Evaluation of Antiasthamic Activity of Electrohomeopathy Formulation Pettorale on Experimental Animals

Objective: The current study was planned to evaluate the antiasthamatic effect of Electrohomeopathic medicine Pettorale in various experimental models. Methods: The antiasthmatic activity of Electrohomeopathic medicine Pettorale was studied on different experimental animals like histamine induced bronchospasm in guinea pig, haloperidol induced catalepsy in rats, egg albumin induced paw anaphylaxis in rats and milk induced leukocytosis in mice. Conclusion: Preliminary phytochemical screening has revealed the presence of alkaloids, glycosides, carbohydrates, amino acids, proteins, steroids and terpenoids. Petorella exhibited best antihistaminic activity at the dose of 400 mg/kg. It inhibited haloperidol-induced catalepsy, increased leukocyte count and increased eosinophil count due to milk allergen. Antiasthmatic activity of Pettorale may be possible due to the membrane stabilising potential, suppression of antibody production and inhibition of antigen induced histamine release. Keywords: Electrohomeopathy, Pettorale, catalepsy, asthma, histamine

Thioperamide Alleviates Lipopolysaccharide-Induced Neuroinflammation and Promotes Neurogenesis by Histamine Dependent Activation of H2R/PKA/CREB Pathway

Background Adult neurogenesis in hippocampus dentate gyrus (DG) is associated with numerous neurodegenerative diseases such as aging and Alzheimer's disease (AD). Overactivation of microglia induced neuroinflammation is well acknowledged to contribute to the impaired neurogenesis in pathologies of these diseases and then leading to cognitive dysfunction. Histamine H3 receptor (H3R) is a presynaptic autoreceptor regulating histamine release via negative feedback way. Recently, studies show that H3R are highly expressed not only in neurons but also in microglia to modulate inflammatory response. However, whether inhibition of H3R is responsible for the neurogenesis and cognition in chronic neuroinflammation induced injury and the mechanism remains unclear. Methods Microglia activity, inflammation and neurogenesis were assessed in vivo by using lipopolysaccharide (LPS) induced model of inflammation. Mice were treated with thioperamide, pyrilamine or cimetidine to evaluate the effect of thioperamide on inflammation and the involving role of histamine. Protein levels of PKA/CREB and NF-κB were assessed to investigate the mechanism by which thioperamide regulate inflammatory response and neurogenesis. The cognitive function was tested by novel object recognition, Y maze and morris water maze. Results In this study, we found that inhibition of H3R by thioperamide reduced the microglia activity and promoted a phenotypical switch from pro-inflammatory M1 to anti-inflammatory M2 in microglia, and ultimately attenuated LPS induced neuroinflammation in mice. Additionally, thioperamide rescued the neuroinflammation induced impairments of neurogenesis and cognitive function. Mechanically, the neuroprotection of thioperamide was involved in histamine dependent H2 receptor (H2R) activation, because cimetidine, an H2R antagonist but not pyrilamine, an H1R antagonist reversed the above effects of thioperamide. Moreover, thioperamide activated the H2R downstream phosphorylated protein kinase A (PKA)/cyclic AMP response element-binding protein (CREB) pathway but inhibited nuclear factor kappa-B (NF-κB) signaling. Activation of CREB by thioperamide promoted interaction of CREB-CREB Binding Protein (CBP) to increase anti-inflammatory cytokines (Interleukin-4 and Interleukin-10) and brain-derived neurotrophic factor (BDNF) release but inhibited NF-κB-CBP interaction to decrease pro-inflammatory cytokines (Interleukin-1β, Interleukin-6 and Tumor necrosis factor α) release. H89, an inhibitor of PKA/CREB signaling, abolished effects of thioperamide on neuroinflammation and neurogenesis. Conclusions Taken together, these results suggested under LPS induced neuroinflammation, the H3R antagonist thioperamide inhibited microglia activity and inflammatory response, and ameliorated impairment of neurogenesis and cognitive dysfunction via enhancing histamine release. Histamine activated H2R and reinforced CREB-CBP interaction but weakened NF-κB-CBP interaction to exert anti-inflammatory effects. This study uncovered a novel histamine dependent mechanism behind the therapeutic effect of thioperamide on neuroinflammation.

