Targeting ATP May Yield New Drugs for Interstitial Cystitis
Andersson KE. Purinergic signalling in the urinary bladder. Auton Neurosci. 2015 Apr 30. pii: S1566-0702(15)00048-X. doi: 10.1016/j.autneu.2015.04.012. [Epub ahead of print]
Adenosine triphosphate (ATP) is often referred to as the energy currency of life, because it is used as a transport for energy within cells for purposes of metabolism. When released from cells, ATP can play a role in bladder contraction, bladder filling, urgency, and other urological functions. The release of ATP can be affected by urological diseases including interstitial cystitis; thus investigators hope that ATP may one day represent a target for future drugs designed to treat lower urinary tract disorders. Those drugs might target either the mechanisms of ATP release, or the receptors that ATP activates.
Plant-Derived Compound With Cannabinoid Effects May Be Protective in Cystitis
Pessina F, Capasso R, Borrelli F, Aveta T, Buono L, Valacchi G, Fiorenzani P, Di Marzo V, Orlando P, Izzo AA. Protective effect of palmitoylethanolamide in a rat model of cystitis. J Urol. 2015 Apr;193(4):1401-8. doi: 10.1016/j.juro.2014.11.083. Epub 2014 Nov 18.
Palmitoylethanolamide (PEA), a fatty acid discovered several decades ago, has been shown to reduce inflammation and allergic reactions in animals, as well as influenza symptoms in humans. Now, one group of investigators is reporting that PEA seems to have a protective effect in a rat model of cystitis. To test PEA’s effects, researchers induced cystitis in female rats. They found that PEA reduced pain-associated behavior, bladder inflammation, and urinary dysfunction. While animal studies are considered preliminary, these findings do suggest this plant-derived compound may have a protective role. Researchers say PEA seems to work due to its attraction to the brain’s cannabinoid receptors, which are involved in pain, mood, memory, and other processes.
New THC-Like Drug May Treat Chronic Pain Without Side Effects of Medical Marijuana
Deng L, Guindon J, Cornett BL, Makriyannis A, Mackie K, Hohmann AG. Chronic cannabinoid receptor 2 activation reverses paclitaxel neuropathy without tolerance or cannabinoid receptor 1-dependent withdrawal. Biol Psychiatry. 2015 Mar 1;77(5):475-87. doi: 10.1016/j.biopsych.2014.04.009. Epub 2014 Apr 25.
Medical marijuana may be useful for treating chronic pain, but its use can be associated with side effects in the nervous system, tolerance, and even physical withdrawal. Now, researchers have evidence that a drug similar to the active ingredient in marijuana, but more selective in its effects on brain receptors, may effectively treat pain without the unwanted side effects. The drug, known as AM1710, was administered to mice who had been given a chemotherapy agent to induce pain. Repeated treatments successfully suppressed that pain. Moreover, researchers saw no tolerance, withdrawal, hypothermia, or motor dysfunction among the treated mice; researchers think that’s because AM1710 avoids hitting a target in the brain called the cannabinoid CB1 receptor; instead, it selectively targets another receptor known as CB2. By contrast, the main psychoactive ingredient in marijuana, known as Δ9-tetrahydrocannabinol (Δ9-THC), acts on both the CB1 and CB2 receptors. While these results are promising, further research--particularly trials in humans--would be necessary before this drug could be a treatment option for patients with IC who suffer chronic pain.
Antispasmodic Agent May Prove Useful as an IC Treatment
He YQ, Zhang WT, Shi CH, Wang FM, Tian XJ, Ma LL. Phloroglucinol Protects the Urinary Bladder Via Inhibition of Oxidative Stress and Inflammation in a Rat Model of Cyclophosphamide-induced Interstitial Cystitis. Chin Med J (Engl). 2015 5th Apr;128(7):956-962. doi: 10.4103/0366-6999.154316.
In a preliminary study, a compound called phloroglucinol showed anti-disease activity in a rat model of interstitial cystitis (IC). Phloroglucinol, an antispasmodic agent that is known to play a role in inflammatory responses, was administered to rats that had IC induced by injections of a drug called cyclophosphamide. After 8 days of treatment, the bladders of the rats were examined. Investigators found that phloroglucinol suppressed bladder inflammation and reversed overactive bladder in the rats with induced IC. The treatment also reversed markers of inflammation. Taken together, the results suggest phloroglucinol might deserve further study as a potential treatment option.
Biomarker Called TLR-4 Linked to IC/BPS; May Lead to New Treatments
Schrepf A, Bradley CS, O'Donnell M, Luo Y, Harte SE, Kreder K, Lutgendorf S; Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network. Toll-like Receptor 4 and comorbid pain in Interstitial Cystitis/Bladder Pain Syndrome: A Multidisciplinary Approach to the Study of Chronic Pelvic Pain research network study. Brain Behav Immun. 2015 Mar 11. pii: S0889-1591(15)00074-4. doi: 10.1016/j.bbi.2015.03.003. [Epub ahead of print]
Researchers have linked an inflammation-associated biomarker with IC/BPS, a finding that could lead to new and advanced treatment options. In their study, the researchers analyzed blood and saliva samples from 66 women with IC/BPS. They found that women with increased in toll-like receptor 4 (TLR-4) inflammatory response were substantially more likely to report pain outside of the pelvic area. This is significant because experimental drugs that target TLR-4 have proven effective in animal models of pain. While much more research would need to be done, particularly in humans, this study helps demonstrate that TLR-4 inflammatory responses may be linked to widespread pain in IC/BPS.
