activation in cognitive functions associated with attention.
Astragalosides (ASTs) have been traditionally used in the treatment of various cardiovascular and cerebrovascular diseases. The aim of the present study was to investigate the neuroprotective effects of AST on learning and memory following focal cerebral ischemia/reperfusion in a rat model. A Morris water maze was used to measure the effect of AST on learning and memory impairments. A histological examination and Hoechst 33258 staining was used to observe the neuronal changes and apoptosis in the hippocampus. The activity of phospho-extracellular signal‑regulated kinases (p‑ERK), p‑c-Jun N-terminal kinases (JNK) and p‑Akt was measured by western blotting. The data revealed that AST improved the rats learning and memory abilities, attenuated neuronal cells apoptosis, increased the expression of p‑ERK and p‑Akt, and decreased the expression of p‑JNK. These findings indicated that AST has protective effects that may be correlated with the inhibition of neuronal cell apoptosis and the regulation of p‑ERK, p‑Akt and p‑JNK expression.
Vascular dementia or vascular cognitive impairment occurs as a result of persistently compromised blood flow to the brain and represents the second most common type of dementia after Alzheimer's disease. In order to investigate its underlying mechanisms, a mouse model of chronic cerebral hypoperfusion has been developed, which involves the narrowing of the bilateral common carotid arteries with newly designed microcoils. This mouse model provides a unique platform to investigate the mechanisms of angiogenesis following chronic cerebral hypoperfusion and to explore potential drugs or cell therapies designed to enhance angiogenesis as a preclinical step toward developing novel treatments for dementia of vascular origin.
Ischemia induces blood-brain barrier (BBB) disruption by matrix metalloproteases (MMPs) activation, leading to neuronal cell death. Here, we show that fluoxetine inhibits apoptotic cell death of hippocampal neuron and memory impairment by blocking BBB disruption after transient global ischemia. Fluoxetine treatment (10 mg/kg) after global ischemia significantly inhibited mRNA expression of MMP-2 and -9 and reduced MMP-9 activity. By Evan blue assay, fluoxetine reduced ischemia-induced BBB permeability. In parallel, fluoxetine significantly attenuated the loss of occludin and laminin in the hippocampal area after ischemia. By immunostainning with occludin antibody, fluoxetine preserved the integrity of vascular networks, especially in hippocampal areas after injury. Fluoxetine also prevented the infiltration of macrophages and inhibited the mRNA expression of inflammatory mediators after injury. In addition, the activation of microglia and astrocyte in hippocampal regions was significantly attenuated by fluoxetine. Finally, fluoxetine reduced apoptotic cell death of hippocampal neurons as well as vascular endothelial cell death and improved learning and memory. Thus, our study suggests that the neuroprotective effect of fluoxetine is likely mediated by blocking MMP activation followed BBB disruption after transient global ischemia, and the drug may represent a potential therapeutic agent for preserving BBB integrity following ischemic brain injury in humans.
Early growth response gene 1 (Egr1) is a member of the immediate early gene (IEG) family of transcription factors and plays a role in memory formation. To identify EGR1 target genes in brain of Alzheimer's disease (AD) model mice - APP23, we applied chromatin immunoprecipitation (ChIP) followed by high-throughput DNA sequencing (ChIP-seq). Functional annotation of genes associated with EGR1 binding revealed a set of related networks including synaptic vesicle transport, clathrin-mediated endocytosis (CME), intracellular membrane fusion and transmission of signals elicited by Ca(2+) influx. EGR1 binding is associated with significant enrichment of activating chromatin marks and appears enriched near genes that are up-regulated in the brains of APP23 mice. Among the putative EGR1 targets identified and validated in this study are genes related to synaptic plasticity and transport of proteins, such as Arc, Grin1, Syn2, Vamp2 and Stx6, and genes implicated in AD such as Picalm, Psen2 and App. We also demonstrate a potential regulatory link between EGR1 and its newly identified targets in vivo, since conditions that up-regulate Egr1 levels in brain, such as a spatial memory test, also lead to increased expression of the targets. On the other hand, protein levels of EGR1 and ARC, SYN2, STX6 and PICALM are significantly lower in the brain of adult APP mice than in age-matched wild type animals. The results of this study suggest that EGR1 regulates the expression of genes involved in CME, vesicular transport and synaptic transmission that may be critical for AD pathogenesis.
