Capsaicin, The Vanilloid Receptor TRPV1 Agonist in Neuroprotection: Mechanisms Involved and Significance.

Hot peppers, also called chilli, chilli pepper, or paprika of the plant genus Capsicum (family Solanaceae), are one of the most used vegetables and spices worldwide. Capsaicin (8-methyl N-vanillyl-6-noneamide) is the main pungent principle of hot green and red peppers. By acting on the capsaicin receptor or transient receptor potential cation channel vanilloid subfamily member 1 (TRPV1), capsaicin selectively stimulates and in high doses defunctionalizes capsaicin-sensitive chemonociceptors with C and Aδ afferent fibers.

Toxicokinetic Study of a Gastroprotective Dose of Capsaicin by HPLC-FLD Method.

Background: A low dose of capsaicin and its natural homologs and analogs (capsaicinoids) have shown to prevent development of gastric mucosal damage of alcohol and non-steroid anti-inflammatory drugs. Based on this experimental observation, a drug development program has been initiated to develop applicable capsaicin containing drugs to eliminate gastrointestinal damage caused by non-steroid anti-inflammatory drugs.

Methods: As a part of this program, a sensitive and selective reverse-phase high-performance liquid chromatography-based method with fluorescence detection has been developed for quantification of capsaicin and dihydrocapsaicin in experimental dog's plasma.

Membrane-bound ATP-dependent Energy Systems, as Extra- and Intracellular Key Signals for Gastrointestinal Functions and their Regulations in the Gastrointestinal Mucosa.

Aims: Our research group has carried out various biochemical examinations in rat gastric ulcer models and in human gastrointestinal resecates obtained from patient who underwent gastric intervention due to peptic ulcer disease. Biochemical methods gave excellent possibility to approach the biochemical events taking place in tissues, cellular and subcellular regulatory levels during of ulcer development and of its prevetions. This paper gives a brief summary of these biochemical examinations conducted during this study period started from the 1960's up till now.

Cellular Energetical Actions of "Chemical" and "Surgical" Vagotomy in Gastrointestinal Mucosal Damage and Protection: Similarities, Differences and Significance for Brain-Gut Function.

Background: The authors, as internists, registered significant difference in the long lasting actions of surgical and chemical (atropine treatment) vagotomy in patients with peptic ulcer during second half of the last century (efficency, gastric acid secretion, gastrointestinal side effects, briefly benefical and harmful actions were examined).

Aims: 1. Since the authors participated in the establishing of human clinical pharmacology in this field, they wanted to know more and more facts of the acute and chronic effects of surgical and chemical (atropine treatment) on the gastrointestinal mucosal biochemisms and their actions altered by bioactive compounds and scavengers regarding the development of gastric mucosal damage and protection.

Orally given gastroprotective capsaicin does not modify aspirin-induced platelet aggregation in healthy male volunteers (human phase I examination).

Capsaicin is a well-known component of red pepper. Recent studies have shown that capsaicin could prevent gastric ulcer provoked by various NSAID-s like acetylsalicylic acid (ASA). Primary objective of this human clinical phase I trial was to investigate whether two different doses of capsaicin co-administered with ASA could alter the inhibitory effect of ASA on platelet aggregation.

A validated HPLC-FLD method for analysis of intestinal absorption and metabolism of capsaicin and dihydrocapsaicin in the rat.

A sensitive and selective reverse-phase high performance liquid chromatographic method with fluorescence detection has been developed for determination of capsaicin (8-methyl-N-vanillyl-(trans)-6-nonenamid) and dihydrocapsaicin (8-methyl-N-vanillylnonanamide) in samples generated in rat small intestine luminal perfusion experiments. The experiments were designed to study the biotransformation of capsaicinoids in the small intestine in the rat. The chromatographic separation was performed at room temperature on a ZORBAX Eclipse(®) XDB-C8 column using isocratic elution with a mobile phase consisting 0.

Capsaicin as new orally applicable gastroprotective and therapeutic drug alone or in combination with nonsteroidal anti-inflammatory drugs in healthy human subjects and in patients.

Background: Capsaicin is a specific compound acting on capsaicin-sensitive afferent nerves.

Aim: Capsaicin was used to study the different events of human gastrointestinal physiology, pathology, and clinical pharmacology, and possible therapeutic approaches to enhance gastrointestinal mucosal defense in healthy human subjects and in patients with various different gastrointestinal disorders as well as its use with nonsteroidal anti-inflammatory drugs (NSAIDs) in healthy subjects and in patients.

