Novel Options for the Pharmacological Treatment of Chronic Anal Fissure – Role of Botulin Toxin

Madalinski, Mariusz; Kalinowski, Leszek

doi:10.2174/157488409787236083

Cited by 26 publications

(16 citation statements)

References 68 publications

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“…It has been shown before that the basal tone in the IAS in different species including humans is primarily myogenic in nature (2,5,7,17,25), because of the characteristic properties of the IAS smooth muscle cells (SMCs) (7,23,25). Knowledge of molecular determinants of basal tone in the IAS is critical for treating a number of rectoanal motility disorders such as fecal incontinence, Hirschsprung's disease, recurrent anal fissures, and hemorrhoids (3,17).…”

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confidence: 99%

RhoA/ROCK pathway is the major molecular determinant of basal tone in intact human internal anal sphincter

Rattan

Singh

2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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Rattan S, Singh J. RhoA/ROCK pathway is the major molecular determinant of basal tone in intact human internal anal sphincter. Am J Physiol Gastrointest Liver Physiol 302: G664 -G675, 2012. First published January 12, 2012; doi:10.1152/ajpgi.00430.2011.-The knowledge of molecular control mechanisms underlying the basal tone in the intact human internal anal sphincter (IAS) is critical for the pathophysiology and rational therapy for a number of debilitating rectoanal motility disorders. We determined the role of RhoA/ROCK and PKC pathways by comparing the effects of ROCK-and PKCselective inhibitors Y 27632 and Gö 6850 (10 Ϫ8 to 10 Ϫ4 M), respectively, on the basal tone in the IAS vs. the rectal smooth muscle (RSM). Western blot studies were performed to determine the levels of RhoA/ROCK II, PKC-␣, MYPT1, CPI-17, and MLC20 in the unphosphorylated and phosphorylated forms, in the IAS vs. RSM. Confocal microscopic studies validated the membrane distribution of ROCK II. Finally, to confirm a direct relationship, we examined the enzymatic activities and changes in the basal IAS tone and p-MYPT1, p-CPI-17, and p-MLC20, before and after Y 27632 and Gö 6850. Data show higher levels of RhoA/ROCK II and related downstream signal transduction proteins in the IAS vs. RSM. In addition, data show a significant correlation between the active RhoA/ROCK levels, ROCK enzymatic activity, downstream proteins, and basal IAS tone, before and after ROCK inhibitor. From these data we conclude 1) RhoA/ ROCK and downstream signaling are constitutively active in the IAS, and this pathway (in contrast with PKC) is the critical determinant of the basal tone in intact human IAS; and 2) RhoA and ROCK are potential therapeutic targets for a number of rectoanal motility disorders for which currently there is no satisfactory treatment. smooth muscle tone; Rho kinase; rectoanal incontinence ALTHOUGH MULTIFACTORIAL, the basal tone in the IAS plays an important role in rectoanal incontinence (3,24). It has been shown before that the basal tone in the IAS in different species including humans is primarily myogenic in nature (2,5,7,17,25), because of the characteristic properties of the IAS smooth muscle cells (SMCs) (7,23,25). Knowledge of molecular determinants of basal tone in the IAS is critical for treating a number of rectoanal motility disorders such as fecal incontinence, Hirschsprung's disease, recurrent anal fissures, and hemorrhoids (3,17).Mechanisms underlying the agonists-induced sustained contraction of intestinal smooth muscle involve prolonged myosin light chain (MLC 20 ) phosphorylation (p-MLC 20 ), the phosphorylation of cytoskeleton filaments and associated proteins, increase in Ca 2ϩ influx, and Ca 2ϩ sensitization (19). It is well known that RhoA/ROCK and PKC play a significant role in this regard. In the phasic contraction, p-MLC 20 is rapidly dephosphorylated via myosin light chain phosphatase (MLCP). In the sustained contraction, on the other hand, this dephosphorylation is prevented or delayed primarily via MLCP inhibition by...

