neuropeptide-y and Stroke

Ischemic stroke is the third leading cause of death and disability worldwide, with no available satisfactory prevention or treatment approach. The current treatment is limited to the use of "reperfusion methods," i.e., an intravenous or intra-arterial infusion of a fibrinolytic agent, mechanical removal of the clot by thrombectomy, or a combination of both methods. It should be stressed, however, that only approximately 5% of all acute strokes are eligible for fibrinolytic treatment and fewer than 10% for thrombectomy. Despite the tremendous progress in understanding of the pathomechanisms of cerebral ischemia, the promising results of basic research on neuroprotection are not currently transferable to human stroke. A possible explanation for this failure is that experiments on in vivo animal models involve healthy young animals, and the experimental protocols seldom consider the importance of protecting the whole neurovascular unit (NVU), which ensures intracranial homeostasis and is seriously damaged by ischemia/reperfusion. One of the endogenous protective systems activated during ischemia and in neurodegenerative diseases is represented by neuropeptide Y (NPY). It has been demonstrated that activation of NPY Y2 receptors (Y2R) by a specific ligand decreases the volume of the postischemic infarction and improves performance in functional tests of rats with arterial hypertension subjected to middle cerebral artery occlusion/reperfusion. This functional improvement suggests the protection of the NVU. In this review, we focus on NPY and discuss the potential, multidirectional protective effects of Y2R agonists against acute focal ischemia/reperfusion injury, with special reference to the NVU.

Topics: Animals; Brain Ischemia; Humans; Infarction, Middle Cerebral Artery; Ischemia; Ligands; Neuropeptide Y; Rats; Reperfusion; Stroke

Neuropeptide Y (NPY) has a modulatory role in learning and memory, and is involved in the pathophysiology of neurodegenerative diseases. However, there was no population-based evidence on the relationship between NPY and post-stroke cognitive impairment (PSCI). We aimed to prospectively examine the association between plasma NPY and cognitive impairment among patients with acute ischemic stroke.. On the basis of samples from the China Antihypertensive Trial in Acute Ischemic Stroke, 593 patients with baseline plasma NPY levels were finally included in this study. The study outcome was cognitive impairment (Montreal Cognitive Assessment score < 26) at 3 months after ischemic stroke. Logistic regression models were used to estimate the risk of cognitive impairment.. After 3 months of follow-up, 422 participants (71.2 %) experienced cognitive impairment. Multivariable-adjusted odds ratio (95 % confidence interval) for the highest tertile of NPY was 0.58 (0.36-0.92) compared with the lowest tertile. Each 1-SD higher log-NPY was associated with a decreased risk of 20 % (95 % confidence interval 2 %-34 %) for PSCI. The addition of plasma NPY to the basic model with conventional risk factors improved the risk reclassification (continuous net reclassification index was 22.8 %, p = 0.01; integrated discrimination improvement was 0.9 %, p = 0.02) for PSCI.. We measured plasma NPY only once at baseline and failed to explore the association between NPY changes and PSCI.. Elevated plasma NPY levels were associated with a decreased risk of cognitive impairment, suggesting plasma NPY may serve as a predictive factor and potential therapeutic target for PSCI.

Topics: Antihypertensive Agents; Brain Ischemia; Clinical Trials as Topic; Cognitive Dysfunction; Humans; Ischemic Stroke; Neuropeptide Y; Stroke

Post-ischemic stroke epilepsy (PISE) is one of the common complications of stroke.. Methods To determine the risk factors of PISE, in this study, 78 patients with PISE and 86 patients without PISE were recruited. Clinical data and serum neuropeptide Y (NPY) levels were collected and the relative factors including clinical data and serum were analyzed.. Logistic regression showed that low serum NPY was significantly associated with PISE. Every 5 ng/ml increment of serum NPY was associated with 62% risk decrease in patients with PISE. The area under curve of serum NPY was 0.910 with a sensitivity of 84.62% and a specificity of 86.05%. The cut-off value of serum NPY was 90 ng/ml. According to cut-off value of serum NPY, the percentage of patients with PISE decreased from 84.6% in low serum NPY group to 14.0% in high serum NPY group. Furthermore, patients were divided into different tertiles according to serum NPY. The percentage of patients with PISE reduced from 90.0% in the lowest tertile (NPY < 85 ng/ml) to 3.5% in the highest tertile (NPY ≥ 105 ng/ml). Compared with patients with normal video-electroencephalogram (VEEG), serum NPY levels significantly decreased in patients with abnormal VEEG; however, serum NPY levels were not associaated with epileptic seizure subtypes.. Serum NPY was an independent risk factor for PISE. Targeting serum NPY may be used to the prevention and treatment of PISE.