Background:
Hyperbaric oxygen therapy (HBOT) has been used to treat a variety of conditions and has shown possible efficacy for treating vascular dementia (VaD) in experimental and preliminary clinical studies.
Objectives:
To assess the efficacy and safety of HBOT for VaD, used alone or as an adjuvant treatment.
Search methods:
We searched ALOIS: the Cochrane Dementia and Cognitive Improvement Group Specialised Register on 20 December 2011 using the terms: hyperbaric OR oxygen OR HBO OR HBOT. ALOIS contains records of clinical trials identified from monthly searches of a number of major healthcare databases, numerous trial registries and grey literature sources. We also searched the Chinese Biomedical Database (CBM), the Chinese National Knowledge Infrastructure (CNKI) and the VIP Chinese Science and Technique Journals Database on 10 November 2011 using the terms 'gaoyayang', 'xueguanxingchidai' and 'chidai'. In addition, we contacted authors of included studies for additional information.
Selection criteria:
Trials were eligible for inclusion if they were randomised controlled trials comparing HBOT to no intervention or to sham HBOT, or comparing HBOT plus another treatment to the same other treatment in patients with VaD.
Data collection and analysis:
Two review authors independently assessed trial quality and extracted data.
Main results:
One study involving 64 patients was included. It compared HBOT as an adjuvant to donepezil with donepezil alone. This one included study was judged to be of poor methodological quality. Patients receiving HBOT plus donepezil had significantly better cognitive function than the donepezil only group after 12 weeks of treatment, measured by the Mini-Mental State Examination (MMSE) (WMD 3.50; 95% CI 0.91 to 6.09) or by Hasegawa's Dementia Rating Scale (HDS) (WMD 3.10; 95% CI 1.16 to 5.04). There were no deaths or withdrawals, and the study did not mention safety assessment at all. Global function, behavioral disturbance and activities of daily living were not investigated in the study.
Authors' conclusions:
There is insufficient evidence to support HBOT as an effective treatment for patients with VaD. Future trials should be randomised, double-blind comparisons of HBOT to sham HBOT.
The aim of this study was to determine the prevalence of dementia and its major subtypes in China. Forty-eight eligible studies were included in this review. The pooled prevalence for the population aged 60years and older of Alzheimer's disease (AD) was 1.9%, vascular dementia (VaD) was 0.9%, and total dementia was 3.0%. The prevalence of VaD was significantly higher in Northern China than in Southern China. The prevalence of VaD was significantly higher in urban compared to rural areas. The prevalence of dementia and prevalence of AD increased with age in both males and females, and a higher prevalence of AD than VaD was observed in all age groups. AD has become more common than VaD in China since 1990. The current prevalence of dementia in China may be similar to that of developed countries.
The goal of this study was to investigate the mechanisms of nanocopper-induced nephrotoxicity by analyzing renal gene expression profiles phenotypically anchored to conventional toxicological outcomes. Male Wistar rats were given nanocopper (50, 100, 200 mg/kg) and microcopper (200 mg/kg) at different doses for 5 days. We found nanocopper can induce widespread renal proximal tubule necrosis in rat kidneys with blood urea nitrogen and creatinine increase. Whole genome transcriptome profiling of rat kidneys revealed significant alterations in the expression of many genes involved in valine, leucine, and isoleucine degradation, complement and coagulation cascades, oxidative phosphorylation, cell cycle, mitogen-activated protein kinase signaling pathway, glutathione metabolism, and others may be involved in the development of these phenotypes. Results from this study provide new insights into the nephrotoxicity of copper nano-particles and illustrate how toxicogenomic approaches are providing an unprecedented amount of mechanistic information on molecular responses to nanocopper and how they are likely to impact hazard and risk assessment.