Materials And Methods: The observations were carried out in 198 healthy human subjects and in 178 patients with different gastrointestinal (GI) diseases (gastritis, erosions, ulcer, polyps, cancer, inflammatory bowel diseases, colorectal polyps, cancers), and in 69 patients with chronic (Helicobacter pylori positive and negative) gastritis (before and after eradication treatment).

Role of nitric oxide in the central interferon-alpha-induced inhibition of gastric acid secretion in rats.

Cytokines are known to play a key role in regulation of gastric functions. Interferon-alpha (IFN-α) has been published to impair gastric motility. Aims of this study were to clarify effect of IFN-α on gastric acid secretion (GAS) and determine role of nitric oxide (NO) in the process.

Molecular pharmacological approaches to effects of capsaicinoids and of classical antisecretory drugs on gastric basal acid secretion and on indomethacin-induced gastric mucosal damage in human healthy subjects (mini review).

Background: Actions of various drugs have been tested on the gastric acid basal secretion and on the drug (Indomethacin)- induced gastric mucosal damage; however their physiological and pharmacological mechanisms have not been compared.

Aims: The effects of capsaicinoids, atropine, cimetidine, omeprazole, famotidine and ranitidine were studied on gastric basal acid output, whereas the gastric mucosal preventive effects of capsaicinoids (capsaicin), atropine and cimetidine were tested on the indomethacin-induced gastric mucosal microbleedings in human healthy subjects. Results were presented by molecular pharmacological method; affinity (pD) and intrinsic activity (α-values) were calculated.

Capsaicin-sensitive afferentation represents an indifferent defensive pathway from eradication in patients with H. pylori gastritis.

Aim: To study the role of capsaicin-sensitive afferent nerves in Helicobacter pylori (H. pylori) positive chronic gastritis before and after eradication.

Methods: Gastric biopsy samples were obtained from corpus and antrum mucosa of 20 healthy human subjects and 18 patients with H.

Approaches to gastrointestinal cytoprotection: from isolated cells, via animal experiments to healthy human subjects and patients with different gastrointestinal disorders.

Our clinical observations proved that the the duodenal ulcer in patients healed without any inhibition of gastric acid secretion (1965), and the healing rates of atropine vs cimetidine vs Carbenoxolone were equal and superior to that of placebo in randomized, prospective and multiclinical study of DU patients (1978). The phenomenon of gastric cytoprotection was defined by André Robert in rats (1979). The essential point of this phenomenon is that the prostaglandins prevent the chemical-induced gastric mucosal damage without affecting gastric acid secretion, this being originally suggested as a reaction specific to prostaglandins.

Serum prohepcidin levels in chronic inflammatory bowel diseases.

Background And Aims: One of the major symptoms of chronic inflammatory bowel diseases is anemia. The two most common diseases are Crohn's disease and ulcerative colitis. Anemia may develop due to intestinal bleeding, iron absorption disturbances, or high levels of inflammatory cytokines.

Gastric cytoprotection 30 years after its discovery by André Robert: a personal perspective.

It is generally accepted that the development of gastric mucosal injury and protection is a consequence of an imbalance between the existing aggressive and defensive factors in the gastric mucosa. The excess secretion of gastric acid and increased production of pepsin have been considered as the main etiological factors in the development of peptic ulcer diseases in humans. André Robert and his coworkers (Kalamazoo, Michigan, USA) identified a new pathway for the gastric mucosal protection against the gastric mucosal damage injury (e.

Production of orally applicable new drug or drug combinations from natural origin capsaicinoids for human medical therapy.

It is well known that the capsaicin stimulates (in small doses) or impairs (in high doses) the capsaicin-sensitive afferent nerves and the final effects of capsaicin depend on its applied doses. The effects of capsaicin were analyzed on the gastrointestinal mucosal protection and injury in animal experiments and in human beings (from 1980 up to now). From 2005 to 2008 an interdisciplinary group (21 researchers) participated in the production of orally applicable drug or drug combinations from capsaicin for human medical therapy of patients suffering from cardiovascular, degenerative joint and locomotor diseases, who received in their treatments non-steroidal anti-inflammatory compounds (NSAIDs).

Plasma carnitine ester profiles in Crohn's disease and ulcerative colitis patients with different IGR2230a_1 genotypes.

An association has been repeatedly demonstrated between inflammatory bowel disease (IBD) and the IBD5 locus in the 5q31 chromosomal region. The aim of the present study was to examine the prevalence of the IGR2230a_1 intronic nucleotide polymorphism of the slc22a5 gene (coding for the OCTN2 carnitine transporter protein) lying within this region, and its possible relationship with the carnitine metabolism in Hungarian IBD patients and controls. We genotyped by restriction fragment length polymorphism 200 Crohn's disease (CD) and 246 ulcerative colitis (UC) patients, as well as 187 healthy controls.