PGE2 May Be a Bad Actor Specifically in IC With Hunner Lesions
Wada N, Ameda K, Furuno T, Okada H, Date I, Kakizaki H. Evaluation of prostaglandin E2 and E-series prostaglandin receptor in patients with interstitial cystitis. J Urol. 2015 Jan 13. pii: S0022-5347(15)00031-2. doi: 10.1016/j.juro.2015.01.010. [Epub ahead of print]
There’s been an ongoing controversy over the role of Prostaglandin E2 (PGE2) in interstitial cystitis (IC). Some studies show PGE2, which is associated with inflammation and pain, is elevated in IC patients. Other studies do not show a conclusive link. Now, researchers are reporting that PGE2 elevation may be specific to the subset of IC patients with Hunner lesions. The analysis included 20 women with IC, 9 control patients, and 10 healthy volunteers. Levels of PGE2 detected in the urine were significantly higher in IC patients with Hunner lesions, as compared with IC patients without Hunner lesions (as well as the control subjects and volunteers). Likewise, PGE2 levels in bladder biopsies were significantly higher in IC patients with Hunner lesions than in the control subjects. Investigators also looked at specifically at prostaglandin receptors, and again found elevated levels in the IC patients with Hunner lesions. Although there are no immediate clinical implications for this study, it’s possible that drugs blocking the action of PGE2 could one day be used to provide symptom relief for IC patients with Hunner lesions.
Pain Severity Similar in Both Sexes; Pain Most Bothersome Symptom
Clemens JQ, Clauw DJ, Kreder K, Krieger JN, Kusek JW, Lai HH, Rodriguez L, Williams DA, Hou X, Stephens A, Landis JR; MAPP Research Network. Comparison of baseline urologic symptoms in men and women in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (Mapp) research cohort. J Urol. 2014 Nov 13. pii: S0022-5347(14)04861-7. doi: 10.1016/j.juro.2014.11.016. [Epub ahead of print] PMID: 25463989
In a study of 191 men and 233 women with IC/BPS or CP/CPPS, MAPP (Multidisciplinary Approach to the Study of Chronic Pelvic Pain)(http://www.mappnetwork.org) researchers assessed urinary urgency, frequency, pain and overall symptom severity, and a single question about the most bothersome pelvic symptom. The findings indicate that pain severity is similar in both sexes, and that bladder-focused symptoms (urgency, suprapubic pain, frequency) are more common in women. However, a substantial proportion of men also report these types of bladder symptoms. It was also found that the most bothersome single symptom in both men and women was pain in the pubic/bladder area (34% of men, 58% of women).
Protamine Sulfate Provides Pain Relief in Mouse Study
Stemler KM, Crock LW, Lai HH, Mills JC, Gereau RW, Mysorekar IU. Protamine sulfate induced bladder injury protects from distention induced bladder pain. J Urol. 2013 Jan;189(1):343-51. doi: 10.1016/j.juro.2012.08.189. Epub 2012 Nov 20.
In a mouse model study, protamine sulfate was found to protect against bladder pain. The research mice received protamine sulfate, lipopolysaccharide, or uropathogenic E. coli, followed a day later by bladder distillation. Protamine sulfate relieved the pain of the distillation, protected bladder tissue from damage, and suppressed the inflammatory response normally associated with pain. In contrast, E. coli significantly increased the pain response and the lipopolysaccharide had no effect.
Chondroitin Sulphate and Colchicine Have Similar Effects on IC
Sinanoglu O1, Dogan Ekici I2, Ekici S3. Comparison of intravesical application of chondroitin sulphate and colchicine in rat protamine/lipopolysaccharide induced cystitis model. Urol J. 2014 Mar 4;11(1):1296-300.
In an animal study, researchers found that colchicine (Col) (commonly used for gout) and chondroitin sulphate (CS) had similar effects in the bladders of rats with protamine/lipopolysaccharide induced IC. Both drugs decreased leucocyte and mast cell infiltration in the bladder to the same extent; CS also reduced interstitial edema (swelling). The researchers conclude that Col may be an alternative treatment for painful bladder conditions such as IC.
Melatonin Improves Bladder Symptoms in Rats
Zhang QH, Zhou ZS, Lu GS, Song B, Guo JX. Melatonin Improves Bladder Symptoms and May Ameliorate Bladder Damage via Increasing HO-1 in Rats. Inflammation. 2013 Jun;36(3):651-7. doi: 10.1007/s10753-012-9588-5.
Chinese researchers investigated the effects of melatonin on bladder symptoms in rats and found that when the hormone was given before inducing IC, the rats that received it had fewer bladder symptoms and less tissue damage than the rats that did not. Melatonin, which affects inflammatory and immune responses, improved IC symptoms by diminishing bladder oxidative stress, blocking nitric oxide synthase (iNOS), upregulating heme oxygenase-1 (HO-1), and downregulating the expression of substance P (SP). Further study is needed to determine whether it would have the same effect on IC symptoms in humans.