Dimerized Translationally Controlled Tumor Protein-Binding Peptide 2 Attenuates Systemic Anaphylactic Reactions Through Direct Suppression of Mast Cell Degranulation

Dimerized translationally controlled tumor protein (dTCTP) amplifies allergic responses through activation of several types of immune cells and release of inflammatory mediators. In particular, dTCTP plays an important role in histamine release by triggering mast cells and has been proposed as a target in the treatment of allergic diseases. dTCTP-binding peptide 2 (dTBP2) is known to attenuate severe allergic rhinitis and asthma through inhibition of dTCTP activity on airway epithelial cells and T cells; however, it is unclear whether dTBP2 affects mast cell function and mast cell disease. In this study, we explored the effects of dTBP2 on mast cell degranulation and allergen-induced anaphylactic reactions. We found that bacterial product lipopolysaccharide increased the expression of dTCTP in mast cells and rapidly released dTCTP by the mast cell stimulator compound 48/80. Interestingly, the released dTCTP further promoted mast cell degranulation in an autocrine activation manner and increased calcium mobilization in mast cells, which is essential for degranulation. Furthermore, dTBP2 directly and dose-dependently inhibited in vitro mast cell degranulation enhanced by compound 48/80, suggesting a direct and potent anti-anaphylactic activity of dTBP2. dTBP2 also significantly suppressed the dTCTP-induced degranulation and histamine release through inhibition of the p38 MAPK signaling pathway and suppression of lysosomal expansion and calcium mobilization in mast cells. More importantly, in vivo administration of dTBP2 decreased mortality and significantly attenuated histamine release and inflammatory cytokine production in compound 48/80-induced systemic anaphylactic reactions. These results suggest that dTBP2 is beneficial for the control of anaphylaxis with increased dTCTP.

Rno-miR-199a-3p targets Nedd4 to promote sensitization of ST36 acupoints via mast cell activation in a rat model of knee osteoarthritis

Selecting routine points on related meridians is widely accepted as the foundational principle of acupuncture. When the body is suffering disease or injury, corresponding acupoints are thought to be activated and manifest in several sensitized forms. Sensitized acupoints hold high clinical value as a reflection of disease activity on the body surface. Mast cells have been implicated in the process of acupoint sensitization but the underlying regulatory mechanisms remain unclear. In the present study, we evaluated ST36 as a sensitized acupoint in the monosodium iodoacetate-induced knee osteoarthritis rat model. We first confirmed sensitization at the ST36 acupoint through decreases in the acupoint mechanical pain threshold and instructively found an accompanying increase in skin mast cell degranulation. Thereafter, we used highthroughput RNA sequencing to reveal potential molecular mechanisms of acupoint sensitization. We showed that rno-miR-199a-3p was highly expressed in the sensitized ST36 acupoint and its expression was associated with mast cells. Functional experiments revealed that overexpression of rno-miR-199a-3p increased mast cell histamine release whereas inhibition of rno-miR-199a-3p decreased histamine release. Mechanistically, we established rno-miR-199a-3p acted to inhibit neural precursor cell expressed developmentally down-regulated 4 (Nedd4) protein expression through miRNA-mediated targeting of the 3’-UTR of Nedd4 mRNA. Moreover, we found ectopic expression of Nedd4 antagonized histamine release in mast cells and blocked the actions of rno-miR-199a-3p overexpression. Thus, our study establishes that mast cells participate in the process of acupoint sensitization, and further reveals a novel miRNA-based mechanism which is crucial for further understanding of acupoint sensitization and acupuncture applications.