Insulin-like growth factor-1 (IGF-1) has been demonstrated to have neuroprotective effects, but little is known concerning its role in vascular dementia (VaD). This study aimed to evaluate expression of IGF-1 signaling in hippocampus in rat model of VaD, and probe the underlying mechanisms. Permanent occlusion of bilateral common carotid arteries (2-VO) was used as VaD model. Learning and memory functions were declined significantly in 2-VO rats, and these impairments were further deteriorated with the prolongation of 2-VO treatment. IGF-1, IGF-1 receptor (IGF-1R), total Akt and phosphorylated Akt (p-Akt) were all measured at 1, 2 and 4 months following 2-VO injury. Compared with controls, IGF-1, IGF-1 mRNA and p-Akt expression were significantly decreased in hippocampus of 2-VO rats. However, changes of IGF-1R and total Akt levels were not significant. These results suggest that down-regulation of IGF-1 and p-Akt may contribute to the impairments of learning and memory functions after 2-VO. IGF-1/IGF-1R signaling system may involved in the onset and development of VaD.
Rats subjected to bilateral common carotid artery (CCA) occlusion or 2-vessel occlusion (2VO) have been used as animal models of subcortical ischemic vascular dementia. However, this model possesses an inherent limitation in that cerebral blood flow (CBF) drops too sharply and substantially after ligation of CCAs. To circumvent such hypoxic-ischemic conditions, we tested implantation of the ameroid constrictor device on bilateral CCAs of male Wistar-Kyoto rats and more precisely replicated chronic cerebral hypoperfusion by gradual narrowing of the CCAs (2-vessel gradual occlusion; 2VGO). The acute cerebral blood flow reduction and resultant inflammatory responses observed in the 2VO rats were eliminated in the 2VGO rats. Thus, chronic cerebral hypoperfusion was segregated, and induced selective white matter changes with relatively preserved neurovascular coupling and substantially less metabolic and histological derangements in the gray matter including the hippocampus. This led to significant spatial working memory impairment of a magnitude similar to the 2VO rats at 28 days postoperation. The 2VGO model may more closely mimic cognitive impairment subsequent to selective white matter damage.
Alzheimer's disease (AD) has been recognized as the most common cause of sporadic dementia. It represents both a medical and social problem, as it affects 10% of over-65 population. Even if the elderly are the most involved population, aging alone cannot be considered as the only cause of this disease. In this review we wanted to focus on the last hypotheses on the possible causes of this neuronal affection. We focused in particular on the role of inflammation and alteration of the inflammatory status that is typical of the elderly and may lead to chronic inflammation. The inflammation seems to be a cause of neuronal impairment and loss. Some studies have proposed a protective role of antiinflammatory drugs. Then we analyzed the role of genetic polymorphisms of some pro-inflammatory substances that seem to be linked to some cases of dementia. The complement system seems to have a role too, as some factors have been found in senile plaques, representing a possible involvement of classical complement pathway. One of the latest hypotheses is about the role of blood-brain barrier (BBB), as its loss of integrity may lead to a passage of proteins in cerebro spinal fluid (CSF), causing a compromised role of BBB in preserving the brain as an "immune sanctuary".
Alzheimer's disease and cerebrovascular disease are two illnesses common to the elderly. Conventional wisdom has sought to separately describe and treat these two diseases. Accumulating evidence, however, shows that cerebrovascular risk factors may cause asymptomatic brain injury, share genetic risk with Alzheimer's disease and possibly accelerate the Alzheimer's process. Such evidence suggests that these two diseases may act additively or synergistically to cause clinical dementia. This review focuses on evolving data that support this hypothesis.
