vasoactive-intestinal-peptide and Parkinsonian-Disorders

Nurr1 is critical for the development and maintenance of midbrain dopaminergic (DA) neurons in mouse. Loss of Nurr1 function early during development in mice leads to the absence of midbrain DA neurons. Reduction of Nurr1 function in adulthood leads to a slowly progressive loss of striatal DA and markers for DAergic neurons, supporting its selective roles in the maintenance of DAergic neuronal survival and function. To understand the molecular mechanisms of Nurr1 action, our group has identified VIP as a potential target gene of Nurr1. Nurr1 regulates VIP mRNA and protein levels, and transactivates the VIP promoter through Nurr1-responsive cis elements. Nurr1 loss of function leads to the decrease of VIP mRNA level in developing midbrain, suggesting that Nurr1 is involved in the in vivo regulation of VIP expression in midbrain. Our group has also cloned a novel protein interactor for Nurr1. We identified a family of gene products that interact and regulate the activity of Nurr1 by screening yeast two-hybrid library and termed the longest splicing form, NuIP. In vivo NuIP protein is largely colocalized with Nurr1 in adult midbrain dopaminergic neurons. NuIP interacts and positively regulates the activity of Nurr1 protein and could also possibly mediate cross talk between Nurr1 and GTPase mediated signaling pathways. Other recently identified potential target genes and interacting proteins of Nurr1 are also summarized and discussed in this review.

Topics: Animals; DNA-Binding Proteins; Dopaminergic Neurons; Gene Expression Regulation, Developmental; Humans; Mesencephalon; Nerve Degeneration; Neurogenesis; Nuclear Receptor Subfamily 4, Group A, Member 2; Parkinsonian Disorders; Signal Transduction; Vasoactive Intestinal Peptide

Gastroparesis is a common non-motor system symptom of Parkinson's disease (PD). However, the mechanism responsible for the gastric motor abnormality is not clear. We previously reported on the impaired gastric motility in 6-hydroxydopamine (6-OHDA) rats, which were treated with a bilateral microinjection of 6-OHDA in the substantia nigra (SN). We hypothesize that the enhanced dopamine system and reduced acetylcholine (Ach) in gastric tissues might contribute to the delayed gastric emptying observed in PD.. A strain gauge force transducer, digital X-ray imaging system, Western blot, immunofluorescence and Radio Immunoassay were used in this study.. Dopaminergic neurones in the SN were greatly reduced following the bilateral microinjection of 6-OHDA. 6-OHDA rats exhibited impaired gastric motility and delayed gastric emptying, accompanied by increased dopamine content and the overexpression of D2 receptors in the stomach. The administration of the D2 receptor antagonist domperidone relieved gastric dysmotility in 6-OHDA rats, but the D1 receptor antagonist SCH23390 failed to do so. Subdiaphragmatic vagotomy prevented the increase in the gastric dopamine content and D2 receptor expression and improved gastric dysmotility in 6-OHDA rats.. Dopaminergic deficiency in the SN results in impaired gastric motility, possibly as a result of the enhanced activity of dopamine system and reduced Ach in gastric tissue. The vagus nerve plays an important role in peripheral gastric motility disorder.

Topics: Acetylcholine; Animals; Blotting, Western; Disease Models, Animal; Dopamine; Fluorescent Antibody Technique; Gastric Mucosa; Gastrointestinal Motility; Gastroparesis; Male; Oxidopamine; Parkinsonian Disorders; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Stomach; Substantia Nigra; Sympatholytics; Vagus Nerve; Vasoactive Intestinal Peptide

6-Hydroxydopamine (6-OHDA) is an oxidative stress neurotoxin, which is oxidized in neurons, causes respiratory inhibition, and induces free radical formation and oxidative stress. Therefore, a 6-OHDA-induced Parkinson's disease (PD) experimental model can be used to test a candidate molecule for use as an antioxidant that could be a promising therapeutic for treating Parkinson's disease. Recent studies have shown that vasoactive intestinal peptide (VIP) might be a good candidate agent for the treatment of PD. In this study, the anti-apoptotic and antioxidant actions of VIP were investigated using the 6-OHDA-lesioned rat model for PD. Twenty-four young adult Sprague-Dawley rats were used. The rats were separated into the following groups: group I (n = 8), sham operated; group II (n = 8), 6-OHDA lesioned; group III (n = 8), 6-OHDA lesioned + i.p. VIP-injected (25 ng/kg) every 2 days for 15 days. The first i.p. injection of VIP was made 1 h after the intrastriatal 6-OHDA microinjection. Antioxidant enzymatic activity [super oxide dismutase (SOD) and catalase (CAT)], lipid peroxidation, nitric oxide and DNA fragmentation were measured from homogenates isolated from the corpus striatum. SOD, CAT, malondialdehyde, and DNA fragmentation were measured using a spectrophotometer, and nitric oxide (NO) levels were measured by capillary electrophoresis. 6-OHDA significantly induced oxidative stress, lipid peroxidation, and DNA fragmentation in the corpus striatum of rats. VIP significantly protected neuronal tissue from oxidative stress and apoptosis by reducing lipid peroxidation and DNA fragmentation. 6-OHDA toxicity did not cause significant changes in NO production in the corpus striatum. However, VIP treatment significantly reduced NO levels in brain tissue.

