neuropeptide-y and Brain-Ischemia

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

This review describes the neuropathology and pathophysiology of interneurons in dorsal hippocampus of the adult rat subjected to transient global cerebral ischemia. The object is to verify if the interneurons die or survive after an ischemic insult, and study if ischemia changes GABA inhibition in the period preceding delayed CA1 pyramidal cell death. The findings are discussed from the point of the hypothesis that loss of GABA inhibition may result in excitatory hyperactivity (possibly epilepsy) and excitotoxic glutamate release. Thereby, early ischemic damage to interneurons may exacerbate the ischemic process resulting in the major and delayed CA1 cell death in hippocampus. Interneurons, located in dentate hilus, and a small number of interneurons located in the mossy fiber layer are selectively lost after ischemia. These interneurons contain somatostatin and neuropeptide Y, but the inhibitory or excitatory nature of them is unknown. However, counts of all hippocampal cells immunoreactive for glutamic acid decarboxylase showed that the GABA interneurons survive ischemia. It is therefore suggested that the vulnerable interneurons in hilus and the mossy fiber layer do not contain GABA. As the GABA interneurons, other hippocampal interneurons also survive ischemia. Among these, the CA1 and CA3 interneurons containing neuropeptide Y demonstrate permanently reduced immunoreactivity for neuropeptide Y, evident 1-2 days after ischemia. Another subpopulation transiently shows a decrease in immunoreactivity for parvalbumin approximately 4 days after ischemia. These results are in contrast to the finding that protein synthesis in hippocampal interneurons returns to preischemic levels 9 hours after ischemia. The integrity between excitation and inhibition in CA1 is unchanged in hippocampal slices taken from animals 1-2 days after ischemia. Furthermore, GABA can readily be released upon potassium stimulation in the period preceding CA1 pyramidal cell death. Binding to hippocampal benzodiazepine sites, however, declines prior to ischemic CA1 pyramidal cell death. It is demonstrated that administration of diazepam and GABA uptake inhibitors during this period offers postischemic neuron protection in CA1. There is no conclusive evidence of excitatory hyperactivity preceding ischemic CA1 pyramidal cell death. On the contrary, results from Chang et al. (1) suggest that ischemic loss of interneurons in the dentate hilus is associated with an increase in inhibition. Howe

Topics: Animals; Autoradiography; Brain Ischemia; Calcium-Binding Proteins; Cell Death; Cholecystokinin; Disease Models, Animal; gamma-Aminobutyric Acid; Glutamate Decarboxylase; Hippocampus; Interneurons; Neuropeptide Y; Pyramidal Cells; Rats; Receptors, GABA; Somatostatin

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

Glucagon-like peptide 1 receptor (GLP-1R) agonists administered before or immediately after induction of experimental stroke have been shown to provide acute neuroprotection. Here, we determined whether delayed treatment with a GLP-1R agonist could improve metabolic and functional recovery after stroke. Rats were subjected to middle cerebral artery occlusion (MCAO) and given the well-established GLP-1R agonist liraglutide (50, 100, or 200μg/kg) or normal saline (NS) daily for 4 weeks, starting 1 day after MCAO. Cerebral glucose metabolism and neurological deficits were evaluated using

Topics: Adenosine Triphosphate; Animals; Brain Ischemia; Eating; Energy Metabolism; Glucagon-Like Peptide-1 Receptor; Liraglutide; Male; Membrane Proteins; Mice, Inbred C57BL; Mice, Knockout; Nerve Tissue Proteins; Neuropeptide Y

