neuropeptide-y and Cerebral-Infarction

Bifemelane hydrochloride (BH) is widely employed in Japan in the treatment of cerebral infarction patients with depressive symptoms and its antidepressant action is considered to be caused by the normalizing effects of neurotransmitters. The relationship between the normalizing effects of neurotransmitters of BH and the depressive state of patients with cerebral infarction was examined. BH 150 mg/day was administered for three months to 13 cerebral infarction patients with depressive state. We measured the plasma neuropeptide Y (NPY), 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) and 5-hydroxy-indole acetic acid (5-HIAA), and assessed the depressive symptoms using the 21-item Hamilton's Rating Scale for Depression (HRSD) before and after administration of BH. After treatment, the plasma NPY concentration was significantly increased, the plasma MHPG concentration and total score of HRSD were significantly decreased, and the plasma 5-HIAA concentration showed no changes. These findings suggest that the antidepressant effect of BH is caused by the normalizing effects of NPY and noradrenalinergic neurons.

Topics: Aged; Antidepressive Agents; Benzhydryl Compounds; Cerebral Infarction; Chromatography, High Pressure Liquid; Depression; Female; Humans; Hydroxyindoleacetic Acid; Male; Methoxyhydroxyphenylglycol; Middle Aged; Neuropeptide Y; Nootropic Agents; Psychiatric Status Rating Scales; Radioimmunoassay

Neuropeptide Y (NPY), a highly potent vasoconstrictive neuropeptide, is widely expressed in the human brain, regulating vessel diameter and cerebral blood flow. Earlier studies focusing on the possible role of NPY in the context of aneurismal subarachnoid hemorrhage (SAH) and vasospasm have produced conflicting results. However, despite extensive research efforts, the pathophysiological mechanisms underlying the SAH-related vasospasm and delayed cerebral ischemia (DCI) have not been clarified. We, therefore, attempted to investigate the role of NPY in SAH-induced vasospasm in a larger, well documented patient population utilizing modern analytical tools. We focused on the release of the potent vasoconstrictor NPY in cerebrospinal fluid (CSF) and blood, and its correlation to vasospasm and stroke in the early clinical stage.. Thirty-seven patients with SAH and a control group consisting of 29 patients were included. Eighteen patients developed stroke, 21 patients met the Doppler sonographical criteria for vasospasm. Twenty-nine patients had aneurysms of the anterior circulation and four patients of the posterior circulation. All patients had ventricular drainage inserted and an arterial catheter. Blood and CSF were drawn daily for NPY analysis during a 10-day interval.. The levels of NPY in CSF and plasma were significantly higher after SAH than in the control group (p = 0.001). The vasospasm group showed NPY levels in CSF which continuously ranged above the NPY levels of the non-vasospasm group (p = 0.001). Patients with stroke caused by vasospasm had significantly higher levels of NPY (p = 0.001).. NPY is released excessively into blood and CSF following SAH. Patients with cerebral infarction caused by vasospasm had significantly higher levels of NPY. Our results indicate a certain role for NPY in the pathophysiology of vasospasm due to SAH and justify further studies in this area of research.

Topics: Adult; Aged; Aged, 80 and over; Cerebral Infarction; Cerebrovascular Circulation; Female; Humans; Male; Middle Aged; Neuropeptide Y; Subarachnoid Hemorrhage; Ultrasonography; Up-Regulation; Vasospasm, Intracranial; Young Adult

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

Recent studies have shown increased immunoreactivity for neuropeptide Y (NPY) within the perilesional cortex following experimental middle cerebral artery occlusion (MCAO) or focal excitotoxic damage. Downregulation of the NPY Y1 receptor gene using an antisense oligodeoxynucleotide produced a doubling of the infarct volume, implying that NPY may mediate neuroprotection against focal ischemia. The effects of treatment with NPY on infarct volume and hemodynamic parameters were investigated in the present study. Adult male Sprague-Dawley rats were anesthetized with sodium pentobarbital to undergo right-sided endovascular MCAO for 2 h. A single dose of NPY was given via intracarotid injection (10 microg/kg) at the beginning of reperfusion, intracisternal injection (10 or 30 microg/kg) at 30 min of ischemia, or intracerebroventricular (i.c.v.) injection (10 or 70 microg/kg) at 30 min of ischemia. Control groups received the vehicle only via the same route. Body temperature was maintained constant, and hemodynamic parameters were monitored during anesthesia. Laser Doppler flowmetry was used to monitor the regional cerebral blood flow (rCBF) during ischemia and reperfusion in some rats. The rats were decapitated on day 3, and their brains were cut into 2-mm thick coronal slices before reaction with a 2% solution of 2,3,5-triphenyltetrazolium chloride to reveal the infarct. Compared to the respective control groups, NPY treatment via any method of administration increased the relative infarct volume. Suppression of rCBF was observed during reperfusion. These results indicate that peripheral or central administration of NPY impairs reperfusion following experimental MCAO and worsens the outcome of focal cerebral ischemia.

