vasoactive-intestinal-peptide and Stroke

More than 30 neurotrophins have been identified, and many of them have neuroprotective effects in brain ischemia or injury. However, all the clinical trials with several neurotrophins for the treatment of acute ischemic stroke or neurodegenerative diseases have failed so far, primarily because of their poor blood-brain barrier (BBB) permeability. This article is an overview of recent progress in the research focused on BBB targeted neurotrophins using a chimeric peptide approach, in which antitransferrin receptor antibody was used as a BBB delivery vector, and neurotrophin peptide was conjugated to the antibody via the avidin/biotin technology. Vasoactive intestinal peptide was the first model chimeric peptide to show an enhanced CNS effect after noninvasive peripheral administration. Brain-derived neurotrophic factor (BDNF) chimeric peptide was neuroprotective in rats subjected to transient forebrain ischemia, permanent focal ischemia, or transient focal ischemia. Delayed treatments with the BDNF chimeric peptide showed an effective time window of 1-2 h after ischemia. Basic FGF chimeric peptide was highly effective in the reduction of infarct volume in the rat model of permanent focal ischemia, with lowest effective dose of 1 mug per rat. Future studies in this exciting area include genetically engineered fusion proteins or humanized antibodies for BBB drug targeting with less immunogenicity and reduced working burden in the chemical conjugation, the use of antihuman insulin receptor antibody for higher BBB delivery efficiency, and combination therapies using chimeric neurotrophins plus other neuroprotectants to achieve additive or synergistic effects.

Topics: Animals; Blood-Brain Barrier; Brain Ischemia; Brain-Derived Neurotrophic Factor; Clinical Trials as Topic; Fibroblast Growth Factor 2; Humans; Nerve Growth Factors; Neuroprotective Agents; Receptors, Transferrin; Recombinant Fusion Proteins; Stroke; Thrombolytic Therapy; Vasoactive Intestinal Peptide

To compare the efficacy between acupuncture with smoothing liver and regulating. Sixty patients were randomized into an acupuncture group and a medication group,30 cases in each one. Based on the comprehensive stroke unit care,acupuncture with smoothing liver and regulating. The time of the first independent defecation was (30.18±16.14) h in the acupuncture group,which was significantly different from (43.22±28.42) h in the medication group(. Acupuncture with smoothing liver and regulating

Topics: Acupuncture Points; Acupuncture Therapy; Constipation; Gastrointestinal Agents; Humans; Lactulose; Liver; Motilin; Qi; Somatostatin; Stroke; Substance P; Treatment Outcome; Vasoactive Intestinal Peptide

Stroke profoundly disrupts cortical excitability which impedes recovery, but how it affects the function of specific inhibitory interneurons, or subpopulations therein, is poorly understood. Interneurons expressing vasoactive intestinal peptide (VIP) represent an intriguing stroke target because they can regulate cortical excitability through disinhibition. Here we chemogenetically augmented VIP interneuron excitability in a murine model of photothrombotic stroke and show that it enhances somatosensory responses and improves recovery of paw function. Using longitudinal calcium imaging, we discovered that stroke primarily disrupts the fidelity (fraction of responsive trials) and predictability of sensory responses within a subset of highly active VIP neurons. Partial recovery of responses occurred largely within these active neurons and was not accompanied by the recruitment of minimally active neurons. Importantly, chemogenetic stimulation preserved sensory response fidelity and predictability in highly active neurons. These findings provide a new depth of understanding into how stroke and prospective therapies (chemogenetics), can influence subpopulations of inhibitory interneurons.

Topics: Animals; Clozapine; Humans; Interneurons; Mice; Neural Inhibition; Receptor, Muscarinic M3; Recovery of Function; Somatosensory Cortex; Stroke; Vasoactive Intestinal Peptide

Background Shengui Sansheng Pulvis (SSP) has about 300 years history used for stroke treatment, and evidences suggest it has beneficial effects on neuro-angiogenesis and cerebral energy metabolic amelioration post-stroke. However, its protective action and mechanisms on blood-brain barrier (BBB) is still unknown. Purpose Based on multiple neuroprotective properties of vasoactive intestinal peptide (VIP) in neurological disorders, we investigate if SSP maintaining BBB integrity is associated with VIP pathway in rat permanent middle cerebral artery occlusion (MCAo) model. Methods Three doses of SSP extraction were administered orally. Evaluations of motor and balance abilities and detection of brain edema were performed, and BBB permeability were assessed by Evans blue (EB) staining. Primary brain microvascular endothelial cells (BMECs) were subjected to oxygen-glucose deprivation, and incubated with high dose SSP drug-containing serum and VIP-antagonist respectively. Transendothelial electrical resistance (TEER) assay and Tetramethylrhodamine isothiocyanate (TRITC)-dextran (4.4 kDa) and fluorescein isothiocyanate (FITC)-dextran (70 kDa) were used to evaluate the features of paracellular junction. Western blot detected the expressions of Claudin-5, ZO-1, Occludin and VE-cadherin, matrix metalloproteinase (MMP) 2/9 and VIP receptors 1/2, and immunofluorescence staining tested VIP and Claudin-5 expressions. Results Our results show that SSP significantly reduces EB infiltration in dose-dependent manner in vivo and attenuates TRITC- dextran and FITC-dextran diffusion in vitro, and strengthens endothelial junctional complexes as represented by decreasing Claudin-5, ZO-1, Occludin and VE-cadherin degradations and MMP 2/9 expression, as well as promoting TEER in BMECs after ischemia. Moreover, it suggests that SSP notably enhances VIP and its receptors 1/2 expressions. VIP-antagonist exacerbates paracellular barrier of BMECs, while the result is reversed after incubation with high dose SSP drug-containing serum. Additionally, SSP also improve brain edema and motor and balance abilities after ischemic stroke. Conclusions we firstly demonstrate that the ameliorated efficacy of SSP on BBB permeability is related to the enhancements of VIP and its receptors, suggesting SSP might be an effective therapeutic agent on maintaining BBB integrity post-stroke.