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

The aim of this study was to define all the areas of changes in expression of nuclear c-Fos protein (c-Fos), cytoplasmic somatostatin (SS) and neuropeptide Y (NPY) in rat brain during experimental ischemia. Using the immunohistochemical method, brain mapping (based on the atlas by Paxinos & Watson) of immunoreactivity for c-Fos, SS and NPY in 39 rats, was studied in telencephalon, diencephalon and midbrain after resistant and transitory ischemia. The first experimental group (R group) was exposed to resistant ischemia by occlusion (10 minutes) of four vessels according to the Pulsinelli method. The second group was first exposed to transitory (4 minutes) ischemia (preconditioning) and, after 72 hours, to total ischemia as in the R group. There was a statistical difference between the R and T group in the c-Fos reaction, especially in the parietofrontal cortex, anterior amygdaloid area, claustrum, reuniens nucleus and suprachiasmatic nucleus. The dominant immunohistochemical reactivity was found for c-Fos protein, and the most reactive in terms of co-localization of c-Fos with SS and NPY was periventricular area of hypothalamus. The mapping showed that both, phylogenetically new as well as phylogenetically older brain structures reacted immunohistochemically. The results of our study, regarding the impact of preconditioning with a short period of ischemia on c-Fos activity and co-localization of c-Fos with SS and NPY immunoreactivity, showed the need for future studies of brain neuropeptides related to regional and time effects, and indicated brain structures which may require pharmacological targeting to achieve neuroprotective level of proto-oncogene activity in populations at risk.

Topics: Animals; Brain; Brain Ischemia; Brain Mapping; Disease Models, Animal; Neuropeptide Y; Proto-Oncogene Proteins c-fos; Rats; Rats, Wistar; Risk Factors; Somatostatin

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

To observe the effect of electroacupuncture (EA) on the contents of hippocampal calcitonin gene-related peptide (CGRP) and neuropeptide Y (NPY) in cerebral ischemia (CI) rats.. Forty SD rats were randomly divided into normal control, sham operation (sham), model and EA groups with 10 cases in each. CI model was duplicated by middle cerebral artery occlusion. EA (2 Hz, 1 mA, continuous waves) was applied to "Shuigou" (GV 26) for 30 min, once daily for 5 days. Hippocampal tissue was taken for assaying the contents of CGRP and NPY with radioimmunoassay.. Compared with sham group and normal control group, hippocampal CGRP content in model group decreased apparently (P<0.01), while NPY content of model group increased significantly (P<0.01). Compared with model group, hippocampal CGRP in EA group increased considerably (P<0.01) and NPY content decreased obviously (P<0.01).. Electroacupuncture of GV26 can effectively adjust hippocampal CGRP and NPY contents in CI rats, which may contribute to its effect in improving cerebral ischemia.

Topics: Acupuncture Points; Animals; Brain Ischemia; Calcitonin Gene-Related Peptide; Disease Models, Animal; Electroacupuncture; Female; Hippocampus; Humans; Male; Neuropeptide Y; Random Allocation; Rats

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

Peroxisome proliferator-activated receptors (PPARs) are involved in energy expenditure, regulation of inflammatory processes, and cellular protection in peripheral tissues. Among the different types of PPARs, PPARbeta is the only one to be widely expressed in cortical neurons. Using PPARbeta knockout (KO) mice, we report here a detailed investigation of the role of PPARbeta in cerebral ischemic damage, associated inflammatory and antioxidant processes as well as food intake regulation after middle cerebral artery occlusion (MCAO). The PPARbeta KO mice had a two-fold increase in infarct size compared with wild-type (WT) mice. Brain oxidative stress was dramatically enhanced in these KO mice, as documented by an increased content of malondialdehyde, decreased levels of glutathione and manganese superoxide dismutase, and no induction of uncoupling protein 2 (UCP2) mRNA. Unlike WT mice, PPARbeta KO mice showed a marked increase of prooxidant interferon-gamma but no induction of nerve growth factor and tumor necrosis factor alpha after MCAO. In WT mice, MCAO resulted in inflammation-specific transient hyperphagia from day 3 to day 5 after ischemia, which was associated with an increase in neuropeptide Y (NPY) mRNA. This hyperphagic phase and NPY mRNA induction were not observed in PPARbeta KO mice. Furthermore, our study also suggests for the first time that UCP2 is involved in MCAO food intake response. These data indicate that PPARbeta plays an important role in integrating and regulating central inflammation, antioxidant mechanisms, and food intake after MCAO, and suggest that the use of PPARbeta agonists may be of interest for the prevention of central ischemic damage.