Topics: Aged; Aged, 80 and over; Biomarkers; Case-Control Studies; Electroencephalography; Epilepsy; Female; Humans; Male; Middle Aged; Neuropeptide Y; Predictive Value of Tests; Risk Assessment; Risk Factors; Stroke

It has been reported that plasma NPY levels were increased in obesity, type 2 diabetes mellitus and hypertension. The symptoms of metabolic syndrome frequently appear in patients with acute ischemic stroke. The association between plasma NPY levels and metabolic markers in women with acute ischemic stroke was investigated in the current study.. Plasma NPY concentrations were determined using radioimmunoassay in 58 women aged 60-85 (mean age: 76.5±0.8) with acute ischemic stroke and in 24 women aged 63-67 (mean age: 65.6±0.6) of the control group. Stroke was defined according to the NIHSS (National Institute of Health Stroke Scale) and was confirmed using CT or MR scan.. The prevalence of type 2 diabetes, hypertension and insulin resistance was higher in the group of patients with stroke. Plasma NPY levels measured during the 1st day and 10 days after the acute phase of stroke were significantly lower (p<0.001) compared to the control group.. In women with acute ischemic stroke plasma NPY concentrations were decreased in spite of higher frequency of the occurrence of the symptoms of metabolic syndrome.

Topics: Aged; Aged, 80 and over; Biomarkers; Brain Ischemia; Diabetes Mellitus, Type 2; Female; Humans; Hypertension; Middle Aged; Neuropeptide Y; Obesity; Radioimmunoassay; Stroke

Stroke is the second most common cause of death in developed countries and a major cause of adult disability and mortality worldwide. New data strongly suggest that neuropeptide Y (NPY) may be a candidate gene for ischemic stroke.. We investigated 450 ischemic stroke patients and 423 healthy controls matched for sex and age in a Han Chinese population. Three functional polymorphisms (-883TGins/del, -602G/T and -399 T/C) located in NPY gene promoter were genotyped using DNA sequencing methods.. Of 3 NPY polymorphisms investigated in our study, the -399CC genotype (OR: 1.699, 95% CI: 1.124-2.567, P=0.011) and the -399C allele (OR: 1.254, 95% CI: 1.031-1.524, P=0.023) were more frequent among ischemic stroke patients than in controls, especially in the small vessel disease (SVD) subtype patients. The similar results were observed in multivariable logistic regression analysis. Haplotype analysis revealed that the -883ins/-399C haplotype was a risk marker for ischemic stroke (P=0.008).. The C allele of -399 T/C polymorphism in the promoter regions of NPY is an independent risk factor for ischemic stroke, suggesting that NYP system may involve in the mechanisms of stroke pathology.

Topics: Aged; Asian People; Brain Ischemia; Case-Control Studies; Female; Gene Frequency; Haplotypes; Humans; Logistic Models; Male; Neuropeptide Y; Polymorphism, Genetic; Stroke

In our previous study, the neuropeptide Y (NPY) C-399T promoter polymorphism (rs16147C>T) was identified as a risk factor for ischemic stroke in Koreans. In this study, we investigated whether age and sex modify the genetic effect of C-399T on susceptibility to ischemic stroke.. A total of 1,350 subjects (802 ischemic stroke patients, 548 healthy controls) were genotyped for C-399T using a primer extension method. The results were statistically analyzed for the genetic association of C-399T with ischemic stroke and clinical parameters.. The TT genotype for C-399T was observed at a significantly lower frequency in stroke patients relative to control (CC+CT vs. TT, odds ratio [OR]=0.578, 95% confidence interval [95% CI]=0.360-0.927, P<0.05). This trend was also observed in female (OR=0.495, 95% CI=0.240-1.022) and older subjects (y>60, OR=0.556, 95% CI=0.304-1.018) with borderline statistical significance (P=0.0571 and P=0.0574, respectively). However, C-399T allele frequency was not different between controls and stroke patients in any groups. The C-399T polymorphism was found to be associated with body mass index and levels of some blood lipids.. The C-399T NPY promoter polymorphism should be considered a genetic risk factor for ischemic stroke in the older adult and female Korean populations.