Inflammation May Explain Why Stress Increases Bladder Symptoms
Merrill L, Malley SE, Vizzard MA. Repeated variate stress (RVS) in male rats induces increased voiding frequency, somatic sensitivity and urinary bladder NGF expression. Am J Physiol Regul Integr Comp Physiol. 2013 May 8. [Epub ahead of print]
Although we know that IC symptoms increase when we’re stressed, we don’t know exactly why. New findings from the University of Vermont suggest that stress causes an inflammatory response, which in turn triggers symptoms. For this study, rats were exposed to repeated variate stress for seven days. Along with increased bladder symptoms (pain, voiding frequency), the rats also showed evidence of an inflammatory response: significant increases in histamine, and MPO, NGF, and CXCL12 protein expression in the bladder. Further study will reveal whether stress related symptoms in humans are related to an inflammatory response and any implications for disease management.
Nitric Oxide Production May Occur in Different Layers of the Bladder
Logadottir Y, Hallsberg L, Fall M, Peeker R, Delbro D. Bladder Pain Syndrome/Interstitial Cystitis ESSIC Type 3C: High Expression of Inducible Nitric Oxide Synthase in Inflammatory Cells. Scand J Urol Nephrol. 2012 Jul 10.
Researchers in Sweden investigated the source of inducible nitric oxide synthase (iNOS), the enzyme that creates nitric oxide (NO) in cells. In a previous study, the results indicated that BPS/IC patients with Hunner’s lesions have high levels of NO in the lumen of the bladder. In this study, the researchers aimed to investigate the source of iNOS and the location of NO production by iNOS. They performed immunohistochemistry using two different markers for iNOS on 10 patients with Hunner’s lesions BPS/IC who expressed high levels of intraluminal NO. The data was then compared with four patients with non-Hunner’s BPS/IC. The researchers also assessed the protein expression of nitrotyrosine, a marker for iNOS activation. The results showed that tissues of Hunner’s lesion BPS/IC patients had inflammatory infiltrates (white blood cells) with different intensities. iNOS and nitrotyrosine were found within the urothelium (mucousal layer) and the inflammatory infiltrates in the lamina propria (submuscousal layer) of these subjects. Because iNOS and nitrotyrosine is present in both areas of Hunner’s lesion BPS/IC patients’ bladders, the researchers concluded the production of NO by iNOS may occur in different tissue compartments of the bladder.
Replenishing Bladder GAGs Eases Inflammation
Engles CD, Hauser PJ, Abdullah SN, Culkin DJ, Hurst RE. Intravesical Chondroitin Sulfate Inhibits Recruitment of Inflammatory Cells in an Acute Acid Damage “Leaky Bladder” Model of Cystitis. Urology. 2011 Nov 30. [Epub ahead of print]
Instilling chondroitin sulfate into irritated bladders in rats actually slowed the inflammation process. During inflammation, inflammatory cells, including neutrophils and mast cells are “recruited” to the site of injury. These researchers found that, with instillation, this recruitment was significantly reduced. This is the first time, said the authors, that research has demonstrated that replenishing the glycosaminoglycan (GAG) layer actually decreases this recruitment of inflammatory cells.
COX-2 Could Be Treatment Target
Yamamoto K, Takao T, Nakayama J, Kiuchi H, Okuda H, Fukuhara S, Yoshioka I, Matsuoka Y, Miyagawa Y, Tsujimura A, Nonomura N. Water avoidance stress induces frequency through cyclooxygenase-2 expression: A bladder rat model. Int J Urol. 2011 Dec 5. doi: 10.1111/j.1442-2042.2011.02905.x. [Epub ahead of print]
Laboratory experiments with stressed rats (stressed with a water avoidance test) indicate that the inflammatory enzyme COX-2 from bladder smooth muscle might be a good treatment target. Rats that undergo this test have their bladder lining deteriorate, have visceral pain, and urinate frequently in small volumes, similar to IC patients. There was a lot of expression of this enzyme in the stressed rats’ bladders exclusively from muscle cells.
“Glowing” Mice Could Screen IC Treatments
Vykhovanets EV, Maclennan GT, Vykhovanets OV, Cherullo EE, Ponsky LE, Gupta S. Molecular Imaging of Nuclear Factor-kappaB in Bladder as a Primary Regulator of Inflammatory Response. J Urol. 2012 Jan;187(1):330-7. Epub 2011 Nov 17.
Mice bred to have their tissues luminesce when nuclear factor-kappaB (NF-kappaB) is activated could help screen IC therapies. NF-kappaB is known to regulate genes involved in the response to infection, inflammation, and stress. In these experiments, female mice bred with a luminescing “tag” for activated NF-kappaB showed the increased luminescence in their bladder tissue when the bladders were irritated. Pretreatment with a steroid significantly reduced the glow and eased inflammation. The researchers concluded that NF-kappaB activity may have an important role in bladder inflammation and that these mice could be useful to screen drugs for their ability to reduce bladder inflammation.