Topics: Animals; Brain Ischemia; Cerebral Infarction; Disease Models, Animal; Gene Expression Profiling; Glutathione; Hyperphagia; Infarction, Middle Cerebral Artery; Interferon-gamma; Ion Channels; Lipid Peroxidation; Male; Membrane Transport Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondrial Proteins; Nerve Growth Factor; Neuropeptide Y; PPAR-beta; RNA, Messenger; Superoxide Dismutase; Uncoupling Protein 2

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

An intracerebroventricular (i.c.v.) injection of neuropeptide Y (NPY) or [Leu31, Pro34]-NPY (non-Y2 receptor agonist) given during middle cerebral artery occlusion (MCAO) increases the infarct volume and nitric oxide (NO) overproduction in the rat brain. An i.c.v. injection of NPY3-36 (non-Y1 receptor agonist) has no effects, while BIBP3226 (selective Y1 receptor antagonist) reduces the infarct volume and NO overproduction. This study examined the effects of NPY or its receptor analog on the immunoreactivity (ir) for three isoforms of NO synthase (NOS) following 1 h of MCAO and 3 h of reperfusion. Focal ischemia/reperfusion led to increased ir for neuronal NOS (nNOS) within the ipsilateral caudate putamen and insular cortex. NPY or [Leu31, Pro34]-NPY enhanced but BIBP3226 suppressed such increase in the nNOS-ir. Focal ischemia/reperfusion also led to an ipsilateral increase in extent and/or intensity of the ir for endothelial NOS (eNOS) in the caudate putamen and/or parietal cortex. NPY or [Leu31, Pro34]-NPY suppressed but BIBP3226 enhanced such change in the eNOS-ir. NPY3-36 did not consistently influence the nNOS-ir or eNOS-ir following MCAO. Specific ir for inducible NOS was undetectable. These opposing effects of NPY-Y1 receptor activation or inhibition on nNOS and eNOS may lead to harmful or beneficial consequences following ischemia/reperfusion.

Topics: Animals; Anti-Anxiety Agents; Arginine; Brain; Brain Ischemia; Cerebral Arteries; Immunohistochemistry; Male; Neurons; Neuropeptide Y; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Protein Isoforms; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; Reperfusion Injury; Temperature; Time Factors

To observe the effects of Salvia miltiorrhiza (SM) on levels of neuropeptide Y1-36 and calcitonin gene-related peptide immune reactive substances (ir-NPY, ir-CGRP) in blood plasma and pons-oblongata after hypoxia-ischemic brain injury (HIBI) in neonatal rats.. Seven-day old rats were randomized into HIBI group (A), HIBI + SM group (B) and sham operation group(C). And each group was subdivided into 4 subgroups according to the different time after operation. 0.5 ml SM was injected intraperitoneally immediately and every 12 hrs afterwards. Changes of ir-NPY and ir-CGRP levels in plasma and pons-oblongata were observed immediately and 12, 24 and 48 hrs after HIBI by radioimmunoassay.. Plasma levels of ir-NPY and ir-CGRP in different times after HIBI were all significantly raised but those in pons-oblongata were either raised or lowered to a certain degree. Part of the elevated ir-NPY could be reversed by SM injection.. Central and peripheral neuropeptide Y1-36 and calcitonin gene-related peptide take part in the pathophysiological process of HIBI, SM could partially reverse the abnormal post-HIBI elevation of ir-NPY, which may be one of the pathways of SM in promoting recovery of damaged brain function.