Topics: Animals; Cerebral Infarction; Cerebrovascular Circulation; Dose-Response Relationship, Drug; Hemodynamics; Humans; Infarction, Middle Cerebral Artery; Injections, Intra-Arterial; Injections, Intraventricular; Male; Microinjections; Neuropeptide Y; Rats; Rats, Sprague-Dawley

The effect of acute cerebral occlusion on the distribution of cerebral perivascular nerves containing catecholamine, neuropeptide Y, and vasoactive intestinal peptide was studied in the three commonly used rat models of cerebral ischemia: Unilateral permanent middle cerebral artery (MCA) occlusion induced with an intraluminal thread technique; unilateral MCA occlusion produced by extraluminal electrocoagulation of the MCA; and transient arterial occlusion of the whole brain induced extracranially by the four-vessel clasp occlusion method for 30 minutes. Animals were sacrificed 3 days after occlusion and the distribution of the perivascular nerves of the MCA studied. Intraluminally occluded MCAs showed a similar distribution of perivascular nerves to those of contralateral and sham-operated MCAs. Extraluminally occluded MCAs demonstrated a marked decrease in perivascular nerves containing catecholamine and peptides while the contralateral MCAs showed normal distribution of the nerves. Extracranial occlusion caused no discernible change in the distribution of perivascular nerves in occluded and sham-operated animals. This study indicates that the different methods of cerebral arterial occlusion have variable effects on the perivascular innervation. Arterial occlusion induced by intraluminal or transient extracranial procedures does not impair cerebral perivascular innervation at least up to 3 days post-occlusion. In contrast, cerebral arterial occlusion by extraluminal electrocoagulation diminishes the perivascular nerves around the occluded cerebral artery.

Topics: Animals; Catecholamines; Cerebral Arteries; Cerebral Infarction; Ischemic Attack, Transient; Male; Microscopy, Fluorescence; Nerve Fibers; Neuropeptide Y; Rats; Rats, Sprague-Dawley; Vasoactive Intestinal Peptide

A small surgical lesion of the parietal cortex induces an increase in the expression of several messenger RNAs varying from 172 to 980% in the entire homolateral cerebral cortex, as detected by quantitative in situ hybridization histochemistry. The messenger RNAs encoding the immediate early genes of the leucine zipper family (c-fos, c-jun, jun-B), the Zinc finger family (zif268), the glucocorticoid receptor family (NGFI-B) and the interferon family (PC4) are increased within 2 h after the lesion and return to normal levels at 6 h. The messenger RNAs encoding cholecystokinin, neuropeptide Y, somatostatin and the synthetizing enzyme of the neurotransmitter GABA, glutamate decarboxylase, are elevated within one day and return to normal levels after six days. An intraperitoneal injection of the N-methyl-D-aspartate receptor antagonist dizocilpine maleate, 30 min before surgery, prevented either the induction of immediate early gene expression or the increase of neuropeptide and glutamate decarboxylase messenger RNA expression. This study demonstrates that a minimal cortical lesion induces extensive changes in gene expression and that the mechanism(s) leading to these changes involves the action of glutamate at the N-methyl-D-aspartate receptor. These modifications may be of importance in explaining diffuse changes not related to neuronal circuitry in several conditions.

Topics: Animals; Cerebral Cortex; Cerebral Infarction; Cholecystokinin; Dizocilpine Maleate; DNA-Binding Proteins; Early Growth Response Protein 1; Female; Gene Expression Regulation; Genes, fos; Genes, Immediate-Early; Genes, jun; Glutamate Decarboxylase; Glutamates; Glutamic Acid; Immediate-Early Proteins; Leucine Zippers; Membrane Proteins; N-Methylaspartate; Nerve Tissue Proteins; Neuropeptide Y; Neurotransmitter Agents; Nuclear Receptor Subfamily 4, Group A, Member 1; Parietal Lobe; Rats; Rats, Wistar; Receptors, Cytoplasmic and Nuclear; Receptors, Steroid; Somatostatin; Time Factors; Transcription Factors; Zinc Fingers