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RhoA/ROCK pathway is the major molecular determinant of basal tone in intact human internal anal sphincter

Rattan

Singh

2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…4,5 Although BoNTs are the most potent of biological poisons, purified BoNTs have found widespread use in medical clinics and are used to treat a growing list of medical ailments. [6][7][8][9] The increasing prevalence of these toxins as biopharmaceuticals makes unintentional overdosing increasingly likely. In addition to accidental or unintentional environmental exposure, the current political climate makes the malicious misuse of BoNTs, through acts of terrorism, a serious possibility.…”

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The Osmolyte Trimethylamine N-Oxide (TMAO) Increases the Proteolytic Activity of Botulinum Neurotoxin Light Chains A, B, and E: Implications for Enhancing Analytical Assay Sensitivity

et al. 2010

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Botulism, the disease caused by botulinum neurotoxins (BoNTs), secreted by the spore-forming, anaerobic bacteria Clostridium botulinum, has been associated with food poisoning for centuries. In addition, the potency of BoNTs coupled with the current political climate has produced a threat of intentional, malicious poisoning by these toxins. The ability to detect and measure BoNTs in complex matrixes is among the highest research priorities. However, the extreme potency of these toxins necessitates that assays be capable of detecting miniscule quantities of these proteins. Thus, signal-boosting strategies must be employed. A popular approach uses the proteolytic activity of the BoNT light chain (LC) to catalyze the cleavage of synthetic substrates; reaction products are then analyzed by the analytical platform of choice. However, BoNT LCs are poor catalysts. In this study, the authors used the osmolyte trimethylamine N-oxide (TMAO) to increase the proteolytic activities of BoNT LCs. Their data suggest that concentrated solutions of TMAO induce complete folding of the LCs, resulting in increased substrate affinity and enhanced enzyme turnover. The authors observed increases in catalysis for BoNT serotypes A, B, and E, and this increased proteolytic activity translated into substantial increases in analytical assay sensitivity for these medically relevant toxins. (Journal of Biomolecular Screening 2010:928-936)

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“…9, 10 A systematic strategy for the identification of the inhibitory neurotransmitter carried out extensively in our laboratory and reviewed recently 3 has translated into diagnosis and therapy of a number of debilitating rectoanal and other GI motility disorders. 5, 11, 12 …”

Section: Nature Of Inhibitory Neurotransmissionmentioning

confidence: 99%

Basal internal anal sphincter tone, inhibitory neurotransmission, and other factors contributing to the maintenance of high pressures in the anal canal

Rattan

Singh

2010

Neurogastroenterology &Amp; Motility

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Maintenance of the basal tone in the internal anal sphincter (IAS) is critical for rectoanal continence. Effective evacuation requires a fully functional rectoanal inhibitory reflex (RAIR)-mediated relaxation of the IAS via inhibitory neurotransmission (INT). Systematic studies examining the nature of the INT in different species have identified nitric oxide (NO) as the major inhibitory neurotransmitter. However, other mediators such as vasoactive intestinal polypeptide (VIP), ATP, and carbon monoxide (CO) may also play species-specific role under certain experimental conditions. Measurements of the intraluminal pressures in the IAS along with the force of the isolated IAS tissues are the mainstay in the basic studies for the molecular mechanisms underlying the basal tone and in the nature of the INT. The identification of NO as the inhibitory neurotransmitter has led to major advances in the diagnosis and treatment of a number of rectoanal motility disorders associated with the IAS dysfunction. Besides the IAS, the high pressures in the anal canal are affected by the external anal sphincter (EAS) function, and its malfunction may also lead to rectoanal incontinence. Different approaches including biofeedback have been attempted to improve the EAS function, with variable outcomes. There is a dire need for the innovative ways to improve the week high pressures zone in the anal canal. This viewpoint focuses on two studies that extend the above concept of multiplicity of inhibitory neurotransmitters1, and that high pressures in the anal canal can be improved by the EAS plication.2

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Novel Options for the Pharmacological Treatment of Chronic Anal Fissure – Role of Botulin Toxin

Cited by 26 publications

References 68 publications

RhoA/ROCK pathway is the major molecular determinant of basal tone in intact human internal anal sphincter

RhoA/ROCK pathway is the major molecular determinant of basal tone in intact human internal anal sphincter

The Osmolyte Trimethylamine N-Oxide (TMAO) Increases the Proteolytic Activity of Botulinum Neurotoxin Light Chains A, B, and E: Implications for Enhancing Analytical Assay Sensitivity

Basal internal anal sphincter tone, inhibitory neurotransmission, and other factors contributing to the maintenance of high pressures in the anal canal

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