Topics: Animals; Animals, Newborn; Brain Ischemia; Calcitonin Gene-Related Peptide; Drugs, Chinese Herbal; Female; Male; Neuropeptide Y; Peptide Fragments; Phytotherapy; Random Allocation; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Salvia miltiorrhiza

Detailed quantitative analysis of the vulnerability of different hippocampal and striatal neurons to global forebrain ischemia has not previously been performed. Here we have studied the survival of immunocytochemically identified neurons using an unbiased stereological method in rats subjected to global forebrain ischemia for 30 min and sacrificed 48 h, 1 week or 4 weeks thereafter. Within the hippocampal formation, there was extensive, progressive loss of CA1 pyramidal neurons and dentate hilar neuropeptide Y (NPY)-positive interneurons. In contrast, no reduction of the number of CA3 and CA4 pyramidal neurons or hilar parvalbumin-positive interneurons was detected. In the dorsolateral striatum, the insult caused a major loss of projection neurons immunoreactive to dopamine- and adenosine 3':5'-monophosphate-regulated phosphoprotein with a molecular weight of 32 kilodalton (DARPP-32). The number of parvalbumin-positive striatal interneurons was significantly reduced, while NPY-positive interneurons were resistant. All striatal cholinergic interneurons survived the ischemic insult. At 48 h following the ischemia, the cholinergic interneurons within the lesioned striatum transiently expressed the p75 neurotrophin receptor (p75(NTR)), as shown by double-label immunocytochemistry. Furthermore, there was a significant increase in the number of choline acetyltransferase (ChAT)- and TrkA-immunoreactive interneurons at 4 weeks after the insult. Injections with the cell mitotic division marker BrdU provided no evidence that the elevated cholinergic cell number was due to neurogenesis. Probably, the higher number of ChAT- and TrkA-positive interneurons reflected increased intracellular levels of the corresponding proteins leading to more cells detectable with immunocytochemistry. This study gives the first quantitative description of the vulnerability of defined hippocampal and striatal neurons after global forebrain ischemia. The ischemia-induced increases of p75(NTR), TrkA and ChAT in cholinergic striatal interneurons at various time points after the insult suggest that neurotrophin signaling might be important for the survival and function of these cells in the post-ischemic phase.

Topics: Animals; Antigens, Surface; Body Weight; Brain Ischemia; Cell Count; Cell Survival; Choline O-Acetyltransferase; Dopamine and cAMP-Regulated Phosphoprotein 32; Fluoresceins; Fluorescent Dyes; Hippocampus; Immunohistochemistry; Interneurons; Male; Neostriatum; Nerve Degeneration; Nerve Tissue Proteins; Neurons; Neuropeptide Y; Organic Chemicals; Parvalbumins; Phosphoproteins; Pyramidal Cells; Rats; Rats, Wistar; Receptor, Nerve Growth Factor; Receptor, trkA

Severe perinatal asphyxia can lead to injury and dysfunction of the basal ganglia. Post insult administration of insulin-like growth factor-1 is neuroprotective, particularly in the striatum. Insulin-like growth factor-1 is also known to be a neuromodulator of several types of striatal neurons. The striatum comprises various phenotypic neurons with a complex neurochemical anatomy and physiology. In the present study, we examined the specificity of neuronal rescue with insulin-like growth factor-1 on different striatal neurons. Bilateral brain injury was induced in near term fetal sheep by 30 min of reversible carotid artery occlusion. A single dose of 3 microg of insulin-like growth factor-1 was infused over 1 h into the lateral ventricle 90 min following ischemia. The histological and immunohistochemical outcome were examined after 4 days recovery using paraffin tissue preparations. Insulin-like growth factor-1 treatment (n = 11) significantly reduced the percentage of neuronal loss in the striatum compared with the vehicle treated group (n = 10, 28.3+/-5.1% vs 55.5+/-17.3%, P < 0.005). Immunohistochemical studies showed that ischemia resulted in a significant loss of calbindin-28kd, choline acetyltransferase, parvalbumin, glutamate acid decarboxylase, neuronal nitric oxide synthase and neuropeptide Y immunopositive neurons, compared with sham controls. Insulin-like growth factor-1 markedly prevented the loss of calbindin-28kd (n = 7, P < 0.05), choline acetyltransferase (n = 7, P < 0.05), neuropeptide Y (n = 7, P < 0.05), neuronal nitric oxide synthase (n = 8, P < 0.05) and glutamate acid decarboxylase (n = 9, P < 0.05) immunopositive neurons, but failed to protect parvalbumin (n = 6) immunopositive neurons. The present study indicates that the therapeutic effect of insulin-like growth factor-1 in the basal ganglia is selectively associated with cholinergic and some phenotypic GABAergic neurons. These data suggest a potential role for insulin-like growth factor-1 in preventing cerebral palsy due to perinatal asphyxia.