Topics: Age Factors; Aged; Brain Ischemia; Female; Genetic Predisposition to Disease; Humans; Immunoenzyme Techniques; Korea; Male; Middle Aged; Neuropeptide Y; Promoter Regions, Genetic; Sex Factors; Stroke

The common sequence variants of neuropeptide Y (NPY) were known to be associated with some kinds of diseases including stroke. This study investigated the association of NPY promoter polymorphism, C-399T, with ischemic stroke and its underlying mechanism using in vitro systems.. Study subjects consisted of 444 ischemic stroke patients and 326 controls without stroke. C-399T genotyping was conducted by a primer extension-based method. Plasma NPY was quantified with an enzyme immunoassay, and transcription characteristics were investigated by a reporter gene assay and an enzyme mobility shift assay.. A significantly lower frequency of TT genotype was observed in a stroke group (OR[95% CI], 0.399[0.187-0.854], p=0.0180). The C-399T polymorphism affected the transcription efficiency of NPY gene and its genotypes were related to the changes in plasma NPY levels.. This study suggests that NPY promoter polymorphism, C-399T, should be considered a genetic risk factor for ischemic stroke.

Topics: Aged; Base Sequence; Brain Ischemia; Case-Control Studies; DNA Primers; Female; Genetic Predisposition to Disease; Humans; Immunoenzyme Techniques; Male; Middle Aged; Neuropeptide Y; Polymerase Chain Reaction; Polymorphism, Genetic; Promoter Regions, Genetic; Stroke

Knowledge of the genetic architecture of ischemic stroke has been quite limited. Most significant associations of candidate genes with ischemic stroke have been difficult to replicate. This might be because the associations were not strong enough for results to be consistent, and testing a mixture of heterogeneous ischemic strokes might lead to confounded genetic associations.. A preliminary association analysis with 28 sequence variants in 18 candidate genes (ACE, AGT, AGTR1, BDNF, CRP, F13B, LIF, MMP9, NPPA, NPY, PTGS2, SELP, SERPINE1, SREBF2, TFPI, THBD, VCAM1, and VEGF) revealed that NPY might be the most responsible for the susceptibility of ischemic stroke. Forty-five variants were discovered in the NPY gene by full sequencing, and 5 polymorphisms were selected based on their allele frequency and linkage disequilibrium estimates to conduct a thorough examination of their associations with ischemic stroke and its subtypes classified by TOAST. This study was conducted with 271 patients with ischemic stroke and 455 control subjects.. In contrast to a slight significance for an allelic association with ischemic stroke, remarkable discrepancies between haplotype frequencies of control subjects and patients were found. Especially, TA and CC of the haplotypes composed of C4112T and A6411C in the NPY gene were associated with increased risk (P=1.8 x 10(-21), P=2.0 x 10(-13)). The interchanged haplotypes, TC and CA, were protective against the diseases (P=9.3 x 10(-12), P=6.0 x 10(-17)). The associations were also shown in major subtypes of ischemic stroke.. This remarkable haplotypic association suggested that the interaction between the 2 common sequence polymorphisms in NPY contributed to a great amount of phenotypic variability of ischemic stroke.

Topics: Aged; Brain Ischemia; Female; Genetic Predisposition to Disease; Genetic Variation; Haplotypes; Humans; Linkage Disequilibrium; Male; Middle Aged; Neuropeptide Y; Phenotype; Polymorphism, Genetic; Stroke

