calca-protein--human and Disease-Models--Animal

Calcitonin gene-related peptide (CGRP) plays a diverse and intricate role in chronic low-grade inflammation and is closely related to specific cancers. It includes two subtypes, CALCA (

Topics: Adult; Aged; Animals; Calcitonin Gene-Related Peptide; Carcinoma, Pancreatic Ductal; CpG Islands; Disease Models, Animal; DNA Methylation; Female; Humans; Male; Middle Aged; Pancreatic Neoplasms; Promoter Regions, Genetic; Proto-Oncogene Proteins c-akt; Rats; Rats, Transgenic; Signal Transduction

Increasing evidence suggests that inflammatory responses cause brain atrophy and play a prominent and early role in the progression of Alzheimer disease. Recent findings show that the neuroendocrine peptide aminoprocalcitonin (NPCT) plays a critical role in the development of systemic inflammatory response; however, the presence, possible function, regulation, and mechanisms by which NPCT may be involved in Alzheimer disease neuropathology remain unknown. We explored the expression of NPCT and its interaction with amyloid-β (Aβ), and proinflammatory and neurogenic effects. By using brain samples of Alzheimer disease patients and APP/PS1 transgenic mice, we evaluated the potential role of NPCT on Aβ-related pathology. We found that NPCT is expressed in hippocampal and cortical neurons and Aβ-induced up-regulation of NPCT expression. Peripherally administered antibodies against NPCT decreased microglial activation, decreased circulating levels of proinflammatory cytokines, and prevented Aβ-induced neurotoxicity in experimental models of Alzheimer disease. Remarkably, anti-NPTC therapy resulted in a significant improvement in the behavioral status of APP/PS1 mice. Our results indicate a central role of NPCT in Alzheimer disease pathogenesis and suggest NPCT as a potential biomarker and therapeutic target.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Animals; Atrophy; Brain; Calcitonin Gene-Related Peptide; Cerebral Cortex; Disease Models, Animal; Disease Progression; Female; Hippocampus; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Middle Aged; Neurons; Up-Regulation

Glutamate-induced excitotoxicity has been suggested to influence pathogenesis in amyotrophic lateral sclerosis (ALS). Vesicular glutamate transporters (VGLUTs) are responsible for transport of glutamate into synaptic vesicles. Nerve terminals that envelop motor neurons in the spinal cord contain VGLUT2 and are likely responsible for most glutamate release on motor neurons. The role of VGLUT2 in ALS and its potential role to influence motor neuron survival have not previously been studied. Here, in a mouse model of ALS, we show that genetic reduction of VGLUT2 protein levels rescues motor neurons in the lumbar spinal cord and in the brainstem as well as neuromuscular junctions in tibialis anterior. Although the number of remaining motor neurons increased, neither disease onset nor life span was affected. We also show that the motor neuron subpopulation-specific markers calcitonin/calcitonin-related polypeptide alpha (Calca) and estrogen related receptor beta (ERRbeta) respond in a similar way to reduced VGLUT2 as the whole motor neuron population suggesting that the rescued motor neurons are not of a particular motor unit type. Taken together, this suggests that reduced levels of VGLUT2 decrease motor neuron degeneration but do not prevent loss of motor neuron function in the SOD1(G93A) mouse model for ALS.

Topics: Amyotrophic Lateral Sclerosis; Animals; Brain Stem; Calcitonin; Calcitonin Gene-Related Peptide; Cell Survival; Disease Models, Animal; Estrogen Receptor beta; Female; Humans; Male; Mice; Mice, Transgenic; Motor Neurons; Muscle, Skeletal; Nerve Degeneration; Neuromuscular Junction; Protein Precursors; Spinal Cord; Superoxide Dismutase; Vesicular Glutamate Transport Protein 2

Severe sepsis and septic shock are an important cause of mortality and morbidity. These illnesses can be triggered by the bacterial endotoxin LPS (lipopolysaccharide) and pro-inflammatory cytokines, particularly TNF-α (tumour necrosis factor-α) and IL (interleukin)-1β. Severity and mortality of sepsis have also been associated with high concentrations of N-PCT (aminoprocalcitonin), a 57-amino-acid neuroendocrine peptide derived from ProCT (procalcitonin). Previous studies in a lethal model of porcine polymicrobial sepsis have revealed that immunoneutralization with IgG that is reactive to porcine N-PCT significantly improves short-term survival. To explore further the pathophysiological role of N-PCT in sepsis, we developed an antibody raised against a highly conserved amino acid sequence of human N-PCT [N-PCT-(44-57)]. This sequence differs by only one amino acid from rat N-PCT. First, we demonstrated the specificity of this antibody in a well-proven model of anorexia induced in rats by central administration of human N-PCT-(1-57). Next we explored further the therapeutic potential of anti-N-PCT-(44-57) in a rat model of lethal endotoxaemia and determined how this immunoneutralization affected LPS-induced lethality and cytokine production. We show that this specific antibody inhibited the LPS-induced early release of TNF-α and IL-1β and increased survival, even if treatment began after the cytokine response had occurred. In addition, anti-N-PCT-(44-57) may increase long-term survival in LPS-treated rats by up-regulating the late production of counter-regulatory anti-inflammatory mediators such as ACTH (adrenocorticotropic hormone) and IL-10. In conclusion, these results support N-PCT as a pro-inflammatory factor in both the early and the late stages of lethal endotoxaemia, and suggest anti-N-PCT as a candidate for septic shock therapy.