Acid-sensing Ion Channels Could Play Role in IC Pain
Sánchez-Freire V, Blanchard MG, Burkhard FC, Kessler TM, Kellenberger S, Monastyrskaya K. Acid-sensing channels in human bladder: expression, function and alterations during bladder pain syndrome. J Urol. 2011 Oct;186(4):1509-16. Epub 2011 Aug 19.
Using tissue from IC patients and cultured urothelial tissue, these researchers looked at the cells’ acid-sensing ion channels. They found these channels are regulated as cells mature. In IC patients, two of these channels were up-regulated, suggesting these are involved in increased pain and hyperalgesia (increased sensitivity to pain).
Low Oxygen May Be Key to Glomerulation, Hyperbaric Treatment Success
Lee JD, Lee MH. Increased Expression of Hypoxia-inducible Factor-1α and Vascular Endothelial Growth Factor Associated With Glomerulation Formation in Patients With Interstitial Cystitis. Urology. 2011 Aug 1. [Epub ahead of print]
IC bladders are known to have a decreased blood perfusion, and therefore a decreased oxygen supply. That’s why these researchers looked for the expression of a low-oxygen factor and overexpression of vascular endothelial growth factor, which are typical with low tissue oxygenation. IC bladder tissue showed increases in both these factors, especially in the very top layer of bladder lining cells. The authors suggested that expression of these factors may be associated with the glomerulations formed during hydrodistention and that these may help explain how hyperbaric oxygen helps IC.
Getting a Grip on How Pain Signals Come from the Bladder
Daly DM, Collins VM, Chapple CR, Grundy D. The afferent system and its role in lower urinary tract dysfunction. Curr Opin Urol. 2011 Jul;21(4):268-74.
This review article shows that recent research has changed concepts of how sensation is transmitted from the bladder. Our understanding has gone beyond activation of nerve fibers—although we have learned much more about their receptors and their sensitivities. There is interplay between the bladder lining and a host of mediators released from the lining, such as ATP and nitric oxide. Other biochemical pathways, such as those affected by anticholinergic drugs (eg, overactive bladder drugs), alpha blockers, cannabinoids, and TRP-related compounds, also play a role in signaling. Understanding bladder signaling mechanisms better may lead to more effective treatments.
IC Unclear in the Animal Mirror
Bjorling DE, Wang ZY, Bushman W. Models of inflammation of the lower urinary tract. Neurourol Urodyn. 2011 Jun;30(5):673-82. doi: 10.1002/nau.21078.
So much of the research to find out what causes IC and what treatments might work has to be done in animals, but the best way to do that isn’t entirely clear. There are lots of animal “models” of IC and other types of bladder inflammation: a natural kind of IC in cats, and cystitis induced in rodents by irritation with chemical or bacterial products, alterations of the immune or nervous systems, and infection. How relevant any of these models are is unclear because we don’t understand the underlying cause of IC or other types of lower urinary tract inflammation. Comparative studies and translational (that is, from animals to people) studies need to be done to fulfil the potential of these animal models, said the authors.
New IC Model Could Boost Research
Palma TF, Seabra A, Souto SC, Maciel L, Alvarenga M, Siniscalchi R, Ganzarolli M, Ricetto C. A new experimental model for inducing interstitial cystitis by oxidative stress using bladder instillation of a nitric oxide donor gel. [Article in English, Spanish] Actas Urol Esp. 2011 Mar 25. [Epub ahead of print]
Often, researchers use animals with irritated bladders to study potential IC causes, mechanisms, and treatments. Commonly used irritants are protamine and potassium chloride. This team tried an alternative—a polymer solution containing a chemical donor of nitric oxide (NO). High levels of NO are produced when there is inflammation, and higher levels have been found in IC bladders than in healthy bladders. Instilling the NO donor solution in the bladders produced inflammation similar to that seen with protamine and potassium chloride instillation.
Bladder Irritation Prompts iNOS, Aquaporin Production
Cho KH, Hyun JH, Chang YS, Na YG, Shin JH, Song KH. Expression of nitric oxide synthase and aquaporin-3 in cyclophosphamide treated rat bladder. Int Neurourol J. 2010 Oct;14(3):149-56. Epub 2010 Oct 31.
Nitric oxide synthase (NOS) is an enzyme that plays a role in nitric oxide production from L-arginine. iNOS, a type of NOS, which plays a role in the inflammation response, may play a role in IC. Aquaporin plays a role in regulating the flow of water across cell membranes. The researchers found irritation prompted release of both these molecules from the dome, or top, of the bladder.
Not Quite Like IC
Jin LH, Shin HY, Kwon YH, Park CS, Yoon SM, Lee T. Urodynamic findings in an awake chemical cystitis rat model observed by simultaneous registrations of intravesical and intraabdominal pressures. Int Neurourol J. 2010 Apr;14(1):54-60. Epub 2010 Apr 30.
Researchers need to tease out the physiology of IC and test drugs first on laboratory animals. But when the animals don’t show all the typical characteristics of IC, that can make drawing research conclusions difficult. In this study, researchers did urodynamics on bladders of rats that had an induced chemical cystitis and on rats that only had instillations of saline. Unlike IC patients, the animals with irritated bladders actually had greater bladder capacity, volume of voided urine, volume of urine left in the bladder after urination, and longer times between urinations than those that got saline. On the other hand, the rats with irritated bladders had more bladder muscle spasms when the bladder pressure rose above a certain point, showing problems as the bladder fills, which is typical of IC patients.