A distinctive feature of galanin expression is that it is extensively increased by neuronal injury, estrogens, Alzheimer's disease and during development. Since stroke is amongst the clinically most important causes of neuronal injury we studied the tissue concentrations of galanin in a rat stroke model and the possibility of modulating this effect with estrogen. Transient focal middle cerebral artery ischemia was induced in rats that 2 weeks earlier underwent ovariectomy and received 1.5mg 17beta-estradiol slow-release or placebo pellets. The concentrations of galanin and neuropeptide Y were measured after observation periods of 3, 7 and 14 days in extracts of punch biopsies from both the lesioned and the contra lateral control hemisphere. The galanin levels were not changed in any of the brain regions studied except in the hippocampus where they were lower in the ischemic hemisphere in both the estrogen- and placebo-treated animals compared to the corresponding contra lateral intact hemisphere (p=0.015). Estrogen treatment up-regulated galanin concentrations in both the ventral and dorsal hippocampus (p=0.003). The effects on the galanin concentrations were similar after all observation periods: 3, 7 and 14 days (p=0.144). No significant changes were observed in the concentration of neuropeptide Y in response to the lesions. The ischemic lesions were markedly larger in the estrogen-treated animals observed after 3 days compared to the corresponding control group. In the estrogen group the lesion was largest at bregma and the slice 2mm anterior to the bregma, 82% and 435% larger than in the control group (p<0.001). A similar, but much less pronounced (not statistically significant) difference was seen in the groups observed after 7 and 14 days. Earlier studies of lesions in the peripheral and central nervous systems have generally shown an up-regulation of galanin markers in response to but at a distance from the injury. Our results indicate that galanin is not involved in the response of the ischemic penumbra itself to stroke, whereas it may participate in the reactions of the neural stem-cell rich hippocampus to stroke.

Topics: Animals; Brain Chemistry; Brain Ischemia; Cerebellum; Corpus Striatum; Estradiol; Female; Galanin; Hippocampus; Neurons; Neuropeptide Y; Rats; Rats, Sprague-Dawley; Stroke

The neuropeptide Y (NPY) signal peptide polymorphism T1128C has been linked to several risk factors for cardiovascular disease. The aim of the present study was to evaluate the significance of this polymorphism for cardiovascular and cerebrovascular disease outcome.. In a prospective study cohort, 1032 hypertensive patients (174 myocardial infarction and 170 stroke patients and 688 matched controls) were analysed for the T1128C polymorphism in the NPY gene.. The dynamic allele specific hybridization (DASH) method was used for genotyping. Serum from the same participants was analysed for total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and triglycerides.. The frequency of the NPY T1128C polymorphism was 8.4% among patients with a myocardial infarction or stroke, as compared to 5.1% in the control group (P = 0.040). The difference remained significant after adjustment for the cardiovascular risk factors age, sex, smoking status, body mass index, systolic and diastolic blood pressure, presence of diabetes, total cholesterol, HDL, LDL and triglycerides.. The present study indicates that the NPY T1128C polymorphism is an independent predictor for myocardial infarction and stroke in a Swedish hypertensive population.

Topics: Female; Genotype; Humans; Hypertension; Male; Middle Aged; Neuropeptide Y; Phenotype; Polymorphism, Genetic; Predictive Value of Tests; Protein Sorting Signals; Risk Factors; Stroke; Sweden

The aim of the present study was to compare in man the innervation pattern and the functional responses to neuronal messengers in medium sized lenticulostriate and branches of the posterior cerebral arteries (PCA). The majority of the nerve fibers found were sympathetic and displayed specific immunoreactivity for tyrosine hydroxylase (TH) and neuropeptide Y (NPY). Only few nerve fibers displayed vasoactive intestinal polypeptide (VIP), calcitonin gene-related peptide (CGRP) and substance P (SP) immunoreactivity. In both arteries, the contractions induced by noradrenaline (NA), NPY and 5-hydroxytryptamine (5-HT) and the relaxant responses induced by acetylcholine (ACh), VIP and pituitary adenylate cyclase activating peptide-27 (PACAP) as well as CGRP and SP were compared in vitro. In conclusion, there was no major difference in innervation pattern or vasomotor sensitivity (pEC50 and pIC50 values) between the two vessels. However, the general pattern indicates stronger vasomotor responses (Emax and Imax) in the PCA branches as compared to the lenticulostriate arteries which may lend support for the clinical observation of a difference in stroke expression between the two vascular areas.

