Chronic prostatitis/chronic pelvic pain syndrome increases susceptibility to seizures in rats and alters brain levels of IL-1β and IL-6

Šutulović, Nikola; Grubač, Željko; Šuvakov, Sonja; Jovanović, Đurđa; Puškaš, Nela; Đuro, Macut; Marković, Aleksandra; Simić, Tatjana; Stanojlović, Olivera; Hrnčić, Dragan

doi:10.1016/j.eplepsyres.2019.03.014

Cited by 25 publications

(38 citation statements)

References 70 publications

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“…To the best of our knowledge, this is the first report of carrageenan-induced prostatitis in mice. According to the literature, in the rat model, injection of carrageenan with a concentration ranging from 1 to 3% and a volume from 20 to 100 μl can successfully induce prostatitis (1%, 20 μl: [27, 28]; 1%, 100 μl: [29, 30]; 2%, 50 μl: [31]; 3%, 25 μl: [19]; 3%, 50 μl: [32]; 3%, 100 μl [33]). We used histological examination to compare mouse models of different concentrations (1%, 2%, and 3%) and volumes (20 or 50 μl) of carrageenan-induced prostatitis (data not shown).…”

Section: Discussionmentioning

confidence: 99%

“…Previous reports have found that the levels of some molecules associated with pain conditions, including CCL3, IL-1B, TNF-α, brain-derived neurotrophic factor (BDNF), and substance P, are increased in the spinal cord of prostatitis animal models [11, 41]. Moreover, a recent study has shown higher levels of IL-1β and IL-6 in the thalamus and cortex in CP/CPPS rats compared to Sham [32]. The present study showed that carrageenan injection induced persistent prostate pain in 2 weeks that lasted for more than 6 weeks.…”

Section: Discussionmentioning

confidence: 99%

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Activated spinal astrocytes contribute to the later phase of carrageenan-induced prostatitis pain

Deng

Zhao

et al. 2019

J Neuroinflammation

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BackgroundProstatodynia is the main symptom of chronic prostatitis and the main reason that patients go to the hospital for treatment. Although a variety of factors, including inflammatory immune response, nervous system sensitization, and psychological factors, have been shown to play important roles in the induction and development of chronic pain in prostatitis, the underlying cause of chronic prostatodynia maintenance in prostatitis patients remains unclear.MethodsA mouse model of chronic prostatitis induced by carrageenan injection was used. The von Frey test was used to measure pain behavior. The microglial and astrocyte activations were immunohistochemically demonstrated with antibodies against Iba1 and GFAP. The expression of cytokine or signaling pathway was detected by enzyme-linked immunosorbent assay (ELISA) and Western blotting.ResultsIn this study, we provide several lines of evidence to demonstrate that activated spinal astrocytes contribute to the later phase (5 weeks after carrageenan injection) of carrageenan-induced prostatitis pain. First, activation of spinal astrocytes but not microglia was found in the spinal cord dorsal horn at 5 weeks. Second, intrathecal injection of the astroglial toxin L-2-Aminoadipate acid (L-AA) but not microglial inhibitor minocycline reduced mechanical allodynia at 5 weeks. Third, chronic prostatitis induced a profound and persistent upregulation of connexin-43 hemichannels in spinal astrocytes, and spinal injection of the connexin-43 inhibitor carbenoxolone (CBX) effectively reduced pain symptoms. Fourth, increased expression and release of chemokine C-X-C motif ligand 1 (CXCL1) in the spinal dorsal horn and intrathecal injection of a CXCL1 neutralizing antibody or the CXCR2 (a major receptor of CXCL1) antagonist SB225002 significantly reduced mechanical allodynia at 5 weeks.ConclusionsIn this study, we found that a novel mechanism of activated spinal astrocytes plays a crucial role in maintaining chronic prostatitis-induced persistent pain via connexin-43-regulated CXCL1 production and secretion.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Activated spinal astrocytes contribute to the later phase of carrageenan-induced prostatitis pain

Deng

Zhao

et al. 2019

J Neuroinflammation

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“…In this study, we used EAP rats as subjects to explore the mechanism on the high incidence of PE in patients with prostatitis. Previous studies have shown that EAP rat is a mature animal model mimicking human CP/CPPS 8‐11,23 . However, no studies have been conducted to observe and evaluate the ejaculatory behavior of the EAP model.…”

Section: Discussionmentioning

confidence: 99%

“…These receptors and their neurotransmitters form complex networks of interactions, and our present results are probably an account of the balance of multiple effects. Currently, increasing researches have searched out various clues and regarded prostate‐derived inflammation cytokines as the key, who crossing the blood‐brain barrier to intervene the CNS 8‐11 . Therefore, developing practical clinical strategies, such as antibodies of inflammation cytokines, to eliminate or block prostate‐derived cytokines might cure or relieve PE symptom for CP/CPPS patients.…”