How Urinary Painkiller Exerts its Effect
Aizawa N, Wyndaele JJ. Effects of phenazopyridine on rat bladder primary afferent activity, and comparison with lidocaine and acetaminophen. Neurourol Urodyn. 2010 Nov;29(8):1445-50.
These urologists discovered how phenazopyridine may work to kill urinary tract pain. Phenazopyridine is the active ingredient in Azo and related medications. By measuring nerve activity of different nerve fibers when rats got phenazopyridine, lidocaine, or acetaminophen after their bladders were filled, the researchers discovered that phenazopyridine decreased the activity only of A-delta nerve fibers. That effect was related to the dose of phenazopyridine. Those nerve fibers are sensitive to pressure, which carry signals related to bladder filling and emptying. The finding might explain how phenazopyridine exerts its effect in conditions where the bladder is hypersensitive, said the authors.
Awareness Grows of ERK Enzymes’ Role in Bladder, Other Pain
White JP, Cibelli M, Fidalgo AR, Nagy I. Extracellular signal-regulated kinases in pain of peripheral origin. Eur J Pharmacol. 2010 Oct 13. [Epub ahead of print]
Researchers are increasingly recognizing the role of a family of enzymes known as extracellular signal-regulated kinases (ERKs) (also known as mitogen-activated protein kinases or MAPKs) in the development and maintenance of pain in many inflammatory conditions, such as in IC. The authors urge all pain researchers to be aware of the importance of these enzymes, which are already serving as markers of pain processing.
How Stress Makes Bladder Vessels “Leaky”
Boucher W, Kempuraj D, Michaelian M, Theoharides TC. Corticotropin-releasing hormone-receptor 2 is required for acute stress-induced bladder vascular permeability and release of vascular endothelial growth factor. BJU Int. 2010 Nov;106(9):1394-9.
Acute stress changes the permeability or “leakiness” of blood vessels in mouse bladders through effects on the receptors for corticotropin-releasing hormone (CRH), one of the stress hormones. Blocking one of the receptors, CRH-R2 with a compound known as astressin 2B inhibited release of vascular endothelial growth factor, a signaling protein that increases the permeability of blood vessels. Stress is a common instigator of IC flares, and patients find stress management techniques to be helpful. But someday, there may be medical therapy to head off these types of flares—and maybe more—based on these findings.
Urothelial Cell-Line RT4 Expresses A Glucosaminogl Ycan (GAG) Layer on its Outer Surface; In Vitro Model for the Bladder GAG-layer
Janssen, D, Schalken, J, ten Dam, G, Heesakkers, J. American Urological Association (AUA) 2010 Annual Meeting, May 29 – June 3, 2010, San Francisco, CA.
Replacing a damaged glycosaminoglycan (GAG) layer is the aim of a number of IC therapies, but the approach is based mainly on theory. Now, these biochemists have found a way to study how the GAG layer acts and reacts. They tested a number of lines of urinary tract lining cells and found one (RT4) that produces the same mix of GAGs (chondroitin sulfate, heparin sulfate, and dermatan sulfate) as lining cells do in the bladder. This will make much more research possible on how the GAG layer functions and how to restore it.
The Role of Opiate Receptors in the Inhibitory Pudendal to Bladder Reflex in Cats
Chen, M, Shen, B, Wang, J, Liu, H, Roppolo, J, de Groat, W, Tai, C. American Urological Association (AUA) 2010 Annual Meeting, May 29 – June 3, 2010, San Francisco, CA.
To get a better understanding of how neuromodulation might work, these investigators looked at what makes the reflex from the pudendal nerve to the bladder tick. They found that stimulating the pudendal nerve suppresses bladder activity and increases bladder capacity. Using an opioid blocker reverses that effect. Activating opioid receptors, they concluded, may be one way pudendal neuromodulation works, so new treatments might combine medication and neuromodulation.
Enkephalin Gene Therapy Using Herpes Simplex Virus Vector Suppresses Cytokine Elevation in Bladder and Urine of Rats with Cystitis
Yokoyama, H, Oguchi, T, Nishizawa, O, Goins, W, Goss, J, Glorioso, J, Yoshimura, N. 2010 American Urological Association Meeting, Chicago, IL.
Researchers looking at gene therapy for IC bladder pain speculated that one way the treatment may work is by reducing the production of inflammatory compounds in the bladder. Measuring these compounds might be a useful way to gauge bladder inflammation and the effectiveness of treatment. Rats with irritated bladders got bladder instillations of a virus carrying a gene coding for one of the body’s own opioid painkilling substances or an inert instillation. The animals that got the gene produced much lower levels of the inflammatory cytokines IL-1 beta and IL-6 than the rats that did not get the gene.