Topics: Animals; Calcitonin; Calcitonin Gene-Related Peptide; Cytokines; Disease Models, Animal; Eating; Endotoxemia; Gene Expression; Hypothalamus; Immunotherapy; Inflammation Mediators; Lipopolysaccharides; Male; Peptide Fragments; Protein Precursors; Rats; Rats, Wistar; Survival Analysis

Procalcitonin (PCT) has been described as an early, discriminating marker of bacteria-associated sepsis in patients. However, little is known of its source and actions, in part because no appropriate animal models have been available. We tested the hypothesis that plasma PCT increases during various pathophysiological conditions, such as hemorrhagic shock and sepsis, which differ with regard to the degree of associated endotoxemia. We further hypothesized that in sepsis, PCT would be significantly different in survivors vs. nonsurvivors.. Prospective, blinded analysis of previously collected plasma of experimental animals.. Independent nonprofit research laboratory in a trauma hospital and a contract research institute.. A total of 22 male baboons (17.5-31 kg).. Hemorrhagic-traumatic shock was induced by hemorrhage for up to 3 hrs, reperfusion with shed blood and infusion of cobra venom factor (n = 7). By using a similar experimental setup, severe hyperdynamic sepsis was induced (n = 15) by intravenous infusion of live Escherichia coli (2 x 10(9) colony-forming units/kg) over 2 hrs, followed by antibiotic therapy (gentamicin 4 mg/kg twice a day).. Plasma PCT at baseline was barely detectable, but levels increased significantly (p < .05) to 2+/-1.8 pg/mL 2 hrs after the start of reperfusion in the shock group, and to 987+/-230 pg/mL at 4 hrs after E. coli in the sepsis group. Levels were maximal between 6 and 32 hrs and had returned nearly to baseline levels at 72 hrs. Interleukin-6 levels paralleled the course of PCT measurements, whereas a significant increase in neopterin was seen at 24 hrs. PCT levels were approximately three times higher in the sepsis group than in the shock group, corresponding to endotoxin levels (at the end of hemorrhage, 286+/-144 pg/mL vs. 3576+/-979 pg/mL at the end of E. coli infusion; p = .003). PCT levels were significantly different at 24 hrs between survivors (2360+/-620 pg/mL) and nonsurvivors (4776+/-563 pg/mL) in the sepsis group (p = .032), as were interleukin-6 (1562+/-267 vs. 4903+/-608 pg/mL; p = .01) and neopterin/creatinine ratio (0.400+/-0.038 vs. 0.508+/-0.037; p = .032).. PCT is detectable in the baboon as in humans, both in hemorrhagic shock and sepsis. PCT levels are significantly higher in sepsis than in hemorrhage, a finding that is probably related to the differences in endotoxin. The baboon can be used for the study of PCT kinetics in both models; PCT kinetics are clearly different from other markers of sepsis, either IL-6 or neopterin, in both models. There are significant differences between survivors and nonsurvivors in the sepsis model.

Topics: Animals; Calcitonin; Calcitonin Gene-Related Peptide; Cytokines; Disease Models, Animal; Escherichia coli Infections; Interleukin-6; Male; Neopterin; Papio; Protein Precursors; Shock, Hemorrhagic; Shock, Septic; Survival Rate; Systemic Inflammatory Response Syndrome; Wounds and Injuries

Procalcitonin (PCT), a precursor of calcitonin, and endotoxin were determined in the burn wound sepsis model in which 21 Sprague-Dawley rats were scalded approximately 30% on their back. On day 2 post burn, the wounds were inoculated 1 x 10(8) colony-forming units of Pseudomonas aeruginosa. On day 5 post burn P. aeruginosa was detected by blood culture in 10 of the 21 rats (47.6%). The mortality rate 7 days after burn was 90.5%. Significant correlations were observed between serum endotoxin levels and serum PCT levels on day 5 post burn (r = 0.860, p<0.001). It was suggested that endotoxin may induce the release of PCT and that measuring the levels of PCT may be useful in diagnosing burn wound sepsis.

Topics: Animals; Biomarkers; Burns; Calcitonin; Calcitonin Gene-Related Peptide; Disease Models, Animal; Humans; Male; Protein Precursors; Pseudomonas aeruginosa; Pseudomonas Infections; Rats; Rats, Sprague-Dawley; Sepsis; Wound Infection