Activity-dependent regulation of Egr1/Zif268, a transcription factor (TF) of the Egr family, is essential for stabilization of dentate gyrus synaptic plasticity and consolidation and reconsolidation of several forms of memory. The gene can be rapidly induced in selective brain circuits after certain types of learning or after recall. Here, we focused on area CA1 and examined regulation of Egr1, Egr2, and Egr3 mRNA and protein, and their DNA binding activity to the Egr response element (ERE) at different times after LTP in vivo and after learning and recall of a fear memory. We found LTP in CA1 leads to rapid induction of the three Egrs, however only Egr1 protein was overexpressed without a co-ordinated change in binding activity, indicating a fundamental difference between CA1 and dentate gyrus LTP. Our investigations in fear memory reveal that both learning and retrieval lead to an increase in binding of constitutively expressed Egr1 and Egr3 to the ERE, but not Egr2. Memory recall was also associated with increased Egr1 protein translation. The nature and temporal dynamics of these changes and tests for interactions between TFs suggest that in addition to ERE-mediated transcription, Egr1 in CA1 may interact with the TF c-Fos to regulate genes via other DNA response elements.
Neural stem cell treatment and neurogenesis stimulation have gained attention as potential treatments for vascular dementia (VD). Currently, research mainly focuses on neurogenesis occurring in the sub-ventricular zone and dentate gyrus, while the research of the piriform cortex (Pir) is limited. Few results showed that weak neurogenesis exists in the Pir of adult rats. Since neurogenesis occurs in the Pir and is closely related to cognitive function, this study addressed the question of whether neurogenesis occurs in the Pir of an animal with the VD. PRIMARY OBJECTIVE AND HYPOTHESIS: This study investigated the effects of hyperbaric oxygen therapy on brain blood supply and neurogenesis in the piriform cortex (Pir) of rats with VD.
Compared to non-VD control rats (NC), rats with VD showed reduced rCBF, increased rCBV and slower MTT in the Pir. However, following hyperbaric oxygen (HBO) treatment in VD rats, rCBF increased, rCBV decreased and MTT increased. To determine whether the restoration in brain blood supply was associated with increased neurogenesis, immunohistochemical detection of nestin and doublecortin (DCX) was used. In the Pir of both normal and VD rats, nestin positive cells were localized to layer II (superficial cellular layer) and layer III (deep cellular layer). Nestin expression was increased in Pir cells in VD rats and was even more intensely expressed after the HBO treatment. DCX positive cells were mostly located in layer II from amygdaline fissure to rhinal fissure.
These results suggest that HBO therapy can improve the blood supply and promote the neurogenesis in the Pir of adult rats with the VD.
Researchers are more and more concerning the safety of fetus or offspring derived from assisted reproductive technology (ART) treatment. As the placenta is a critical organ that sustains and protects the fetus, we hypothesize that altered global gene expression of the placenta subjected to ART manipulation may reflect changes associated with ART procedures and subsequently causal related to offspring health.
Three term placenta samples were obtained from patients undergone in vitro fertilization and embryo transfer due to oviductal factors only. Other three control placentae were from those underwent normal pregnancy. A GeneChip Affymetrix HG-U133 Plus 2.0 Array was utilized to analyze the genes. Using qRT-PCR we certified microarray data from 10 dysregulated genes. Five genes were localized precisely in the placenta as per immunohistochemistry.
Twenty-six differentially expressed genes were identified in the ART-treated placentae: 17 up-regulated; 9 down-regulated. Eighteen of these were classified into six groups according to critical placental function: immune response; transmembrane transport; metabolism; oxidative stress; cell differentiation; and other functions. Genes involved in immune response, such as ERAP2 and STAT4, and those regulating cell differentiations, such as MUC1, were discerned to be differentially expressed. These gene products were expressed in the placental villus tissues, either in the cytoplasm or in the membrane of syncytiotrophoblastic cells.
To our knowledge, this is the first study in comparing differentially expressed genes in placentae from patients undergone ART treatment vs. those underwent normal pregnancy. Abnormal profiles of critical placental functioning genes, such as ERAP2, STAT4 and MUC1, may be valuable biomarkers to understand how the placenta affects fetal development and ART-derived offspring's health problems.