Topics: Animals; Blood-Brain Barrier; Brain Ischemia; Claudin-5; Drugs, Chinese Herbal; Endothelial Cells; Endothelium, Vascular; Infarction, Middle Cerebral Artery; Male; Permeability; Rats, Inbred Strains; Receptors, Vasoactive Intestinal Peptide, Type II; Receptors, Vasoactive Intestinal Polypeptide, Type I; Stroke; Vasoactive Intestinal Peptide

Pituitary adenylate cyclase-activating polypeptide (PACAP) has widespread physiological/pathophysiological actions and there is increased interest for its use therapeutically, especially in the CNS (neuroprotection). Unfortunately, no selective PACAP-analogs exist for PACAP-preferring PAC1-receptors, primarily because of its high sequence identity to VIP and particularly, because of the inability of structure-function studies to separate the pharmacophore of PAC1-R from VPAC1-R, which has high affinity for PACAP and VIP. The present study attempted to develop PAC1-R-selective agonists primarily by making conformationally restricted PACAP-analogs in positions important for receptor-selectivity/affinity. Forty-six PACAP-related-analogs were synthesized with substitutions in positions 1-4, 14-17, 20-22, 28, 34, 38 and receptor-selectivity determined in PAC1-R,VPAC1-R,VPAC2-R-transfected or native cells from binding or cAMP-generation experiments. Fifteen PACAP-analogs had 6-78-fold higher affinities for PAC1-R than VPAC1-R and 13 were agonists. Although binding-affinities correlated significantly with agonist potency, the degree of receptor-spareness varied markedly for the different PACAP-analogs, resulting in selective potencies for activating the PAC1 receptor over the VPAC1 receptor from 0- to 103-fold. In addition, a number of PACAP-analogs were identified that had high selectivity for PAC1-R over VPAC2-R as well as PACAP-analogs that could prove more useful therapeutically because of substitutions known to extend their half-lives (substitutions at potential sites of proteolysis and attachment of long-chain fatty acids). This study provides for the first time a separation of the pharmacophores for PAC1-R and VPAC1-R, resulting in PACAP-related analogs that are PAC1-R-preferring. Some of these analogs, or their modifications, could prove useful as therapeutic agents for various diseases.

Topics: Animals; Brain Injuries; Cell Line, Tumor; Humans; Mice; NIH 3T3 Cells; Pituitary Adenylate Cyclase-Activating Polypeptide; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; Receptors, Vasoactive Intestinal Peptide, Type II; Receptors, Vasoactive Intestinal Polypeptide, Type I; Stroke; Vasoactive Intestinal Peptide

VPAC2 receptor is a potential target for the treatment of type 2 diabetes and may also convey neuroprotective effects. The aim of this study was to determine the potential efficacy of the VPAC2 receptor agonist Bay 55-9837 against stroke in type-2 diabetic Goto-Kakizaki (GK) rats. GK rats were treated intravenously once daily for 7 days with 0.25 or 0.025 nmol/kg Bay 55-9837 or vehicle before inducing stroke by transient middle cerebral artery occlusion. Treatments were then continued for 7 further days. The glycemic effects of Bay 55-9837 were assessed by measuring fasting blood glucose and oral glucose tolerance. The severity of stroke was measured by assessing ischemic volume. The results show that Bay 55-9837 is not effective in lowering fasting glycemia and does not facilitate glucose disposal. The highest dose of Bay 55-9837 (0.25 nmol/kg) led to increased mortality and brain hemorrhage when compared to control. The lower dose of Bay 55-9837 (0.025 nmol/kg) did not increase mortality rate but caused a threefold increase of the ischemic lesion size with signs of brain hemorrhages as compared to control. In conclusion, Bay 55-9837 did not show antidiabetic or antistroke efficacy in the type 2 diabetic GK rat. Contrarily, Bay 55-9837 treatment led to increased mortality and worsening of the severity of stroke.

Topics: Animals; Blood Glucose; Cell Count; Diabetes Mellitus, Type 2; Disease Progression; Glucose Tolerance Test; Immunohistochemistry; Infarction, Middle Cerebral Artery; Intracranial Hemorrhages; Male; Middle Cerebral Artery; Neurons; Peptide Fragments; Rats; Receptors, Vasoactive Intestinal Peptide, Type II; Stroke; Vasoactive Intestinal Peptide

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