CPPS, oxidative stress and isoprostanes... could it be this?

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Wolfcub
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CPPS, oxidative stress and isoprostanes... could it be this?

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Med Hypotheses. 2011 Nov;77(5):837-40. doi: 10.1016/j.mehy.2011.07.050. Epub 2011 Aug 19.
Are prostatitis symptoms associated with an isoprostane-mediated vicious circle?
Silver Türk a,⇑, Tiiu Kullisaar b / Medical Hypotheses 77 (2011) 837–840
a Department of Microbiology, Tartu University, Ravila 19, Tartu 50411, Estonia
b Department of Biochemistry, Tartu University, Ravila 19, Tartu 50411, Estonia


Abstract

Prostatitis is a disease that seriously affects the quality of patients’ life. In the majority of cases, chronic prostatitis (chronic pelvic pain syndrome – CPPS) has an unclear pathogenesis. Anti-inflammatory and anti-infectious treatments have remained controversial. According to the latest research, prostatitis has been associated with oxidative stress (OxS) and/or OxS-related genetic polymorphisms. We have observed that prostatitis patients have systemic OxS in case of inflammation and pain. We propose a new explanation for the role of OxS in the pathogenesis of prostatitis and describe the putative OxSrelated pathways in detail. The neural vicious circle starts by activation of primary sensory afferents. Glutamate mediates the signal to the neurons in the dorsal horn of the spinal cord, and facilitates calcium influx into their mitochondria. The latter causes an increased production of superoxide radicals. If the superoxide production is not effectively controlled by mitochondrial superoxide dismutase (Mn-SOD), then superoxide leads to OxS and lipid peroxidation. Consequent release of electrophilic lipid peroxidation products (LPP) from dorsal horn of the spinal cord causes pain by activating the primary sensory afferents, again. Additional LPP-mediated causes of pain include glutathione depletion and neuron sensitisation by isoprostanes. Excretion of LPP into urine may exert positive feedback as well. Currently, different information exists about chronic prostatitis (inflammation, pain, oxidative stress, neural sensitisation, lower urinary tract symptoms). The clear links between these data are actually absent. We propose that vicious circle based on LPP, especially isoprostanes, is the linking mechanism.

Hypothesis

The data revealed about prostatitis, OxS and nociception enables to identify possible positive feedback pathways that can be responsible for the chronicity of pain, allodynia and hyperalgesia experienced by prostatitis patients. Pain signaling begins by activation of primary sensory afferents. Cell bodies of primary sensory afferents lie in the dorsal root ganglia, one process reaching into the periphery and another to the neurons in the dorsal horn of the spinal cord. A noxious stimulus opens the pain sensors coupled to ion channels (including TRPA1 and TRPV1), leading to influx of sodium and calcium into the cell, and subsequent depolarization of a primary sensory afferent [21]. Depolarization leads to the next stage of signal transmission, which is the release of glutamate into the synapses in the dorsal horn of spinal cord. Dorsal horn neurons accept the signal by ionotropic glutamate receptors. Of these, NMDAR (N-methyl D-aspartate receptor) and Ca2+-permeable AMPAR (a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor) facilitate influx of calcium into the cell and into the mitochondria [22]. Entry of calcium into the mitochondria increases the superoxide (O2 ) output of mitochondria [23,19]. Unless metabolized by Mn-SOD (manganese superoxide dismutase), superoxide may generate more dangerous hydroperoxyl radicals (HO 2 ) that are capable of initiating lipid peroxidation [24]. Therefore, peripheral stimuli (initial pain) can lead to spinal OxS (Fig. 1(1)). This is in agreement with animal experiments that have revealed analgesic properties of Mn-SOD, and that peripheral injury is a sufficient cause of spinal OxS. Mn-SOD and superoxide are relevant for prostatitis because prostatitis patients have elevated prevalence of Mn- SOD polymorphisms [25]. Moreover (Fig. 1(2)) it has been shown that spinal OxS is a sufficient cause of pain [20]. Therefore, spinal OxS can be a key link in pain-causing pathways. Three positive feedback pathways that stem from spinal OxS (lipid peroxidation due to uncompensated superoxide overproduction) are elaborated below.

The first pathway consists of glutathione depletion by electrophilic LPP. Electrophilic LPP readily react with glutathione. If the level of glutathione is low, then these electrophilic LPP are more likely to distort proteins and deoxyribonucleic acid (DNA) [26,13]. More importantly, an animal experiment has shown that glutathione loss in the spinal cord induces pain and that systemic or intrathecal administration of glutathione can reverse such induction of pain [27].