Topics: Animals; Brain Ischemia; Calbindins; Choline O-Acetyltransferase; Corpus Striatum; Fetus; Glutamate Decarboxylase; Immunohistochemistry; Insulin-Like Growth Factor I; Neurons; Neuropeptide Y; Neuroprotective Agents; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Parvalbumins; Phenotype; S100 Calcium Binding Protein G; Sheep

To observe the changes of some neuropeptides and the effect of Fusheng powder (FSP) on neuropeptides in rat's brains in a stable cerebral ischemia and reperfusion (I/L) model.. The models of rat's brain injured were established by repeated cerebral I/R in rats with hyperlipidemia. Radioimmunoassay (RIA) was performed to determine the level of neuropeptides.. After 1 day of I/R, compared with the control group, the contents of endothelin-1 (ET-1), calcitonin gene related peptide (CGRP) and neuropeptide Y (NPY) in the model animals were significantly increased by 24.3%, 33.7% and 51.86% respectively, while the level of somatostatin (SS) decreased by 37.86% (all P < 0.01). Meanwhile after FSP treatment, the contents of neuropeptides were alleviated respectively (P < 0.05, P < 0.01). Apart from the ET, the releases of CGRP, NPY and SS were all recovered in different degree after 7 days of I/R.. There were obvious imbalance of neuropeptides in rat's brains after cerebral I/R and the FSP might antagonize ischemic injury of brain through modulating neuropeptides, which may be one of the therapeutical mechanism in treating cerebral vascular diseases with FSP.

Topics: Animals; Brain; Brain Ischemia; Calcitonin Gene-Related Peptide; Drugs, Chinese Herbal; Endothelin-1; Hyperlipidemias; Male; Neuropeptide Y; Random Allocation; Rats; Rats, Wistar; Reperfusion Injury

This study was undertaken to elucidate the pattern of vascular innervation in areas of pial angiomatosis in Sturge-Weber disease (SWD) and eventually correlating it with the pathophysiology of the disease, namely its chronic ischemic changes.. We processed part of a surgical specimen resected from a 3-year-old female patient who underwent functional hemispherectomy for SWD and characterized the pattern of innervation of the malformative cortical vessels using histochemical, immunohistochemical, and ultrastructural techniques.. Cortical vessels were observed to be supplied with numerous varicose nerve fibers containing immunoreactivity for neuropeptide tyrosine and the catecholamine-synthesizing enzyme, tyrosine, tyrosine hydroxylase. In contrast, no nerve fibers containing acetylcholinesterase activity and immunoreactivity for Substance P, a calcitonin gene-related peptide and vasoactive intestinal peptide, were detected. Ultrastructural studies revealed the presence of numerous axon varicosities at the adventitial-medial border. Neuropeptide tyrosine immunoreactivity was localized in large granular vesicles in nerve varicosities that also contained numerous small granular vesicles.. These results demonstrate that nerve supplying cortical vessels in SWD are arranged in a distribution pattern similar to the one observed in human normal cortical veins and suggest that these abnormal vessels are innervated only with noradrenergic sympathetic nerve fibers. This represents a clear difference from the pattern of innervation observed in both normal cortical arteries and veins, and is the consequence of the anatomic and functional dysangiogenic process characteristic of the affected cortical areas in SWD.

