Publications (38) View all
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Article: Deciphering intracellular localization and physiological role of nociceptin and nocistatin.
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ABSTRACT: Nociceptin and nocistatin are endogenous ligands of G protein coupled receptor family. Numerous techniques have been used to study the diverse parameters including, localization, distribution and ultrastructure of these peptides. The majority of the studies parameters are based on their physiological roles in different organ systems. The present study presents an overview of the different methods used for the study of nociceptin, nocistatin and their receptors. Nociceptin has been implicated in many physiological functions including, nociception, locomotion, stressed-induced analgesia, learning and memory, neurotransmitter and hormone release, renal function, neuronal differentiation, sexual and reproductive behavior, uterine contraction, feeding, anxiety, gastrointestinal motility, cardiovascular function, micturition, cough, hypoxic-ischemic brain injury, diuresis and sodium balance, temperature regulation, vestibular function, and mucosal transport. It has been noted that the use of light and electron microscopy was less frequent, though it may be one of the most promising tools to studying the intracellular localization of these neuropeptides. In addition, more studies on the level of circulating nociceptin and nocistatin are also necessary for investigating their clinical roles in health and disease. A variety of modern tools including physiological, light and electron microscopy (EM) are needed to decipher the extent of intracellular localization, tissue distribution and function of these peptides. The intracellular localization of nociceptin and nocistatin will require a high resolution transmission EM capable of identifying these peptides and other supporting molecules that co-localize with them. A tracing technique could also elucidate a possible migratory ability of nociceptin and nocistatin from one cellular compartment to the other.Peptides 02/2013; · 2.43 Impact Factor -
Article: Sub-chronic exposure to paraoxon neither induces nor exacerbates diabetes mellitus in Wistar rat.
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ABSTRACT: There is an increasing belief that organophosphorus compounds (OPCs) impair glucose homeostasis and cause hyperglycemia and diabetes mellitus. The present study was undertaken to investigate the putative diabetogenic effect of sub-lethal and sub-chronic exposure to paraoxon (POX), an extremely hazardous OPC used in pesticides. The effect of paraoxon on streptozotocin-induced diabetic rats was also examined. Each rat was injected with 100 nmol of POX 5 days per week for 6 weeks. Blood glucose levels and red blood cell acetylcholinesterase activity were measured weekly. Biochemical analysis and morphological studies were performed at the end of the experiment. The results revealed that POX neither induces nor exacerbates diabetes mellitus in experimental rats. Liver and kidney/body weight ratios revealed statistically insignificant differences when compared with controls. Biochemical analysis of urine samples showed a small but not significant increase in protein level in all groups. Urine bilirubin was significantly higher in the diabetes + POX group when compared with the control group. The number of blood cells in urine was significantly higher in the POX-treated group compared with the control group. Hyperglycemia was noted in the diabetes and diabetes + POX groups, but neither in the saline control nor in POX-treated normal rats. Electron microscopy of POX-treated pancreas did not show any morphological changes in beta cells. These results suggest that POX does not cause diabetes mellitus at sub-lethal sub-chronic exposure. Copyright © 2012 John Wiley & Sons, Ltd.Journal of Applied Toxicology 08/2012; · 2.48 Impact Factor -
Article: N3,N7-diaminophenothiazinium derivatives as antagonists of α7-nicotinic acetylcholine receptors expressed in Xenopus oocytes.
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ABSTRACT: Derivatization of phenothiazine (PTZ, 1) has been a commonly used method to develop drugs with various pharmacological properties. In the present study, a series of PTZ derivatives 1-11 were investigated on the inhibition of the cloned α7 subunit of the human nicotinic acetylcholine receptor (α7-nAChR) expressed in Xenopus oocytes by using the two-electrode voltage-clamp technique. In the first series of experiments, the effect of unsubstituted phenothiazine 1 on α7-nAChRs was compared with that of the N3,N7-diaminophenothiazin-5-ium derivative 2, and of sequentially methylated derivatives 3-6. In the second set of experiments, the effects of N3,N7-tetra-ethyl- to n-hexylphenothiazin-5-ium derivatives 7-11 were tested. Despite the lack of activity found for 1, a reversible inhibition of α7-nAChRs, ranging from moderate to potent, was observed as a result of a sequential amine- and methylamine substitution of 1. The inhibition of ACh (100 μM)-induced currents was concentration-dependent with IC(50) values ranging from 0.4 to 16.8 μM. However, an optimal inhibitory activity was achieved by prolongation of alkyl chains up to propyl size, as found in PTZ derivative 8, whereas further lengthening of alkyl chains to n-butyl-, n-pentyl-, or n-hexyl groups resulted in inactive derivatives 9-11. The results evidently suggest the presence of a lipophilic binding pocket of narrow tolerability on the receptor protein. These results emphasize the importance of amine and/or alkylamine moieties for the inhibitory effect of PTZ derivatives and provide further insights for the development of novel antagonists targeting α7-nAChRs.Pharmacological Research 06/2012; 66(3):213-8. · 4.44 Impact Factor -
Article: Usefulness of administration of non-organophosphate cholinesterase inhibitors before acute exposure to organophosphates: assessment using paraoxon.