The second pathway of this positive feedback might be mediated by electrophilic LPP that can pass the cell membrane by passive diffusion [26]. Since electrophiles, including cyclopentenone isoprostanes are ligands of TRPA1 [17,18] and since central processes of primary sensory afferents express TRPA1 [28–30], it is plausible that these compounds can contribute to or maintain [31] the pain signal that initiated the superoxide overproduction at the first place.

It has been shown that NGF (nerve growth factor) elevates expression of TRPA1 [28,32]. Association between pain and systemic OxS in the absence of overt inflammation (unpublished data) in one hand, and association between seminal plasma NGF levels and pain severity in prostatitis patients [33] on the other hand lead to a hypothesis that NGF supports the vicious circle mediated by electrophilic LPP by upregulating TRPA1 on the central processes of primary sensory afferents.

The third pathway is mediated by LPP that are ligands of prostanoid receptors. These ligands include but are not limited to 8-isoprostanes [12] and prostaglandin F2a (PGF2a) [34]. Animal experiments have shown the ability of peripheral 8-isoprostanes and spinal PGF2a to cause sensitisation [35,36]. Moreover, it has been shown that prostanoid signaling is a necessary step that converts short-term signaling through NMDAR into long-term changes in neuronal phenotype [37]. This mechanism could provide additional explanation to the previously suggested idea that a sensitized state remains even after the initiating stimulus is lost [1]. A sensitized phenotype in prostatitis patients is evident, as prostatitis patients have increased sensitivity to cold, capsaicin (a TRPV1 agonist) and mechanical stimuli [38–40]. Activation of prostanoid receptors by isoprostanes that are generated by free radicals rather than by cyclooxynegase-2 can explain why cyclooxygenase-2 inhibitors have had conflicting results [5,6]. Highly electrophilic and bioactive cyclopentenone isoprostanes are formed in human neural tissue by the same non-enzymatic pathway as 8-isoprostanes [13]. A generation of cyclopentenone isoprostanes would not occur without the release of 8-isoprostanes into the system (Fig. 1(3)). Therefore, elevation of spinal 8-isoprostanes contributes to elevation of urinary 8-isoprostanes. Spinal OxS contributes to systemic OxS by competing for ratelimiting precursor of glutathione i.e. cysteine [41]. This is in agreement with our observation that in comparison with the controls, the blood level of glutathione is 15% lower in prostatitis patients (983 ± 57 lmol vs 1157 ± 73 lmol) [10].

Our observation also revealed that prostatitis patients’ lipid peroxidation markers 8-isoprostanes were elevated by 132% (5.8 ± 1.5 ng/ml vs 2.5 ± 0.9 ng/ml) [10]. The relatively stable 8-isoprostanes can affect lower urinary tract of rabbits in nanomolar concentrations [42]. This suggests that 8-isoprostanes could contribute to prostatitis symptoms by contracting bladder and urethra, which could cause lower urinary tract symptoms (LUTS), mainly urinary urgency and frequency (Fig. 1(4)). In this way, generation of 8-isoprostanes due to prostate inflammation or nervous OxS, and their accumulation into the urine can exert positive feedback by irritating the primary sensory afferents of bladder, prostate and urethra. Therefore, if the results of the rabbit study [42] apply to humans, then 8-isoprostanes are a valid cause of LUTS. At the same time, patients with asymptomatic inflammatory prostatitis have increased 8-isoprostane levels but no LUTS according to our earlier experiment [10] and newer unpublished data.

Therefore, elevation of 8-isoprostanes is not a sufficient cause of LUTS. However, the level of 8-isoprostanes in urine might determine whether pre-existing urine refluxes, [43] anatomical deviations [44] or leaky urothelia [45,46] remain subclinical or become symptomatic.