Topics: Axons; Brain Ischemia; Cerebral Arteries; Cerebral Cortex; Child, Preschool; Female; Humans; Immunohistochemistry; Intracranial Arteriovenous Malformations; Microscopy, Electron; Microscopy, Fluorescence; Nerve Fibers; Neuropeptide Y; Sturge-Weber Syndrome; Synaptic Vesicles; Tyrosine; Tyrosine 3-Monooxygenase

To investigate whether differences in vulnerability to free radicals might underlie differences among striatal neurons in their vulnerability to neurodegenerative processes such as occur in ischemia and Huntington's disease, we have analyzed the localization of superoxide free radical scavengers in different striatal neuron types in normal rhesus monkey. Single- and double-label immunohistochemical experiments were carried out using antibodies against the enzymes copper, zinc superoxide dismutase (SOD1), or manganese superoxide dismutase (SOD2), and against markers of various striatal cell types. Our results indicate that the striatal cholinergic and parvalbumin interneurons are enriched in SOD1 and/or SOD2, whereas striatal projection neurons and neuropeptide Y/somatostatin (NPY+/SS+) interneurons express only low levels of both SOD1 and SOD2. We also found that projection neurons of the matrix compartment express significantly higher levels of SOD than those in the striosome compartment. Since projection neurons have been reported to be more vulnerable than interneurons and striosome neurons more vulnerable than matrix neurons to neurodegenerative processes, our results are consistent with the notion that superoxide free radicals are at least partly involved in producing the differential neuron loss observed in the striatum following global brain ischemia or in Huntington's disease.

Topics: Animals; Antibodies; Brain Ischemia; Corpus Striatum; Female; Free Radical Scavengers; Humans; Huntington Disease; Immunohistochemistry; Interneurons; Isoenzymes; Macaca mulatta; Male; Nerve Degeneration; Neurons; Neuropeptide Y; Reperfusion Injury; Somatostatin; Superoxide Dismutase

Perinatal hypoxic-ischemic brain injury was induced in 7- to 8-day-old rats by ligating the left carotid artery with subsequent exposure to 9% oxygen atmosphere for 2.5 h. The animals were killed 7 days later and grouped according to the degree of brain injury sustained after hypoxia-ischemia. Total protein content measured in striatum ipsilateral to the ligation, and dissected from brains showing extensive damage, was reduced to 64% of contralateral tissue. The protein content was not altered in other groups including control animals exposed to air and in sham-operated animals exposed to hypoxic conditions. The concentration of (pg/mg protein) and total (pg/striatum) striatal dynorphin A-like immunoreactivity (DLI) from brains with extensive damage were increased to 481% and 285% of the contralateral side, respectively. Hypoxia-ischemia increased striatal neuropeptide Y-like immunoreactivity (NPYLI) concentration from brains with extensive damage to 157% of contralateral side, but when the results were expressed as total NPYLI content per striatum, NPYLI content in striatum with extensive damage remained unaltered. Substance P-like immunoreactivity (SPLI) concentration and total content per striatum from brains with extensive damage were reduced to 66% and 43% of the contralateral side, respectively. D1 and D2 receptor density in animals killed 10 days after injury was reduced by 24% and 22% of control, respectively, in striatum from brains with extensive damage. These results indicate complex changes in brain neuropeptides following neonatal hypoxia-ischemia. Damage in the substance P system could have functional effects on dopaminergic transmission while the increase in NPYLI and in DLI concentrations may respectively reflect the relative preservation from neuronal damage and possibly an increase in neuropeptide synthesis or decrease in release. The decrease in SPLI concentration and the increase DLI concentration induced by hypoxia-ischemia suggests that these peptides may be present in separate neurons.