Hydrogen sulfide (H(2)S) is a gaseous messenger and serves as an important neuromodulator in the central nervous system. The current study was undertaken to investigate whether H(2)S attenuates the neuronal injury induced by vascular dementia (VD). Rats were subjected to bilateral common carotid artery and vertebral artery occlusion for 5 min three times in an interval of 5 min to induce VD. An H(2)S donor, sodium hydrosulfide (NaHS) or an inhibitor of cystathionine-beta-synthase, hydroxylamine (HA) was administered intraperitoneally. The number of neurons in the hippocampus was determined by hematoxylin and eosin staining, and the performance of learning and memory was tested by the Morris water maze. H(2)S content in plasma was evaluated. Apoptosis in the hippocampus was assessed by flow cytometry. In addition, Bcl-2 and Bax expression was analyzed by immunohistochemical staining. The neuronal injury occurred gradually with a decreased number of neurons and increased apoptosis ratio in the hippocampus over 720 h after VD. The H(2)S level was also gradually decreased in plasma over 720 h after VD, which negatively correlated with the apoptosis ratio in the hippocampus after VD. In addition, NaHS treatment significantly attenuated neuronal injury and improved neural functional performance, whereas HA exaggerated the neuronal injury and exacerbated learning and memory at 720 h after VD. Furthermore, NaHS treatment markedly improved the ratio of Bcl-2 over Bax with increased Bcl-2 expression and decreased Bax expression. In contrast, HA reduced the ratio of Bcl-2 over Bax. It is suggested that H(2)S attenuates VD injury via inhibiting apoptosis and may have potential therapeutic value for VD.
Despite mortality due to communicable diseases, poverty, and human conflicts, dementia incidence is destined to increase in the developing world in tandem with the ageing population. Current data from developing countries suggest that age-adjusted dementia prevalence estimates in 65 year olds are high (>or=5%) in certain Asian and Latin American countries, but consistently low (1-3%) in India and sub-Saharan Africa; Alzheimer's disease accounts for 60% whereas vascular dementia accounts for approximately 30% of the prevalence. Early-onset familial forms of dementia with single-gene defects occur in Latin America, Asia, and Africa. Illiteracy remains a risk factor for dementia. The APOE epsilon4 allele does not influence dementia progression in sub-Saharan Africans. Vascular factors, such as hypertension and type 2 diabetes, are likely to increase the burden of dementia. Use of traditional diets and medicinal plant extracts might aid prevention and treatment. Dementia costs in developing countries are estimated to be US$73 billion yearly, but care demands social protection, which seems scarce in these regions.
Vascular dementia is almost always associated with organic brain lesions due to ischemia, not with arteriosclerosis alone. In Japan, more than 50% of dementia in population older than 65 years are of vascular origin. Vascular dementia occurs with diffuse vascular lesions in the cerebral white matter or circumscribed lesions in particular areas such as the thalamus, anterior limb of the internal capsule, and cingulate gyrus, all of which constitute the ascending activating system or the limbic system. Vascular dementia is clinically characterized by stepwise progression, fluctuating course and predominant deterioration of intelligence with relative preservation of personality. Reversibility, disproportionate impairment of intelligence and personality, and dementia caused by a focal lesion observed in vascular dementia pose problems with regard to the classical concept of dementia. The similarity and difference between remitting dementia and disturbance of consciousness remain to be scrutinized.
Alzheimer's disease (AD) and vascular dementia (VD) are the two most common causes of dementia. As yet, no definitive biological antemortem marker has been established for differential diagnosis of AD or VD. In this study, proteins of cerebrospinal fluid (CSF) from AD, VD and control patients were analyzed by two-dimensional (2-D) electrophoresis with immobilized pH gradients in the first dimension. No specific changes for AD or VD could be detected in the 2-D CSF patterns. However, a spot of haptoglobin alpha-1 chains (13.5 kDa; approximate pI 4.6) was found to be present in the majority of 2-D CSF maps from the dementia cases, suggesting a high-molecular-weight transudate type of alteration in the blood-brain barrier with considerable frequency in AD.