Section: Discussionmentioning

confidence: 99%

“…[5][6][7] In recent years, there have been growing recognition on the association between CP/CPPS and central mental health disorders (MHD) including anxiety-/ depression-like symptoms, impaired spatial/ associative memory performance, and increased susceptibility to seizures. [8][9][10][11] Through the studies of experimental autoimmune prostatitis (EAP) animal models, some possible molecular mechanisms have been proposed that prostate-derived cytokines cross the blood-brain barrier to activate ERK1/2 signaling pathways in multiple regions of the brain, or microglia activation leads to changes in synaptic plasticity and neurotransmitter metabolism. [8][9][10][11] Although the exact mechanism behind the association remains obscure, the long-term adverse effects caused by CP/CPPS on central nervous system (CNS) cannot be ignored.…”

Section: Introductionmentioning

confidence: 99%

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Upregulated expression of NMDA receptor in the paraventricular nucleus shortens ejaculation latency in rats with experimental autoimmune prostatitis

Yang

Zhang

et al. 2020

Andrology

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Background Estimated 30%‐40% of patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) suffer from premature ejaculation (PE), which is difficult to cure, but the mechanism is still unknown. Based on the results of our previous clinical studies and animal experiments, we propose that the glutamatergic system dysfunction in the paraventricular nucleus (PVN) may be involved. Methods To test this hypothesis, we used experimental autoimmune prostatitis (EAP) rats to investigate the effects of CP/CPPS on ejaculation behavior through integrating copulatory behavior testing, neuroelectrophysiologic experiments, and molecular biology technologies. Results Histological examination of prostate tissue in EAP rats exhibited consistent pathological findings with that in CP/CPPS patients. Behavior testing showed that ejaculation latency (EL) of EAP rats significantly shortened compared with the controls (5.1 ± 1.8 vs 9.1 ± 2.4 min, P < .001). Sympathetic nervous system (SNS) activity testing revealed that EAP rats displayed significantly higher plasma norepinephrine (NE) level (1780 ± 493 vs 1421 ± 453 pg/mL, P = .043) and SNS sensitivity (67.8 ± 9.6 vs 44.6 ± 8.7%, P < .001). Immunohistochemical detection and Western blot analysis both displayed that NR1 subunit expression of N‐methyl‐D‐aspartic acid (NMDA) receptors in the PVN of EAP rats was significantly upregulated (P = .007 and P < .001). Furthermore, the expression of NMDA NR1 subunit positively correlated both with SNS sensitivity (r = .917, P < .001) and prostatic inflammation scores (r = .964, P < .001). Conclusion This study shows that EAP rats suffer from the same PE symptom as CP/CPPS patients. CP/CPPS‐induced inflammatory‐immune response can significantly upregulate the expression of NMDA receptors in the PVN, which shortening the EL by enhancing SNS sensitivity. However, the exact mechanism of chronic inflammation in the prostate causing the upregulated expression of NMDA receptors needs to be further studied.

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The effect of pirfenidone on rat chronic prostatitis/chronic pelvic pain syndrome and its mechanisms

et al. 2020

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BackgroundChronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is an intractable problem of the urogenital system. The aetiopathogenesis and effective treatments for CP/CPPS are needed to be untangled. Pirfenidone is a molecule that exhibits anti‐inflammatory, antifibrotic, and antioxidative stress capacities in a variety of animal experiments and clinical trials. This study was aimed to investigate the therapeutic effect of pirfenidone on CP/CPPS and to identify the mechanism responsible for it.MethodsA CP/CPPS model was induced in rats by intraprostatic injection of complete Freund's adjuvant (CFA). Blood and prostatic tissues were harvested for assessment after the administration of pirfenidone or vehicle for 4 weeks.ResultsThe findings revealed that pirfenidone significantly ameliorated chronic pelvic pain and inhibited prostatic inflammation and fibrosis. Further study found that pirfenidone suppressed the expression of proinflammatory mediators, including tumor necrosis factor‐α, interleukin‐1β (IL‐1β), IL‐6, IL‐8. Pirfenidone exhibited a potent antioxidant capacity through improving the activities of glutathione, catalase, total superoxide dismutase, and reducing the production of malondialdehyde. Furthermore, pirfenidone also facilitated the polarization of M2 macrophages and suppressed the activation of the nuclear factor‐κB (NF‐κB) signaling pathway.ConclusionsPirfenidone can exert a beneficial effect against CFA‐induced CP/CPPS by anti‐inflammatory, antioxidative, antifibrotic properties, and the function is mediated at least partly through the M2 polarization of macrophages and the inhibition of NF‐κB signaling pathway. These findings suggest that pirfenidone holds promise as a potential therapeutic for the treatment of CP/CPPS.

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Chronic prostatitis/chronic pelvic pain syndrome increases susceptibility to seizures in rats and alters brain levels of IL-1β and IL-6

Cited by 25 publications

References 70 publications

Activated spinal astrocytes contribute to the later phase of carrageenan-induced prostatitis pain

Activated spinal astrocytes contribute to the later phase of carrageenan-induced prostatitis pain

Upregulated expression of NMDA receptor in the paraventricular nucleus shortens ejaculation latency in rats with experimental autoimmune prostatitis

The effect of pirfenidone on rat chronic prostatitis/chronic pelvic pain syndrome and its mechanisms

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