Examination of pituitary adenylate cyclase-activating polypeptide in Parkinson’s disease focusing on correlations with motor symptoms

GeroScience - The neuroprotective effects of pituitary adenylate cyclase-activating polypeptide (PACAP) have been shown in numerous in vitro and in vivo models of Parkinson’s disease (PD)...     

Stimulation of retrotrapezoid nucleus Phox2b‐expressing neurons rescues breathing dysfunction in an experimental Parkinson’s disease rat model

Emerging evidence from multiple studies indicates that Parkinson’s disease (PD) patients suffer from a spectrum of autonomic and respiratory motor deficiencies in addition to the classical motor symptoms attributed to substantia nigra degeneration of dopaminergic neurons. Animal models of PD show a decrease in the resting respiratory rate as well as a decrease in the number of Phox2b‐expressing retrotrapezoid nucleus (RTN) neurons. The aim of this study was to determine the extent to which substantia nigra pars compact (SNc) degeneration induced RTN biomolecular changes and to identify the extent to which RTN pharmacological or optogenetic stimulations rescue respiratory function following PD‐induction. SNc degeneration was achieved in adult male Wistar rats by bilateral striatal 6‐hydroxydopamine injection. For proteomic analysis, laser capture microdissection and pressure catapulting were used to isolate the RTN for subsequent comparative proteomic analysis and Ingenuity Pathway Analysis (IPA). The respiratory parameters were evaluated by whole‐body plethysmography and electromyographic analysis of respiratory muscles. The results confirmed reduction in the number of dopaminergic neurons of SNc and respiratory rate in the PD‐animals. Our proteomic data suggested extensive RTN remodeling, and that pharmacological or optogenetic stimulations of the diseased RTN neurons promoted rescued the respiratory deficiency. Our data indicate that despite neuroanatomical and biomolecular RTN pathologies, that RTN‐directed interventions can rescue respiratory control dysfunction.     

Modified Vaccination Technique for Prophylactic and Therapeutic Applications to Combat Endogenous Antigen–Induced Disorders

Public health can be protected most effectively through vaccination programmes. However, while presently available vaccination techniques protects the individual by provoking immune responses against exogenous antigens (ags), such as those associated with certain bacteria and viruses, they cannot protect against or treat mishaps caused by endogenous ag. Recently, Barabas and colleagues have developed a new vaccination method, called modified vaccination technique (MVT), which allows the presentation of disease causing agents in such a way as to initiate and maintain desired immune response outcomes even in the context of mishaps associated with endogenous ag. For example, in an experimental autoimmune kidney disease, the MVT downregulated/terminated pathogenic immune responses that were causing morphological and functional changes of the kidney. The MVT promises, with appropriate case‐specific modifications, both preventative and curative applications for ailments, such as endogenous ag initiated mishaps (i.e. autoimmune diseases and cancer) and diseases caused by chronic infection, that are presently only treatable with drugs. To achieve specific immune responses, purified components of the vaccine (ag and antibodies) must be produced and assembled into immune complexes having the potential of inducing predetermined corrective immune response outcomes.     

Continuous efficacy of etanercept in severe and advanced ankylosing spondylitis: results from a 12-week open-label extension of the SPINE study

Objective. To evaluate the longer-term efficacy of etanercept in patients with severe and advanced active AS. Methods. Seventy-seven patients who completed the randomized, double-blind, placebo-controlled 12-week SPINE study enrolled in a 12-week open-label extension and received s.c. etanercept 50?mg once weekly. The etanercept/etanercept group received a total of 24 weeks treatment with etanercept (n?=?38); the placebo/etanercept group received placebo during the double-blind study then 12 weeks' etanercept treatment during the open-label extension (n?=?39). Results. At the end of the open-label extension, BASDAI scores in the etanercept/etanercept group had further decreased beyond reductions observed during the double-blind study [mean (s.d.) change from baseline -37.6 (22.4) at end of extension vs -27.4 (23.8) at end of double-blind study]. Mean (s.d.) BASDAI scores also improved in the placebo/etanercept group once switched to etanercept [-28.6 (24.3) vs -15.0 (20.0)]. Similar trends were observed in BASFI and BASMI scores. In the placebo/etanercept group, total back pain decreased to similar levels achieved in the etanercept group in the double-blind study. Pain levels continued to decrease with longer-term etanercept therapy in the etanercept/etanercept group. Conclusion. Despite the improvements in symptoms and inflammatory markers observed shortly after initiation of once-weekly etanercept, there was no notable plateauing effect on patient-reported outcomes. Indeed, signs and symptoms of severe and advanced active AS continued to improve after up to 24 weeks, treatment with etanercept. Trial registration: ClinicalTrials.gov, http://clinicaltrials.gov/ct2/home, NCT00420238.     

Bradykinin and angiotensin-converting enzyme inhibition in cardioprotection

OBJECTIVES:

To show that angiotensin-converting enzyme (ACE) inhibition potentiates subthreshold ischemic preconditioning (IPC) via the elevation of bradykinin activity, leading to a fully delayed cardioprotective response.