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ABSTRACT: Reversible acetylcholinesterase (AChE) inhibitors can protect against the lethal effects of irreversible organophosphorus AChE inhibitors (OPCs), when administered before OPC exposure. We have assessed in vivo the mortality-reducing efficacy of a group of known AChE inhibitors, when given in equitoxic dosage before exposure to the OPC paraoxon. Protection was quantified in rats by determining the relative risk (RR) of death. Best in vivo protection from paraoxon-induced mortality was observed after prophylactic administration of physostigmine (RR = 0.30) or the oxime K-27 (RR = 0.34); both treatments were significantly superior to the pre-treatment with all other tested compounds, including the established substance pyridostigmine. Tacrine (RR = 0.67), ranitidine (RR = 0.72), pyridostigmine (RR = 0.76), tiapride (RR = 0.80) and 7-MEOTA (RR = 0.86) also significantly reduced the relative risk of paraoxon-induced death, but to a lesser degree. Methylene blue, amiloride and metoclopramide had an unfavorable effect (RR ≥ 1), significantly increasing mortality. When CNS penetration by prophylactic is undesirable K-27 is a promising alternative to pyridostigmine. Copyright © 2012 John Wiley & Sons, Ltd.Journal of Applied Toxicology 05/2012; · 2.48 Impact Factor -
Article: TERATOGENICITY AND EMBRYOTOXICITY OF ORGANOPHOSPHORUS COMPOUNDS IN ANIMAL MODELS - A SHORT REVIEW
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ABSTRACT: Organophosphorus compounds (OPCs) are a wide group of compounds both structurally and functionally. Each OPC has a unique toxicological profile. The exposure to this type of poison is not limited only to certain occupationally exposed people but also to children, women, pregnant women; all have chances to be exposed to this poison. During the recent past years it has been reported in many poison epidemiological studies and case reports that exposure of OPCs during pregnancy caused malformed fetuses, neural tube defect (NTD) and shortening of pregnancy. The literature for animal models reveals inconclusive evidence. The generalized view is that they are neither teratogenic nor embryotoxic. But it is not true. There is a lack of systematic study and scarcity of reports on the topic. The present study was undertaken to investigate the teratogenicity induced by organophosphorus compounds in different animal models by literature review. Literature was searched by Toxicology Data NetWork (TOXNET), Developmental and Reproductive Toxicology Database (DART), Toxicology Literature Online (TOXLINE), Hazardous Substances Data Bank (HSDB), Pubmed Central, Entrez-Pubmed, Science Direct, Directory Of Open Access Journal (DOAJ), Google Scholar and International Program on Chemical Safety (IPCS-INCHEM), Embase. The terms for literature search were teratogenicity, organophosphorus compounds; fetal toxicity, organophosphorus compounds; organophosphorus poisoning and pregnancy; organophosphorus poisoning and growth restriction; organophosphorus poisoning and IUGR; organophosphorus poisoning and reproduction; organophosphates and reproduction; pregnancy and organophosphates. The outcome of the study concludes that the work on teratogenicity induced by organophosphorus compounds was completely neglected, inconclusive, and only carried out on less than half of the OPCs available in the market. A more comprehensive and systemic study on the subject is clearly needed and its importance should not be ignored because more positive cases are being reported on the teratogenicity and embryotoxicity of OPCs.Mil. Med. Sci. Lett. (Voj. Zdrav. Listy) 2012, vol. 81(1), p. 16-26. 01/2012; 81(1):16-26.