Topics: Aging; Animals; Animals, Newborn; Brain; Brain Ischemia; Corpus Striatum; Dynorphins; Female; Functional Laterality; Hypoxia, Brain; Neuropeptide Y; Pregnancy; Rats; Rats, Sprague-Dawley; Receptors, Dopamine; Receptors, Dopamine D1; Receptors, Dopamine D2; Substance P; Substantia Nigra

Histochemical changes in peptidergic and catecholaminergic neurons during ischemia were investigated in the cerebral neocortex of the gerbil. Catecholaminergic fibers were observed by catecholamine histofluorescence with glyoxylic acid solution, and peptidergic neuron systems such as vasoactive intestinal polypeptide (VIP), somatostatin (SOM), and neuropeptide Y (NPY) were observed by immunohistochemistry. Two hours after unilateral occlusion of the internal carotid artery, catecholaminergic fibers disappeared in the neocortex on the occlusion side, while peptidergic nerve fibers except for NPY fibers were intact after 2 hours of ischemia. NPY fibers had decreased in number on the occlusion side 2 hours after ischemia. VIP-, SOM-, and NPY-immunoreactive neurons showed a decrease of 60% six hours after ischemia, and these neurons completely disappeared in the cerebral neocortex 24 hours after ischemia. These results suggest that catecholaminergic neuron system is more vulnerable than the peptidergic one in ischemic event.

Topics: Animals; Brain Ischemia; Catecholamines; Cerebral Cortex; Gerbillinae; Immunohistochemistry; N-Methylaspartate; Neurons; Neuropeptide Y; Neuropeptides; Somatostatin; Vasoactive Intestinal Peptide

Concentration of neuropeptide Y (NPY) in the cerebrospinal fluid (CSF) of patients with cerebrovascular diseases was measured by using radioimmunoassay. The results showed that NPY concentration in CSF in patients with hemorrhagic cerebrovascular diseases (HCVD) was 4148 +/- 397.2 pg/ml, being significantly higher than the control level of 1083.7 +/- 245.8 pg/ml. While the NPY concentration in CSF of patients with ischemic cerebrovascular diseases (ICVD) was 2214 +/- 289.2 pg/ml, being not significantly different from the level in the control group. The effect of NPY in vasospasm after HCVD was preliminarily discussed.

Topics: Aged; Aged, 80 and over; Brain Ischemia; Cerebral Hemorrhage; Female; Humans; Male; Middle Aged; Neuropeptide Y; Radioimmunoassay; Subarachnoid Hemorrhage

Topics: Animals; Brain Ischemia; Cerebral Arteries; Enkephalins; Neuropeptide Y; Reserpine; Swine

Excitatory amino acids have been implicated in ischemic neuronal injury. To test this hypothesis in neonatal hypoxia-ischemia, lesions of the cortex and striatum were induced in 7-day-old rats by unilaterally ligating their carotid arteries and subjecting them to hypoxic conditions for 2 hours. Brains examined 1 week later demonstrated, within the regions of ischemic damage, a striking preservation of neurons that stained histochemically for nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) activity. Concentrations of the neuropeptides somatostatin and neuropeptide Y, which colocalize in neurons containing NADPH-d, were unaffected in the areas of ischemic damage. The same pattern of injury with sparing of NADPH-d-reactive neurons was reproduced by focal microinfusion of the excitotoxin quinolinic acid, an endogenous N-methyl-d-aspartate (NMDA) agonist, into the striatum. These results support the hypothesis that neonatal hypoxic-ischemic injury is mediated through excitatory transmitters acting at the NMDA receptor and that the NADPH-d-reactive neurons in the neonate are resistant to excitotoxic damage. This pattern of cell vulnerability is unique to the developing striatum and may relate to the distinct pathological appearance of the basal ganglia that follows neonatal asphyxia.

Topics: Animals; Animals, Newborn; Aspartic Acid; Brain Ischemia; Cerebral Cortex; Corpus Striatum; Hypoxia; N-Methylaspartate; NADH, NADPH Oxidoreductases; NADPH Dehydrogenase; Neurons; Neuropeptide Y; Rats; Rats, Inbred Strains; Somatostatin