Antiphospholipid antibodies (aPLAb) may cause both focal ischemic and diffuse brain damage and may be associated with dementia. We have examined the relationship of aPLAb to dementia in the elderly. Blood samples were obtained from 87 consecutive patients with dementia (74 +/- 11 years old) and 69 controls (78 +/- 9 years old), residents of an old age home who were not overtly demented. Levels of aPLAb were measured by a standardized ELISA, utilizing cardiolipin as antigen, and we considered levels above 20 IgG antiphospholipid units (GPLU) as significantly elevated. We found that 5 of the 87 demented patients (6%), but none of the 69 controls, had significantly elevated aPLAb levels (p = 0.03, one-tailed Fisher's exact test). All the patients with high aPLAb levels were diagnosed clinically as having dementia of the Alzheimer type, except for 1 who had mixed dementia, and none had features of an immune-mediated disease. Thus, a small but significant number of patients with dementia have high levels of aPLAb. The role of the aPLAb in these patients, with apparently diffuse brain disease, is currently unknown.
The authors examined the association of incident dementia and subtypes with age, sex, and geographic area in Europe. Incidence data from eight population-based studies carried out in seven European countries were compared and pooled. The pooled data included 835 mild to severe dementia cases and 42,996 person-years of follow-up. In all studies a higher proportion of cases were diagnosed with AD (60 to 70% of all demented cases) than vascular dementia (VaD). The incidence of dementia and AD continued to increase with age up to age 85 years, after which rates increased in women but not men. There was a large variation in VaD incidence across studies. In the pooled analysis, the incidence rates increased with age without any substantial difference between men and women. Surprisingly, higher incidence rates of dementia and AD were found in the very old in northwest countries than in southern countries. This study confirms that AD is the most frequent dementing disorder in all ages, and that there is a higher incidence of dementia, specifically AD, in women than men among the very old. Finally, there may be regional differences in dementia incidence.
Brain ischemia and reperfusion engage multiple independently-fatal terminal pathways involving loss of membrane integrity in partitioning ions, progressive proteolysis, and inability to check these processes because of loss of general translation competence and reduced survival signal-transduction. Ischemia results in rapid loss of high-energy phosphate compounds and generalized depolarization, which induces release of glutamate and, in selectively vulnerable neurons (SVNs), opening of both voltage-dependent and glutamate-regulated calcium channels. This allows a large increase in cytosolic Ca(2+) associated with activation of mu-calpain, calcineurin, and phospholipases with consequent proteolysis of calpain substrates (including spectrin and eIF4G), activation of NOS and potentially of Bad, and accumulation of free arachidonic acid, which can induce depletion of Ca(2+) from the ER lumen. A kinase that shuts off translation initiation by phosphorylating the alpha-subunit of eukaryotic initiation factor-2 (eIF2alpha) is activated either by adenosine degradation products or depletion of ER lumenal Ca(2+). Early during reperfusion, oxidative metabolism of arachidonate causes a burst of excess oxygen radicals, iron is released from storage proteins by superoxide-mediated reduction, and NO is generated. These events result in peroxynitrite generation, inappropriate protein nitrosylation, and lipid peroxidation, which ultrastructurally appears to principally damage the plasmalemma of SVNs. The initial recovery of ATP supports very rapid eIF2alpha phosphorylation that in SVNs is prolonged and associated with a major reduction in protein synthesis. High catecholamine levels induced by the ischemic episode itself and/or drug administration down-regulate insulin secretion and induce inhibition of growth-factor receptor tyrosine kinase activity, effects associated with down-regulation of survival signal-transduction through the Ras pathway. Caspase activation occurs during the early hours of reperfusion following mitochondrial release of caspase 9 and cytochrome c. The SVNs find themselves with substantial membrane damage, calpain-mediated proteolytic degradation of eIF4G and cytoskeletal proteins, altered translation initiation mechanisms that substantially reduce total protein synthesis and impose major alterations in message selection, down-regulated survival signal-transduction, and caspase activation. This picture argues powerfully that, for therapy of brain ischemia and reperfusion, the concept of single drug intervention (which has characterized the approaches of basic research, the pharmaceutical industry, and clinical trials) cannot be effective. Although rigorous study of multi-drug protocols is very demanding, effective therapy is likely to require (1) peptide growth factors for early activation of survival-signaling pathways and recovery of translation competence, (2) inhibition of lipid peroxidation, (3) inhibition of calpain, and (4) caspase inhibition. Examination of such protocols will require not only characterization of functional and histopathologic outcome, but also study of biochemical markers of the injury processes to establish the role of each drug.