Immune/Allergic Activity High in IC Bladder Tissue
Tseng LH, Chen I, Wang CN, Lin YH, Lloyd LK, Lee CL. Genome-based expression profiling study of Hunner’s ulcer type interstitial cystitis: an array of 40-gene model. Int Urogynecol J Pelvic Floor Dysfunct. 2010 Mar 4. [Epub ahead of print]
Genes active in the bladder lining cells of Hunner’s ulcer patients code for various immune system proteins and indicate allergic inflammation. Finding what genes may be active by extracting the RNA active in translating genes to proteins can help reveal what functions are going awry in the disease process and can also aid diagnosis. These researchers used the technique on bladder lining cells from areas with and without Hunner’s ulcers in IC patients who had Hunner’s ulcers. The genes that were highly expressed in both types of tissue were for:
There was also an indication of allergic inflammation and immune system response. The investigators termed those changes “bladder remodeling,” and said that gene expression profiling could be used to diagnose Hunner’s ulcer-type IC in clinical practice.
- Major histocompatibility class IF and II molecules, which are immune components
- Leukocyte immunoglobulin-like receptors, which are receptors on certain white blood cells for immune regulating molecules
- Hepatitis A virus cellular receptor 2
- Interleukin 32, an immune signaling cytokine
Stress May Prompt Bladder Bleeding Mechanism
Boucher W, Kempuraj D, Michaelian M, Theoharides TC. Corticotropin-releasing hormone-receptor 2 is required for acute stress-induced bladder vascular permeability and release of vascular endothelial growth factor. BJU Int. 2010 Mar 1. [Epub ahead of print]
Stress seems to prompt release of a growth factor implicated in glomerulations, the pinpoint bleeding in the bladder often seen in IC patients. In this study, mice that had normal receptors for the stress hormone called corticotropin-releasing hormone (CRH) and others without these receptors underwent a stress test and were also given two types of CRH blockers. Then, the researchers studied their bladders immunologically. One of the CRH blockers knocked out production of vascular endothelial growth factor (VEGF). Stress induced an increase in VEGF from the mice who did not have one of the CRH receptors. Some of the bladders of normal mice showed reactivity in one of the CRH receptors. The researchers concluded that acute stress could prompt leaky blood vessels and release of VEGF, and the process depends on the CRH-2 receptor. CRH and VEGF might play a role in IC and provide new therapeutic targets.
Gene Hunters Chase Down Hunner’s Ulcer Culprits
Ogawa T, Homma T, Igawa Y, Seki S, Ishizuka O, Imamura T, Akahane S, Homma Y, Nishizawa O. CXCR3 Binding Chemokine and TNFSF14 Over Expression in Bladder Urothelium of Patients With Ulcerative Interstitial Cystitis. J Urol. 2010 Mar;183(3):1206-1212. Epub 2010 Jan 22.
Genes that might play a role in Hunner’s ulcer IC are related to immune and inflammatory responses. Using DNA microarray analysis and quantitative real-time polymerase chain reactions, these researchers looked for genetic differences between the tissue in the Hunner’s “ulcers” or patches from nine patients with IC and normal-looking tissue from nine patients with other urologic conditions. Among the Hunner’s patch patients, the investigators found 564 “probes” expressed in mRNA at least four times more frequently than in the control patients. The top three functions of those implicated genes were
The genes have potential as IC biomarkers, said the team.
- cell-to-cell signaling and interaction and hematological system development and function
- inflammatory disease
- cellular development
Why NGF is Important in the Bladder
Chung CW, Zhang QL, Qiao LY. Endogenous nerve growth factor regulates collagen expression and bladder hypertrophy through Akt and MAPK pathways during cystitis. J Biol Chem. 2010 Feb 5;285(6):4206-12. Epub 2009 Dec 7. Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298-0551, USA.
Blocking nerve growth factor (NGF) may ease cystitis symptoms, but it might have nothing to do with nerves. This research team found that collagen could be the key. They discovered that when bladder tissue was irritated by a harsh chemical, it increased production of type 1 collagen, which thickened the inflamed bladder wall and increased the weight of the bladder. But neutralizing NGF reduced collagen production during that process and also reversed the increase in bladder weight. The researchers also discovered specific changes in biochemical pathways in bladder inflammation and how NGF affects them.
More than IC Pushes Up Urine NGF Levels
Jacobs BL, Smaldone MC, Tyagi V, Philips BJ, Jackman SV, Leng WW, Tyagi P. Increased nerve growth factor in neurogenic overactive bladder and interstitial cystitis patients. Can J Urol. 2010 Feb;17(1):4989-94.
Nerve growth factor (NGF) in urine doesn’t look like it could be marker for IC because levels are also high in some other conditions. But the clues are intriguing. These researchers found urine levels of NGF were high in patients with IC patients and neurogenic overactive bladder (such as in spinal-cord injury). The levels were also somewhat higher, although not significantly so, in patients who had kidney stones. The connection with nervous system abnormalities is intriguing, but the significance isn’t clear and needs more study. More research needs to be done on what the levels mean and whether NGF could be used as a marker for diagnosis or prognosis in IC or other urologic conditions.
Receptors Active in IC Pain Identified
Chen X, Molliver DC, Gebhart GF. The P2Y2 Receptor Sensitizes Mouse Bladder Sensory Neurons and Facilitates Purinergic Currents. J Neurosci. 2010 Feb 10;30(6):2365-72.