We propose that the chronic pelvic pain in prostatitis patients is caused by a vicious circle where LPP from dorsal horn of the spinal cord excites and sensitizes the primary sensory afferents. In addition, we propose that 8-isoprostanes that are secreted with urine may contribute to LUTS in vulnerable prostatitis patients, and that in patients with spinal OxS, elevation of urinary 8-isoprostane levels corresponds partially to their spinal OxS
Age: 30 | Onset Age: 19| Symptoms: Urinary frequency, Urinary urgency, constant 24/7 sensation in the penis (in the tip mainly - burning/pressure/discomfort/"wetness"), Nocturia, discomfort and pressure in the pelvic region radiating to the abdomen and becoming severe as time passes since last urination (resolved in 2014 by myofascial release), Stream velocity is somewhat slow and prolonged with an average velocity of ~13cc/min (and max 18cc/min) found in flowmetry test when bladder is filled with 500cc at age 25 (I always feel like I need to press my abdomen to urinate, improved later on when using alpha blockers)| Helped By: especially MYOFASCIAL RELEASE (especially in the areas of hips and abdomen) - generally resolved my abdominal aches, but penile symptoms remained the same| Worsened By: Coffee and possibly some other food as well| Other comments: Quercetin and acupuncture helped me no more than a placebo effect. Age 25-26: Diagnosed with indirect inguinal hernia and medium hydrocele at the same side. After operation many of the acute symptoms disappeared, but the chronic urinary and pelvic symptoms remained much the same.
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Re: CPPS, oxidative stress and isoprostanes... could it be t

Post by webslave »

Isoprostane from wikipedia
https://en.wikipedia.org/wiki/Isoprostane

Still very much a hypothesis...
Prostate. 2012 Jun 15;72(9):977-83. doi: 10.1002/pros.21502. Epub 2011 Oct 24.
Oxidative stress--cause or consequence of male genital tract disorders?
Kullisaar T, Türk S, Punab M, Mändar R.
Department of Biochemistry, University of Tartu, Tartu, Estonia.


BACKGROUND: Inflammatory prostatitis patients are characterized by oxidative stress (OxS) at local and systemic levels. Less is known about the occurrence of OxS in the case of other frequent male genital tract disorders.

METHODS: The study included 196 men: controls (n = 28), asymptomatic inflammatory (NIH category IV) prostatitis patients (n = 21), non-inflammatory (NIH category IIIb) chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) patients (n = 48), inflammatory (NIH category IIIa) CP/CPPS patients (n = 44), benign prostate hyperplasia (BPH) patients (n = 33), and patients with BPH and NIH IV category prostatitis (n = 22). In all subjects, 8-isoprostanes (8-EPI) in urine were determined by competitive enzyme-linked immunoassay.

RESULTS: The levels of 8-EPI were substantially higher in all diseased groups-inflammatory CP/CPPS (P < 0.001), non-inflammatory CP/CPPS (P = 0.03), asymptomatic inflammatory prostatitis (AIP; P = 0.02), BPH (P = 0.007), and BPH + AIP (P = 0.014) in comparison with controls. Importantly, our study showed that OxS is also present in the case of NIH IIIb category prostatitis when the patients have just chronic pelvic pain but no inflammation in prostate-specific materials, as well as in the patients with just lower urinary tract symptoms without pain or overt inflammation.

CONCLUSIONS: This study revealed that several male genital tract disorders-BPH and different forms of prostatitis (NIH categories IIIa, IIIb, and IV)-are tightly interconnected via OxS-mediated pathways. Acknowledging OxS as an important pathogenesis mechanism of these diseases helps to open up new horizons for their treatment.

PMID: 22025397
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Wolfcub
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Re: CPPS, oxidative stress and isoprostanes... could it be t

Post by Wolfcub »

"Still very much a hypothesis..." - Indeed, yet I find it very appealing.
Age: 30 | Onset Age: 19| Symptoms: Urinary frequency, Urinary urgency, constant 24/7 sensation in the penis (in the tip mainly - burning/pressure/discomfort/"wetness"), Nocturia, discomfort and pressure in the pelvic region radiating to the abdomen and becoming severe as time passes since last urination (resolved in 2014 by myofascial release), Stream velocity is somewhat slow and prolonged with an average velocity of ~13cc/min (and max 18cc/min) found in flowmetry test when bladder is filled with 500cc at age 25 (I always feel like I need to press my abdomen to urinate, improved later on when using alpha blockers)| Helped By: especially MYOFASCIAL RELEASE (especially in the areas of hips and abdomen) - generally resolved my abdominal aches, but penile symptoms remained the same| Worsened By: Coffee and possibly some other food as well| Other comments: Quercetin and acupuncture helped me no more than a placebo effect. Age 25-26: Diagnosed with indirect inguinal hernia and medium hydrocele at the same side. After operation many of the acute symptoms disappeared, but the chronic urinary and pelvic symptoms remained much the same.
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Re: CPPS, oxidative stress and isoprostanes... could it be t

Post by dshoskes »

The finding of elevated oxidate stress in prostate fluid was one of the rationales to try quercetin for therapy.

http://pubmed.ncbi.nlm.nih.gov/10975414
J Androl. 2000 Sep-Oct;21(5):669-75.
Oxidative stress in prostatic fluid of patients with chronic pelvic pain syndrome: correlation with gram positive bacterial growth and treatment response.
Shahed AR, Shoskes DA.
Division of Urology, Harbor-UCLA Medical Center, Torrance, California, USA.