We examined the effects of the immunosuppressant tacrolimus (FK506) on the discrimination learning impairment induced by chronic cerebral hypoperfusion in rats. Chronic cerebral hypoperfusion was prepared by permanent ligation of bilateral common carotid arteries for male Wistar rats aged 9 weeks. FK506 (0.05 mg/kg, s.c.) recovered the learning impairment and also prevented the rarefaction of white matter and striatal neuronal cell damage. Our findings suggest that FK506 ameliorates the learning impairment mainly due to preventing neuropathological alterations.
Accumulated evidence indicates that the adenylyl cyclase (AC)/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/cAMP-responsive element binding protein (CREB) signal transduction system may be linked to learning and memory function.
The effects of nefiracetam, which has been developed as a cognition enhancer, on spatial memory function and the AC/cAMP/PKA/CREB signal transduction system in rats with sustained cerebral ischaemia were examined.
Microsphere embolism (ME)-induced sustained cerebral ischaemia was produced by injection of 700 microspheres (48 μm in diameter) into the right hemisphere of rats. Daily oral administration of nefiracetam (10 mg kg−1 day−1) was started from 15 h after the operation.
The delayed treatment with nefiracetam attenuated the ME-induced prolongation of the escape latency in the water maze task that was examined on day 7 to 9 after ME, but it did not reduce the infarct size.
ME decreased Ca2+/calmodulin (CaM)-stimulated AC (AC-I) activity, cAMP content, cytosolic PKA Cβ level, nuclear PKA Cα and Cβ levels, and reduced the phosphorylation and DNA-binding activity of CREB in the nucleus in the right parietal cortex and hippocampus on day 3 after ME. The ME-induced changes in these variables did not occur by the delayed treatment with nefiracetam.
These results suggest that nefiracetam preserved cognitive function, or prevented cognitive dysfunction, after sustained cerebral ischaemia and that the effect is, in part, attributable to the prevention of the ischaemia-induced impairment of the AC/cAMP/PKA/CREB signal transduction pathway.
British Journal of Pharmacology (2003) 138, 642–654. doi:10.1038/sj.bjp.0705096
Some cytokines have been involved in the pathogenesis of late onset Alzheimer's disease (LOAD). A possible increase in plasma cytokines levels has been reported in LOAD and vascular dementia (VD), but the results of previous studies are conflicting. We evaluated the plasma levels of IL-6, TNF-alpha, IL-1beta, and IL-10 in four groups of older individuals: 60 patients with LOAD, 80 patients with VD, 40 subjects with cerebrovascular disease but without dementia (CDND), and 42 controls (C). By analysis of covariance (adjustment for age, gender, coronary heart disease, diabetes, hypertension, smoking, and alcohol consumption) we found that: *IL-1beta was higher in VD, LOAD, and CDND compared with controls (p<0.005). *TNF-alpha was higher in VD and LOAD compared to C (p<0.05), and in VD compared to LOAD (p<0.03). *IL-6 was higher in VD compared with LOAD (p<0.03). No differences in IL-10 values were found (Kruskal-Wallis, Asymp. Sig. 0.14). By logistic regression analysis, we demonstrated that high levels (defined as above the median) of IL-1beta and TNF-alpha, but not of IL-6, were associated with increased likelihood of having VD and LOAD compared to C, while high IL-6 levels were associated with a increased probability of having VD, compared with LOAD. Our study support the notion of a low-grade systemic inflammation in older patients with LOAD or VD, characterized by an increase in plasma IL-1beta and TNF-alpha levels. The high IL-6 levels found in VD might be not a specific finding, as it might come from several conditions including atherosclerosis and related vascular risk factors, comorbidity, and frailty.