METHODS:

On day 1 of the experiment, pigs were subjected to sham (group 1, controls) or IPC protocols. In groups 2 and 3, 4×5 min and 2×2 min of IPC, respectively, were elicited by occluding the left anterior descending coronary artery with percutaneous transluminal coronary angioplasty inflatable balloon catheter. Group 4 was subjected to the ACE inhibitor perindoprilate only. In group 5, the pigs were pretreated with perindoprilate (0.06 mg/kg) and then subjected to 2×2 min IPC. In group 6, intracoronary HOE 140 (a selective bradykinin B₂ receptor antagonist) was added before the perindoprilateaugmented subthreshold (2×2 min) PC stimulus. On the second day, all animals underwent 40 min left anterior descending coronary artery ligation and 3 h reperfusion, followed by infarct size analysis using triphenyl tetrazolium chloride staining.

RESULTS:

The rates of infarct size and risk zone were the following in the experimental groups: group 1, 42.8%; group 2,19.5% (P<0.05); group 3, ischemia/reperfusion (I/R) 33.4%; group 4, I/R 18.4% (P<0.05); group 5, I/R 31.2%; and group 6, I/R 36.3%. A significant increase of nuclear factor kappa B activation in groups 2 and 4 was seen.

CONCLUSIONS:

Results confirm that ACE inhibitors do not give total pharmacological IPC, but they enhance the induction effect of small ischemic insults, which raises the ischemic tolerance of myocardium. It was determined that enhanced bradykinin activity leads to downstream nuclear factor kappa B activation in this model.     

Ghrelin action in the brain controls adipocyte metabolism

Many homeostatic processes, including appetite and food intake, are controlled by neuroendocrine circuits involving the CNS. The CNS also directly regulates adipocyte metabolism, as we have shown here by examining central action of the orexigenic hormone ghrelin. Chronic central ghrelin infusion resulted in increases in the glucose utilization rate of white and brown adipose tissue without affecting skeletal muscle. In white adipocytes, mRNA expression of various fat storage-promoting enzymes such as lipoprotein lipase, acetyl-CoA carboxylase alpha, fatty acid synthase, and stearoyl-CoA desaturase-1 was markedly increased, while that of the rate-limiting step in fat oxidation, carnitine palmitoyl transferase-1alpha, was decreased. In brown adipocytes, central ghrelin infusion resulted in lowered expression of the thermogenesis-related mitochondrial uncoupling proteins 1 and 3. These ghrelin effects were dose dependent, occurred independently from ghrelin-induced hyperphagia, and seemed to be mediated by the sympathetic nervous system. Additionally, the expression of some fat storage enzymes was decreased in ghrelin-deficient mice, which led us to conclude that central ghrelin is of physiological relevance in the control of cell metabolism in adipose tissue. These results unravel the existence of what we believe to be a new CNS-based neuroendocrine circuit regulating metabolic homeostasis of adipose tissue.     

High density lipoproteins, genetic polymorphism for apo A-I and coronary artery disease

HDL cholesterol and apolipoprotein A-I are associated with the development of coronary artery-disease (CAD). The presence of a PstI site polymorphism adjacent to the gene encoding apo A-I (known as P₂) has also been shown to be associated with CAD but this relationship is controversial. A case control study was conducted in an Australian population to re-examine whether the rare P₂ allele is associated with CAD. Data were derived from 159 cases of angiographically confirmed CAD and 99 healthy controls. The proportion of CAD cases carrying the P₂ allele did not differ significantly from controls (11% versus 9%). In a multiple logistic regression model controlling for the effects of age, country of birth, hypertension and hypotensive drugs, body mass index and lipid variables, the P₂ allele failed to predict significantly the presence of CAD (odds ratio 1.83; 95% confidence interval 0.65–5.19).     

Medicinal chemistry of the vanilloid (Capsaicin) TRPV1 receptor: current knowledge and future perspectives

In peripheral sensory neurons, the vanilloid receptor TRPV1 (transient receptor potential vanilloid subfamily, member 1) functions as a molecular integrator of painful stimuli, including those mediated by capsaicin, acid, and heat. Antagonist blockade of TRPV1 activation is under investigation by several pharmaceutical companies in an effort to identify novel agents for pain management. TRPV1 is also expressed, albeit at lower levels, in the brain and in non‐neuronal tissues, where its function(s) remains elusive. The contribution of TRPV1 receptor activity to physiological reflexes and disease states is complex and is only beginning to be understood. Consequently, the resultant effects of TRPV1 antagonists on the body may be unforeseen. Indeed, clinical trials with a number of TRPV1 antagonists were recently terminated due to their marked hyperthermic activity. In this review article, the medicinal chemistry of TRPV1 antagonists is discussed inasmuch as it relates to the efficacy, safety, tolerability and potential side effects of these compounds. In addition, the available information on the current status of the clinical trials with TRPV1 antagonists is summarized. Drug Dev Res 68:477–497, 2007. © 2008 Wiley‐Liss, Inc.