This team pinpointed which bladder sensory nerve receptor is active in IC pain. Finding the sensitive receptor is an important key to finding treatments that can stop the pain. For some time, researchers have known that the purinergic receptors, which are sensitive to transmitters such as ATP, are important in bladder pain signaling. Using a receptor blocker, electrical current measurements, and measuring which receptors were predominant, the researchers concluded that the P2Y(2) receptors are involved in bladder sensation and may be important contributors to the excitability and hypersensitivity of bladder neurons.
Estrogen Affects Bladder Pain Signals
Cheng Y, Keast JR. Effects of estrogens and bladder inflammation on mitogen-activated protein kinases in lumbosacral dorsal root ganglia from adult female rats. BMC Neurosci. 2009 Dec 28;10:156.
Estrogen does affect bladder pain signaling, but the effects are complex. This research team measured the effects of estrogens on the chemical signaling pathways in the nerves that carry pain signals from the bladder and other pelvic organs. To do this, the team cultured neurons with estradiol and estrogen-receptor stimulators and measured the effects of inflammation and removing the ovaries in experimental animals. Effects of inflammation and hormonal manipulation were different on different receptors. Although the actions of estrogens on bladder pain signals are varied, understanding those effects holds out the possibility of developing new ways to ease pain, said the investigators.
Lining Plays Role in Bladder’s Neurologic Control
Birder L, de Groat W, Mills I, Morrison J, Thor K, Drake M. Neural control of the lower urinary tract: peripheral and spinal mechanisms. Neurourol Urodyn. 2010;29(1):128-39.
This review of neural control of the bladder points out that the bladder lining functions as a kind of sensory web, a discovery made in IC research. This research team, which has long researched the role of the nervous system and pain sensing in IC, detailed concepts of how the nervous system controls bladder function, including the sensing role of the bladder lining, the location and characteristics of bladder nerves, including those that can be sensitized, how nerves control the pelvic floor muscle, and how associated conditions may affect bladder function.
Neurokinin Receptors May Make Good Drug Target
Sanchez Freire V, Burkhard FC, Kessler TM, Kuhn A, Draeger A, Monastyrskaya K. MicroRNAs May Mediate the Down-Regulation of Neurokinin-1 Receptor in Chronic Bladder Pain Syndrome. Am J Pathol.. [Epub ahead of print]
IC patients have fewer neurokinin receptors than healthy people, which means these receptors may be a good target for drug development. These cell biologists showed that two types of neurokinin receptor were very much reduced or “downregulated” in IC patients. In addition, certain molecules responsible for the “leakiness” of lining cells were also downregulated. A bradykinin receptor, a cannabinoid receptor, and muscarinic receptors were all upregulated. Exposing one of the neurokinin receptors to substance P (involved in pain transmission) increased the levels of regulatory types of RNA. Those types of RNAs were also at high levels in the tissue of IC patients, suggesting that IC promotes reduced levels of that receptor by activating certain regulatory RNAs.
Understanding of “Hot Pepper” Receptor Grows
Alawi K, Keeble J. The paradoxical role of the transient receptor potential vanilloid 1 receptor in inflammation. Pharmacol Ther. 2009 Nov 5. [Epub ahead of print]
Basic science is uncovering new information about the vanilloid 1 or TRPV1 receptor, also known as the “hot pepper receptor.” This receptor is thought to play an important role in IC pain and is a target for drug development. TRPV1 receptors occur mainly in sensory nerves and are activated, not only by the hot pepper substance, capsaicin, but also by a cannabinoid receptor activator, heat, and acid. Although these receptors are known to be involved in neuropathic pain, joint inflammation, and other types of inflammatory pain, new protective functions of the receptor are being discovered. They may play a protective role in severe infection of the bloodstream and also have important functions in normal physiology, including urinary bladder function, temperature regulation, and generation of new nerve cells.
Nerve Growth Factor, Not PGE2, Is High in IC, OAB
Liu HT, Tyagi P, Chancellor MB, Kuo HC. Urinary nerve growth factor but not prostaglandin E2 increases in patients with interstitial cystitis/bladder pain syndrome and detrusor overactivity. BJU Int. 2009 Sep 14. [Epub ahead of print]
IC patients and some patients with overactive bladder (OAB) have high levels of nerve growth factor (NGF), but not prostaglandin E2 (PGE2), in their urine. The finding may have implications for both detection and treatment. Among experimental treatments that have been looked at are substances that inhibit NGF, thought to play a role in sensitivity or spasms, or medications that increase levels of PGE2-like activity, which may be low in IC. The researchers did not look at the effects of an NGF inhibitor or of extra PGE2, but they did look at levels of these substances in the urine of women with IC, women with OAB, and healthy women. The OAB group was divided into those who had overactivity of the bladder muscle (spasms) and those with simply with increased bladder sensation. NGF levels were high in the 40 women with IC and in 23 with detrusor overactivity but not in the 31 with increased bladder sensation or in the 27 healthy women. The women with IC had much higher levels of NGF than the women with detrusor overactivity. There were no differences among the groups in PGE2 levels.