The most distinctive feature of Alzheimer's disease (AD) is the specific degeneration of the neurons involved in memory consolidation, storage, and retrieval. Patients suffering from AD forget basic information about their past, loose linguistic and calculative abilities and communication skills. Thus, understanding the etiology of AD may provide insights into the mechanisms of memory and vice versa. The brain is an immunologically privileged site protected from the organism's immune reactions by the blood-brain barrier (BBB). All risk factors for AD (both cardiovascular and genetic) lead to destruction of the BBB. Evidence emerging from recent literature indicates that AD may have an autoimmune nature associated with BBB impairments. This hypothesis suggests that the process of memory consolidation involves the synthesis of novel macromolecules recognized by the immune system as "non-self" antigens. The objective of this paper is to stimulate new approaches to studies of neural mechanisms underpinning memory consolidation and its breakdown during AD. If the hypothesis on the autoimmune nature of AD is correct, the identification of the putative antigenic macromolecules might be critical to understanding the etiology and prevention of AD, as well as for elucidating cellular mechanisms of learning and memory.
Inflammation has been involved in the development of dementia in cerebrovascular diseases. To investigate the cellular activation of the peripheral immune system in patients with Alzheimer's disease (AD) and vascular dementia (VaD), we determined the presence of IL-18 and TGF-beta1 in the plasma by using ELISA. The levels of IL-18 and TGF-beta1 were significantly elevated in patients with AD and VaD compared to non-demented, age-matched subjects. We found an inverse correlation between the levels of IL-18 and TGF-beta1 in AD patients. In VaD patients, the correlation between IL-18 and TGF-beta1 reached a borderline positive value. Whereas, in the non-demented, age-matched subjects, a positive correlation between IL-18 and TGF-beta1 levels was observed. These findings indicate that IL-18 and TGF-beta1 elevation is associated with AD and VaD patients, confirming that the immune system might exert a remarkable role in the development and progression of neurodegenerative disorders. Moreover, as different modifications were detected in the patients affected by AD and VaD, we propose that IL-18 and TGF-beta1 plasma levels might represent possible differential biomarkers.
In older individuals, inflammatory mechanisms have been linked to the pathogenesis of both dementia and functional impairment. In this cross-sectional study we have investigated the possible association between some markers of systemic inflammation and functional status, in a sample of one hundred and forty older demented patients including 60 patients with late onset Alzheimer's disease (LOAD) and 80 with vascular dementia (VD). Functional status was evaluated by Barthel Index (BI); the total score ranged from 0 (total dependency) to 20 (total autonomy). Interleukin-1β, Tumor Necrosis Factor-α, Interleukin- 6, Interleukin- 8, and Transforming Grow Factor β were quantified by ELISA. Among the cytokines evaluated, only IL-6 was correlated with the BI (r: −0.32, p < 0.001). The mean levels of IL-6 progressively decreased from I (9.50 pg/mL), to II (6.40 pg/mL), to III BI tertile (4.80 pg/mL) (p < 0.02).
At multiple regression analysis, IL-6 was associated with BI in the whole sample and in VD, but not in LOAD, independent of age, gender, smoking, alcohol consumption, hypertension, diabetes, coronary heart disease, previous stroke, and mini mental state examination score.
Our study suggests the existence of an independent and negative relationship between IL-6 plasma levels and functional status in older individuals with vascular dementia. This finding might contribute to explain the ‘excess of disability’ phenomenon described in older demented patients. Copyright