Interdisciplinary review for correlation between the plant origin capsaicinoids, non-steroidal antiinflammatory drugs, gastrointestinal mucosal damage and prevention in animals and human beings.

Background: The plant origin capsaicinoids (capsaicin, dihydrocapsaicin, norcapsaicin, dihydrocapsaicin, homocapsaicin, homodihydrocapsaicin) are well known and used as nutritional additive agents in the every day nutritional practice from the last 9,500 years; however, we had have a very little scientifically based knowledge on their chemistry, physiology and pharmacology in animal observations, and in humans up to the mid-twentieth century. Our knowledge about their chemistry, physiology, pharmacology entered to be scientifically based evidence from the year 1980, dominantly in animal observations. The human observations with capsaicin (capsaicinoids), in terms of good clinical practice, have been started only in the last 10-year period (from 1997) in randomized, prospective, multiclinical studies.

Capsaicin research as a new tool to approach of the human gastrointestinal physiology, pathology and pharmacology.

Background: Capsaicin has been found to act on the capsaicin sensitive afferent nerves in animal experiments.

Aim: The specific action of capsaicin on sensory afferent nerves affecting gastrointestinal (GI) functions was investigated in human GI physiology and pathology using pharmacological approaches.

Materials And Methods: Observations were carried out in 98 normal healthy human subjects and in 178 patients with different gastrointestinal diseases (gastritis, erosions, ulcer, polyps, cancer, inflammatory bowel diseases, colorectal polyps, cancers).

Cellular mechanisms of beta-carotene-induced gastric cytoprotection in indomethacin-treated rats.

Indomethacin (IND) is a non-steroidal anti-inflammatory agent which is widely used in the treatment of various inflammatory disorders. The drug causes gastrointestinal injury in humans and experimental animals. The aim of these studies was to examine the time course correlation between the macroscopic appearance of mucosal damage, tissue level of PGE(2) and adenosine nucleotide metabolism during the development of indomethacin (IND)-induced mucosal damage and its prevention by beta-carotene.

Leiden mutation in patients with Crohn's disease.

Background: Inherited resistance to activated protein C is a common risk factor of venous thrombosis. In a majority of patients the defect is caused by single-point mutation in the gene for factor V. This mutated form of factor Va is more stable against proteolytic attack by activated protein C.

Effects of indomethacin, with vitamin A or beta-carotene, on the rat gastric mucosa: extra-and intracellular membrane-bound ATP mechanisms.

Background: Indomethacin (IND) is a widely used non-steroidal anti-inflammatory agent in the treatment of various inflammatory disorders, which causes gastrointestinal injury in humans and animal experiments. Vitamin A and beta-carotene prevent the IND-induced gastric mucosal injury. These compounds modify the membrane-bound ATP-dependent energy systems.

No association of the cytotoxic T-lymphocyte associated gene CTLA4 +49A/G polymorphisms with Crohn's disease and ulcerative colitis in Hungarian population samples.

Aim: The goal of the current work was to analyse the prevalence of the +49A/G variant of the cytotoxic T-lymphocyte antigen 4 gene (CTLA4) in Hungarian patients with Crohnos disease (CD) and ulcerative colitis (UC).

Methods: A total of 130 unrelated subjects with CD and 150 with UC, and 170 matched controls were genotyped for the single nucleotide polymorphism (SNP). The genotypes were determined by using PCR/RFLP test.

Gastrointestinal cytoprotection: from basic science to clinical perspectives.

An essential point of cytoprotection is that the prostaglandins are able to prevent chemical-induced gastric mucosal damage without affecting gastric acid secretion, this being originally suggested as a property specific to prostaglandins. Since then gastrointestinal cytoprotection has been shown with various agents (anticholinergic agents, H(2)RA, growth factors) and retinoids the latter differing from the actions of vitamin A. In examining the various components of gastrointestinal cytoprotection we have performed studies in isolated cells, stable cell lines, animal experiments, healthy human subjects, and in patients with gastrointestinal diseases.

Plasma carnitine ester profiles in Crohn's disease patients characterized for SLC22A4 C1672T and SLC22A5 G-207C genotypes.

Crohn's disease (CD) is a chronic inflammatory bowel disorder caused by environmental and genetic factors. The purpose of this study was to analyse the possible influence of functional variants of genes of OCTN cation transporters on the carnitine ester profile of patients with CD. Genotyping for SLC22A4 1672C --> T, SLC22A5-207G --> C mutations and three common NOD2 variants (R702W, G908R and 1007finsC) were performed in 100 adult CD patients and in ninety-four healthy controls by direct sequencing.