Receptor for New Molecule May Play Top Role in IC Inflammation
Kutlu O, Akkaya E, Koksal IT, Bassorgun IC, Ciftcioglu MA, Sanlioglu S, Kukul E. Importance of TNF-related apoptosis-inducing ligand in pathogenesis of interstitial cystitis. Int Urol Nephrol. 2009 Aug 25. [Epub ahead of print]
Turkish urologists have identified the cellular receptor in IC patients’ bladder tissue that may be the most important one in IC inflammation. They looked for different receptors for TNF-related apoptosis-inducing ligand or TRAIL. Staining IC bladder cells to reveal the receptors showed the receptor TRAIL-R4 to be the dominant one. Recently discovered, TRAIL plays a role in the death of abnormal cells and also in inflammation.
Gene Expression Profiles Could Lead to Diagnostic Test
Tseng LH, Chen I, Chen MY, Lee CL, Lo TS, Lloyd LK. Genome-based expression profiles as a single standardized microarray platform for the diagnosis of experimental interstitial cystitis: an array of 75 genes model. Int Urogynecol J Pelvic Floor Dysfunct. 2009 Jan 20. [Epub ahead of print] AND Tseng LH, Chen I, Chen MY, Lee CL, Lin YH, Lloyd LK. Genome-based expression profiles as a single standardized microarray platform for the diagnosis of bladder pain syndrome/interstitial cystitis: an array of 139 genes model. Int Urogynecol J Pelvic Floor Dysfunct. 2009 Feb 13. [Epub ahead of print]
These researchers are studying the expression of various genes in IC bladder linings. The genes that are highly expressed relate to the bladder lining and to the metabolism of glucose, lipids, nucleotides, chemicals foreign to the body, and amino acids. In addition, the research implicated immune and inflammatory responses, various cell signaling pathways, and nerve function. The team’s second study also pointed to mast cell activation and allergic inflammation. The technique to study gene expression, using cDNA microarrays, may offer ways to diagnose IC/painful bladder syndrome (PBS) and discover drugs with potential as effective treatments, said the investigators.
Nerve Type that Responds to “Hot Pepper” Pinpointed
Malin SA, Christianson JA, Bielefeldt K, Davis BM. TPRV1 expression defines functionally distinct pelvic colon afferents. J Neurosci. 2009 Jan 21;29(3):743-52.
The nerve receptor that responds to hot pepper-like substances is a focus of IC research because of its potential as a pain treatment target. Called the vanilloid receptor or TRPV1, it is found on two distinct types of nerves that send signals from the colon back to the central nervous system, these researchers discovered. One type fires fast, and the other, more slowly. It’s the slow-firing nerves that respond to the hot pepper substance, capsaicin, and to two other irritators, mustard oil and acid. The fast-firing type responds very little. Because this receptor is thought to be responsible for inflammatory pain hypersensitivity in visceral organs, the unique role of these slow-firing nerves that have this receptor might be exploited to design treatments.
IC Cats Have More Sensitive Bladder Coating
Ikeda Y, Birder L, Buffington C, Roppolo J, Kanai A. Mucosal Muscarinic Receptors Enhance Bladder Activity in Cats With Feline Interstitial Cystitis. J Urol. 2009 Jan 19. [Epub ahead of print]
Both calcium ions and muscarinic receptors (which overactive bladder drugs act on) can affect bladder contractions and spasms. This team took a look at those two things in the bladders of cats with IC. They identified alterations in calcium flow through the urothelium in cats with IC. They also found that IC cat bladders were hypersensitive to a stimulator of the muscarinic receptor when the bladder coating (mucosal) layer was intact, but that sensitivity decreased markedly when the mucosal layer was gone, further corroboration that the bladder lining communicates with the rest of the bladder.
Critical Step Discovered in APF Effects on Bladder Cells, Genes
Planey SL, Keay SK, Zhang CO, Zacharias DA. Palmitoylation of Cytoskeletal Associated Protein 4 by DHHC2 Regulates Antiproliferative Factor-mediated Signaling. Mol Biol Cell. 2009 Jan 14. [Epub ahead of print]
This basic research has discovered a critical step in how antiproliferative factor (APF) acts on bladder lining cells. APF is the peptide discovered in IC patients’ urine that suppresses the proliferation of bladder lining cells. The researchers had already learned that that APF binds strongly to the protein CKAP4, which plays a role in APF activity. When the gene for CKAP4 is knocked down, APF signaling is stopped. Now, the team has discovered that a process called palmitoylation of this protein, mediated by an enzyme known as DHHC2, is needed for APF to act. Knocking down the gene for DHHC2 with a small interfering RNA inhibits the events that depend on APF and CKAP4. Interfering RNAs, which help switch off genes, are being researched as a new approach to treating disease.
New Ideas about Gene Expression Could Refocus IC Research
Elgavish A. Epigenetic Reprogramming: A Possible Etiological Factor in Bladder Pain Syndrome/Interstitial Cystitis? J Urol. 2009 Jan 14. [Epub ahead of print]
Basic research on the bladder lining, the nervous system, genetics, and processes that affect gene expression suggest that some reprogramming of gene expression (called epigenetic reprogramming) may explain the abnormalities in bladder lining cells, mast cells, and nerve cells seen in IC. Particularly important may be the expression of genes that are important in maintaining adult stem cells. These genes help silence the expression of other genes but inflammation may reverse that, leading to abnormalities in cell growth and maturation. This idea is a new way of thinking that could refocus some research on the cause of IC and lead to new ways to diagnose and treat it, said the author.
Revised June 25, 2013