DAMP Signaling is a Key Pathway Inducing Immune Modulation after Brain Injury

Acute brain lesions induce profound alterations of the peripheral immune response comprising the opposing phenomena of early immune activation and subsequent immunosuppression. The mechanisms underlying this brain-immune signaling are largely unknown. We used animal models for experimental brain ischemia as a paradigm of acute brain lesions and additionally investigated a large cohort of stroke patients. We investigated the inflammatory potency of HMGB1 and its signaling pathways by immunological in vivo and in vitro techniques. Features of the complex behavioral sickness behavior syndrome were characterized by homecage behavior analysis. HMGB1 downstream signaling, particularly with RAGE, was studied in various transgenic animal models and by pharmacological blockade. Our results indicate that HMGB1 was released from the ischemic brain in the hyperacute phase of stroke in mice and patients. Cytokines secreted in the periphery in response to brain injury induced sickness behavior, which could be abrogated by inhibition of the HMGB1-RAGE pathway or direct cytokine neutralization. Subsequently, HMGB1-release induced bone marrow egress and splenic proliferation of bone marrow-derived suppressor cells, inhibiting the adaptive immune responses in vivo and vitro. Furthermore, HMGB1-RAGE signaling resulted in functional exhaustion of mature monocytes and lymphopenia, the hallmarks of immune suppression after extensive ischemia. This study introduces the HMGB1-RAGE-mediated pathway as a key mechanism explaining the complex postischemic brain-immune interactions

Double-blind, placebo-controlled first in human study to investigate an oral vaccine aimed to elicit an immune reaction against the VEGF-Receptor 2 in patients with stage IV and locally advanced pancreatic cancer

BACKGROUND: The investigational oral DNA vaccine VXM01 targets the vascular endothelial growth factor receptor 2 (VEGFR-2) and uses Salmonella typhi Ty21a as a vector. The immune reaction elicited by VXM01 is expected to disrupt the tumor neovasculature and, consequently, inhibit tumor growth. VXM01 potentially combines the advantages of anti-angiogenic therapy and active immunotherapy. METHODS/DESIGN: This phase I trial examines the safety, tolerability, and immunological and clinical responses to VXM01. The randomized, placebo-controlled, double blind dose-escalation study includes up to 45 patients with locally advanced and stage IV pancreatic cancer. The patients will receive four doses of VXM01 or placebo in addition to gemcitabine as standard of care. Doses from 10(6) cfu up to 10(10) cfu of VXM01 will be evaluated in the study. An independent data safety monitoring board (DSMB) will be involved in the dose-escalation decisions. In addition to safety as primary endpoint, the VXM01-specific immune reaction, as well as clinical response parameters will be evaluated. DISCUSSION: The results of this study shall provide the first data regarding the safety and immunogenicity of the oral anti-VEGFR-2 vaccine VXM01 in cancer patients. They will also define the recommended dose for phase II and provide the basis for further clinical evaluation, which may also include additional cancer indications. TRIAL REGISTRATION: EudraCT No.: 2011-000222-29, NCT01486329, ISRCTN6880927

Diurnal Differences in Toluene Induced Reward-Seeking Behavior Between Melatonin-Proficient (C3H) and Melatonin-Deficient (C57) Mice

Objectives: Abuse of organic volatile substances (inhalants) has become a social health problem that is increasing in the recent years. Toluene as a prototype of inhalants can be use via inhalation, intraperitoneal or intravenous for experimental research on rodents. A conditioning paradigm of toluene inhalation was developed the rewarding effect in mice and rats. Aim of this research, investigation of toluene induced reward-seeking behavior at day and night order in melatonin proficient (C3H) and deficient (C57) mice

A biological tube technique for the repair of peripheral nerve defects using 'stuffed nerves'

BACKGROUND: Presently described is research examining the "stuffed nerve" technique to repair peripheral nerve defects

Effects of Early Litter Loss on Maternal Behavior and Subsequent Generations in Rats: An Attempt for an Animal Model for Loss of a Baby

Objective: Loss of a baby accompanied by complicated grief increases vulnerability to mental disease with adverse consequences both for the mother and the long-term well-being of the subsequent generations. This study presents an animal model and aims to study the reactions of female rats to the loss of their litters and the consequences for the next litter

Erythropoietin prevents motor neuron apoptosis and neurologic disability in experimental spinal cord ischemic injury

The cytokine erythropoietin (EPO) possesses potent neuroprotective activity against a variety of potential brain injuries, including transient ischemia and reperfusion. It is currently unknown whether EPO will also ameliorate spinal cord injury. Immunocytochemistry performed using human spinal cord sections showed abundant EPO receptor immunoreactivity of capillaries, especially in white matter, and motor neurons within the ventral horn. We used a transient global spinal ischemia model in rabbits to test whether exogenous EPO can cross the blood–spinal cord barrier and protect these motor neurons. Spinal cord ischemia was produced in rabbits by occlusion of the abdominal aorta for 20 min, followed by saline or recombinant human (rHu)-EPO (350, 800, or 1,000 units/kg of body weight) administered intravenously immediately after the onset of reperfusion. The functional neurological status of animals was better for rHu-EPO-treated animals 1 h after recovery from anesthesia, and improved dramatically over the next 48 h. In contrast, saline-treated animals exhibited a poorer neurological score at 1 h and did not significantly improve. Histopathological examination of the affected spinal cord revealed widespread motor neuron injury associated with positive terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling in control but not in rHu-EPO-treated animals. These observations suggest both an acute as well as a delayed beneficial action of rHu-EPO in ischemic spinal cord injury. Because rHu-EPO is currently used widely with an excellent safety profile, clinical trials evaluating its potential to prevent motor neuron apoptosis and the neurological deficits that occur as a consequence of ischemic injury are warranted

Protective Effects of Methylxanthines on Hypoxia-Induced Apoptotic Neurodegeneration and Long-Term Cognitive Functions in the Developing Rat Brain

Aminophylline is widely used in the management of premature apnea. The methylxanthines aminophylline, theophylline and caffeine are nonspecific inhibitors of adenosine receptors. There are no proven effects of methylxanthines on acute brain injury and long-term cognitive functions. This study is aimed at investigating the effects of methylxanthines on brain injury and cognitive functions. Newborn rats were allocated to form four groups, which contained at least 21 pups: two groups were exposed to room air and two groups were exposed to intermittent hypoxia. Intraperitoneal aminophylline was administered to treatment groups during postnatal day 1 through postnatal day 7. All rats were sacrificed on postnatal day 8 via intraperitoneal pentobarbital and the effects of the administered drug on brain injury and adenosine receptor expression were determined. Cognitive functions of rats were evaluated via water maze test. Histopathological evaluation demonstrated that aminophylline significantly diminished the number of 'apopto tic cells' in the hippocampal CA1, CA2, CA3 and gyrus dentatus regions in the brain. Aminophylline treatment immediately after hypoxic insult significantly improved long-term neurobehavioral achievements. In conclusion, aminophylline administration immediately after neonatal hypoxic insult provides benefit over a prolonged period in the developing rat brain. Copyright (C) 2010 S. Karger AG, Base