The etiology of chronic pelvic pain syndrome (CPPS)/chronic prostatitis category III remains unknown. Whereas a subset of men respond to antimicrobial therapy, gram positive bacteria isolated from expressed prostatic secretions (EPS) are often considered to be commensal rather than pathogenic. We wished to study oxidative stress as a marker of tissue injury and response in EPS of men with CPPS to determine whether infection with gram positive bacteria is associated with increased oxidative stress. A total of 300 EPS specimens from 100 men with CPPS were collected for microscopy, culture, and biochemical and molecular assays. Oxidant injury was measured by 8-isoprostane F2alpha (IsoP) levels and total antioxidant capacity as Trolox equivalents. Total RNA from EPS was used for gene expression of heme oxygenase-1 (HO-1) and granzyme B. The only bacteria found in EPS were gram positive. For our analysis, these men were classified as having chronic bacterial prostatitis (category II). IsoP levels (pg/mL) were highest in men with category II prostatitis (7315 +/- 1428) followed by nonbacterial prostatitis (category IIIa, 2043 +/- 561), prostatodynia (category IIIb, 319 +/- 81), and asymptomatic controls (298 +/- 99). IsoP levels decreased significantly after successful treatment with antibiotics or an antioxidant supplement (Quercetin). Antioxidant capacity was detected in 11 out of 18, 4 out of 16, and 1 out of 16 men tested with category II, IIIa, and IIIb prostatitis, respectively. No correlation was observed between IsoP levels and the number of white blood cells in EPS. HO-1 and granzyme B expression was highest in men with category II prostatitis than in men with either category III prostatitis or asymptomatic controls. On the basis of elevated oxidative stress, clinical response to antibiotics, and post-treatment reduction in oxidative stress, we conclude that gram positive bacteria in some men with CPPS may be pathogens. It is speculated that oxidative stress may be a key pathway in some men with CPPS that can be targeted with antioxidant therapy.
Daniel Shoskes MD
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Re: CPPS, oxidative stress and isoprostanes... could it be t

Post by Wolfcub »

Thanks, Dr. Shoskes, for your input and clarification. Is there any progress done regarding that hypothesis in recent years that you are aware of?
Age: 30 | Onset Age: 19| Symptoms: Urinary frequency, Urinary urgency, constant 24/7 sensation in the penis (in the tip mainly - burning/pressure/discomfort/"wetness"), Nocturia, discomfort and pressure in the pelvic region radiating to the abdomen and becoming severe as time passes since last urination (resolved in 2014 by myofascial release), Stream velocity is somewhat slow and prolonged with an average velocity of ~13cc/min (and max 18cc/min) found in flowmetry test when bladder is filled with 500cc at age 25 (I always feel like I need to press my abdomen to urinate, improved later on when using alpha blockers)| Helped By: especially MYOFASCIAL RELEASE (especially in the areas of hips and abdomen) - generally resolved my abdominal aches, but penile symptoms remained the same| Worsened By: Coffee and possibly some other food as well| Other comments: Quercetin and acupuncture helped me no more than a placebo effect. Age 25-26: Diagnosed with indirect inguinal hernia and medium hydrocele at the same side. After operation many of the acute symptoms disappeared, but the chronic urinary and pelvic symptoms remained much the same.
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Re: CPPS, oxidative stress and isoprostanes... could it be t

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No, not really
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Re: CPPS, oxidative stress and isoprostanes... could it be t

Post by ppp »

Why is there so little research that goes into CPPS, is hard to understand. At this rate of trials I don't see hope. Is there a way for us to advocate for more funding in some way...?
I have CPPS for more than 10 years now, my fears materialized, and unlike other ailments, there is virtually no hope for some cure soon on the horizon.
Age: 33| Onset Age: 24 | Symptoms: dull ache in pelvic area, tension, feeling the need to urinate, frequency, dribbling after urination, ED symptoms started 6 moths after the onset wrecking my life since, abdominal tension, tension in my thighs. | Helped By: stretching/massage , benzos | Worsened By: Mainly sex, but also sitting and anxiety| Other comments: I have seen periods of substantially less flare-ups, but now I am at a steady state where it comes back almost always after sex.
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