Topics: Acetylcholine; Basal Ganglia; Cerebral Arteries; Humans; Immunohistochemistry; Muscle Contraction; Muscle Relaxation; Nerve Growth Factors; Neuropeptide Y; Neuropeptides; Neurotransmitter Agents; Norepinephrine; Parasympathetic Nervous System; Pituitary Adenylate Cyclase-Activating Polypeptide; Posterior Cerebral Artery; Serotonin; Stroke; Vasoactive Intestinal Peptide; Vasomotor System

To explore the role of brain-derived neurotrophic factor for survival and generation of striatal neurons after stroke, recombinant adeno-associated viral vectors carrying brain-derived neurotrophic factor or green fluorescent protein genes were injected into right rat substantia nigra 4-5 weeks prior to 30 min ipsilateral of middle cerebral artery occlusion. The brain-derived neurotrophic factor-recombinant adeno-associated viral transduction markedly increased the production of brain-derived neurotrophic factor protein by nigral cells. Brain-derived neurotrophic factor was transported anterogradely to the striatum and released in biologically active form, as revealed by the hypertrophic response of striatal neuropeptide Y-positive interneurons. Animals transduced with brain-derived neurotrophic factor-recombinant adeno-associated virus also exhibited abnormalities in body posture and movements, including tilted body to the right, choreiform movements of left forelimb and head, and spontaneous, so-called 'barrel' rotation along their long axis. The continuous delivery of brain-derived neurotrophic factor had no effect on the survival of striatal projection neurons after stroke, but exaggerated the loss of cholinergic, and parvalbumin- and neuropeptide Y-positive, gamma-aminobutyric acid-ergic interneurons. The high brain-derived neurotrophic factor levels in the animals subjected to stroke also gave rise to an increased number of striatal cells expressing doublecortin, a marker for migrating neuroblasts, and cells double-labelled with the mitotic marker, 5-bromo-2'-deoxyuridine-5'monophosphate, and early neuronal (Hu) or striatal neuronal (Meis2) markers. Our findings indicate that long-term anterograde delivery of high levels of brain-derived neurotrophic factor increases the vulnerability of striatal interneurons to stroke-induced damage. Concomitantly, brain-derived neurotrophic factor potentiates the stroke-induced neurogenic response, at least at early stages.

Topics: alpha-Methyltyrosine; Analysis of Variance; Animals; Behavior, Animal; Brain-Derived Neurotrophic Factor; Bromodeoxyuridine; Cell Count; Cell Death; Cell Size; Choline O-Acetyltransferase; Corpus Striatum; Dependovirus; Disease Models, Animal; Doublecortin Domain Proteins; Doublecortin Protein; ELAV Proteins; Electroencephalography; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Green Fluorescent Proteins; Homeodomain Proteins; Immunohistochemistry; Infarction, Middle Cerebral Artery; Luminescent Proteins; Male; Microscopy, Confocal; Microtubule-Associated Proteins; Nerve Tissue Proteins; Neurons; Neuropeptide Y; Neuropeptides; Parvalbumins; Radiation-Sensitizing Agents; Rats; Rats, Wistar; RNA-Binding Proteins; Stroke; Substantia Nigra; Transduction, Genetic

In a rat endovascular middle cerebral artery occlusion (MCAO) stroke model, we previously showed that intracerebroventricular (ICV) injection of neuropeptide Y (NPY) or an Y1 receptor agonist, [Leu(31),Pro(34)]-NPY, increased the infarct volume, that an Y1 receptor antagonist, BIBP3226, reduced the infarct volume, and that an Y2 receptor agonist, NPY3-36, had no effect. In this study, we used electron paramagnetic resonance (EPR) spectroscopy to measure nitric oxide (NO) and examined how ICV administration of NPY or its receptor analogs would modulate the brain NO level between the bregma levels +2 and -4 mm during MCAO, since excessive NO mediates ischemic damage. The relative brain NO concentration was increased to 131.94 +/- 7.99% (mean +/- SEM; n = 8) at 15 min of MCAO. NPY treatment further increased the relative brain NO concentration to 250.94 +/- 50.48% (n = 8), whereas BIBP3226 significantly reduced the brain NO concentration to 69.63 +/- 8.84% (n = 8). [Leu(31),Pro(34)]-NPY (137.61 +/- 14.54%; n = 7) or NPY3-36 (129.23 +/- 21.77%; n = 8) did not affect the brain NO concentration at 15 min of MCAO. Our results suggest that the NPY-Y1 receptor activation mediates ischemic injury via NO overproduction and that inhibition of the Y1 receptor may confer protection via suppression of excessive NO production during ischemia.

Topics: Animals; Arginine; Brain; Electron Spin Resonance Spectroscopy; Injections, Intra-Arterial; Injections, Intraventricular; Male; Neuropeptide Y; Nitric Oxide; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; Stroke