Enzymatic Synthesis of α-Tocopherol Derivative Glycoside, Daidzein Glycoside, Daidzein Oligosaccharide, Resveratrol Oligosaccharide, and Curcumin Oligosaccharides and Their Anti-Allergic Activity and Neuroprotective Activity

Enzymatic glycosylations of an α-tocopherol derivative, daidzein, resveratrol, and curcumin were investigated. The plant polyphenol, resveratrol, was incubated with glucosyltransferase from Phytolacca americana. The resveratrol glycoside obtained was then incubated with cyclodextrin glucanotransferase to obtain resveratrol oligosaccharide. Daidzein and curcumin were also converted into daidzein glycoside, daidzein oligosaccharide, and curcumin oligosaccharides. Also, α-tocopherol derivative, that is, 2, 5,7,8-tetramethyl-2-(4,8-dimethylnonyl)chroman-6-ol, was glycosylated. The glycosides and oligosaccharides had strong anti-allergic activity such as suppression of IgE formation, inhibition of histamine release, and inhibition of O2 - generation. In addition, the glycosides and oligosaccharides showed efficient neuroprotective activity by inhibition of phosphodiesterase.

ROCURONIUM VERSUS CISATRACURIUM: INTUBATING CONDITIONS, EFFICACY, AND SAFETY.

Background: Neuromuscular blockers (NMB) are very important adjuvant to general anesthesia,Rocuronium bromide (aminosteroidal NMB) and cisatracurium besylate (benzylisoquinoline NMB) are recently introduced non-depolarizing muscle relaxants.In a prospective randomized study,we had compared both the drugs as regard to the onset of action, intubating conditions,clinical duration,hemodynamic changes,and adverse effects. Method: 80 female patients ASA I&II,18-60 year old underwent elective abdominal surgery under general anesthesia (GA) were randomly assigned into 2 equal groups.ROC group,where 0.9mg/kg rocuronium was given and CIS group, where 0.15mg/kg cisatracurium was given. Standardized GA was given to all patients as follows, fentanyl 1mcg/kg, propofol 2mg/kg,intubation was tried by the same anesthetist who was blind to the given NMB after 60 sec of injection, intubation was done if the intubating condition was acceptable (excellent or good),and it was re-attempted every 30 sec if it was poor or inadequate.Anesthesia was maintained by 60% N2O in O2 and isoflurane to a total MAC 1.5,controlled ventilation was adjusted to normocapnia.Mean arterial blood pressure (MAP),heart rate,and intubating conditions were recorded. Results: Clinically acceptable intubating conditions were achieved after 60 sec more frequently with rocuronium (80%) than with cisatracurium(0%).Rocuronium had advantage of rapid onset of action with good intubating conditions as compared to Cisatracurium and both were found to be potent and safe with excellent cardiovascular stability and also without any apparent histamine release. Conclusion: Rocuronium has a rapid onset of action with good intubating conditions in comparison to cisatracurium both are potent and safe with excellent cardiovascular stability and do not cause apparent histamine release

Short- and Long-Term Social Recognition Memory Are Differentially Modulated by Neuronal Histamine

The ability of recognizing familiar conspecifics is essential for many forms of social interaction including reproduction, establishment of dominance hierarchies, and pair bond formation in monogamous species. Many hormones and neurotransmitters have been suggested to play key roles in social discrimination. Here we demonstrate that disruption or potentiation of histaminergic neurotransmission differentially affects short (STM) and long-term (LTM) social recognition memory. Impairments of LTM, but not STM, were observed in histamine-deprived animals, either chronically (Hdc−/− mice lacking the histamine-synthesizing enzyme histidine decarboxylase) or acutely (mice treated with the HDC irreversible inhibitor α-fluoromethylhistidine). On the contrary, restriction of histamine release induced by stimulation of the H3R agonist (VUF16839) impaired both STM and LTM. H3R agonism-induced amnesic effect was prevented by pre-treatment with donepezil, an acetylcholinesterase inhibitor. The blockade of the H3R with ciproxifan, which in turn augmented histamine release, resulted in a procognitive effect. In keeping with this hypothesis, the procognitive effect of ciproxifan was absent in both Hdc−/− and αFMH-treated mice. Our results suggest that brain histamine is essential for the consolidation of LTM but not STM in the social recognition test. STM impairments observed after H3R stimulation are probably related to their function as heteroreceptors on cholinergic neurons.