Topics: Animals; Antioxidants; Corpus Striatum; Disease Models, Animal; Female; Inhibitor of Apoptosis Proteins; Male; Oxidopamine; Parkinsonian Disorders; Rats; Rats, Sprague-Dawley; Sympatholytics; Vasoactive Intestinal Peptide

Destruction of the nigrostriatal dopaminergic pathway by the administration of 6-OHDA generates an animal model of Parkinson's disease. The main characteristic of this progressive neurological disorder is the loss of the dopaminergic neurons located in the substantia nigra pars compacta (SNc). Dopaminergic inputs from the SNc innervate the medium spiny neurons of the striatum and modulate the spontaneous activity of the primary output nuclei of the basal ganglia, globus pallidus interna, and substantia nigra pars reticulata. In our previous studies, we showed that systematically administered vasoactive intestinal peptide (VIP) is effective at reversing motor deficits, decreasing neuronal cell death, and repairing the myelin sheet in parkinsonian rats. In the current study, the effects of VIP on the dendritic morphology of the striatal neurons and the number of dopaminergic neurons in the SNc were examined in 6-OHDA-lesioned rats using Golgi-Cox staining and design-based stereological methods, respectively. Adult Sprague-Dawley rats were separated into sham-operated, bilaterally 6-OHDA lesioned and lesioned + i.p. VIP-injected (25 ng/kg) groups. VIP was first injected 1 h after the intrastriatal 6-OHDA microinjection (every 2 days for 15 days). The 6-OHDA significantly decreased the total number of dopaminergic neurons, branching, and spine density of the medium spiny neurons in the striatum. VIP significantly increased the number of neurons immunostained with tyrosine hydroxylase and the density of spines without altering the branching and the total length of dendrites. In conclusion, VIP might display synaptogenetic activity by enhancing the spine density in the striatum of the parkinsonian rats.

Topics: Animals; Antiparkinson Agents; Cell Count; Corpus Striatum; Dendrites; Dopaminergic Neurons; Drug Evaluation, Preclinical; Neuronal Plasticity; Neuroprotective Agents; Oxidopamine; Parkinsonian Disorders; Rats; Rats, Sprague-Dawley; Staining and Labeling; Vasoactive Intestinal Peptide

The ventral anterior nucleus of the thalamus (VATh) gathers motor information from the internal segment of the globus pallidus (GPi) and substantia nigra pars reticulata (SNpr) of the basal ganglia and projects directly to motor areas of cortex. GPi/SNpr send their tonically active gamma-aminobutyric acid (GABA)ergic outputs to VATh. The abnormal firing patterns of GABAergic neurons in GPi/SNpr lead to motor deficits. In Parkinson's disease, the spontaneous firing pattern of GPi/SNpr neurons is abnormal due to the degeneration of the nigrostriatal dopaminergic pathway. In a previous study, we found that systemically administered vasoactive intestinal peptide (VIP) was effective at reversing the motor deficits (but not the decline in striatal dopamine levels) in a rat model of Parkinson's disease (6-hydroxydopamine (6-OHDA) exposure). In addition to the beneficial effects on the motor response, VIP could also attenuate both neuronal cell death and the characteristic loss of the myelin sheath that is associated with 6-OHDA administration into the rat striatum. VIP was thought to preserve neurons by inducing native brain mast cells to adopt a nondegranulating phenotype that had the ability to secrete numerous neuroprotective substances, such as nerve growth factor (NGF) and heparin. In the present study, the effect of systemically administered VIP (25 ng/kg i.p.) was investigated on GABA levels of the VATh, dopamine/3,4-dihydroxyphenylacetic acid (DOPAC) levels in the corpus striatum, and the NGF, rat mast cell protease II (RMCPII), serotonin, and heparin content of brain mast cells in 6-OHDA-lesioned rats. Extracellular concentrations of GABA, dopamine, and DOPAC were measured by microdialysis and high-performance liquid chromatography. NGF, RMCPII, serotonin, and heparin levels were examined by immunohistochemical staining techniques. A total of 48 young adult Sprague-Dawley rats were used in the study, and these were assigned to one of six groups. Unilateral injection of 6-OHDA, 2 microl (6 mg/microl), was made into the right corpus striatum. VIP-treated animals received 25 ng/kg VIP i.p. at 2-day intervals for a period of 15 days. The present results demonstrated that VIP significantly increased the levels of GABA in the VATh that were reduced by 6-OHDA application and increased the number of NGF-immunoreactive mast cells but did not alter dopamine metabolism. Therefore, the protective effect of VIP on motor function is possibly related to the increased

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Female; gamma-Aminobutyric Acid; Heparin; Male; Mast Cells; Microdialysis; Nerve Growth Factor; Oxidopamine; Parkinsonian Disorders; Rats; Rats, Sprague-Dawley; Serotonin; Thalamus; Vasoactive Intestinal Peptide