The immune system is believed to play a major role in repair mechanisms following CN injury. Inhibiting inflammation and the inflammatory response may prevent injury and neurological deficits. In addition, genes involved in injury and repair of the major pelvic ganglion (MPG, the source of the nerves that control erections) in response to CN injury may serve as therapeutic targets for new medications or treatments. Several significant molecular themes have been identified in the immune mechanism of CN injury including transcriptional regulation, chemokines, oxidative stress, apoptosis, and inflammatory cytokines. A number of these cytokines, including tumor necrosis factor alpha (TNF-α), transforming growth factor beta (TGF-β), and chemokines related to macrophage induction including monocyte chemoattractant protein-1 (MCP-1) have been investigated as therapeutic targets. A prior study from the Brady Urological Institute led by Johanna Hannan, PhD, demonstrated a temporal increase in neuroinflammation in the MPG following CNI that was mediated by cytokines (TNF-α, TGF-β) and macrophages (M1 and M2) that may result deleterious effects on neuronal cell survival and nerve regeneration. To further investigate these mechanisms, it is hypothesized that an increase in TNF-α in the MPG and subsequent neuroinflammation contribute to impaired CN regeneration.
|Model of cavernous nerve injury in the male rat. |
A total of six MPGs were harvested from 3 control rats and cultured in Matrigel® with (n = 3) or without TNF-α (20 ng/mL, n=3). Neurite outgrowth length was measured 48 and 72 hours after culture and indicates the animals ability to regenerate injured nerves. We measured the longest neurites in each area (25-40 neurites / MPG) and compared the averages to evaluate the effect of exogenous TNF-α on neurite outgrowth from MPGs.
Average neurite lengths of MPGs cultured with TNF-α at 48 and 72 hours were significantly shorter than those of the control group (329±12.2 μm and 384±13.1 μm, p<0.01 at 48 hours; 369±14.5 and 462±20.0 μm, p<0.01 at 72 hours) (Figure 1). These results demonstrate that exogenous TNF-α treatment inhibits neurite outgrowth from MPGs.
|Average neurite lengths of the control groups and the groups cultured with TNF-α at 48 hours |
(A) and at 72 hours (B) after culture. * indicates significant difference.
Interestingly, neurite outgrowth patterns were different between the 2 groups. Neurites of the control group tended to grow equally, while neurites of the TNF-α group did not (Figure 2.).
|Representative images of neurite outgrowth patterns. (A) Neurites of the control group grew equally. (B) Neurite lengths of the TNF-α were either as long as the average length of the control group or much shorter than that.|
In the TNF-α group, some neurites were as long as the average length of the control group and others were much shorter than that. In order to demonstrate this difference of neurite outgrowth patterns quantitatively, we measured all the neurites measurable and made histograms of neurite lengths. Histograms of the control group showed almost normal distribution. On the other hand, histograms of the TNF-α group showed heavy-tailed distribution (Figure 3.).
|The histograms of the neurite lengths in the control group and the TNF-α group at |
(A) 48 hours and at (B) 72hours. The control group showed almost normal distribution, while the
histograms of the TNF-α group showed heavy-tailed distribution.
|The variances of the neurite lengths in the control group and the TNF-α group at |
(A) 48 hours and at (B) 72hours. * indicates significant difference.
SUMMARYThis study provides additional evidence that exogenous TNF-α inhibits neurite outgrowth inhibition from the MPG. This suggests that TNF-α inhibition may be a future therapeutic target to prevent post-operative ED following RP. In addition, this study indicates that exogenous TNF-α does not inhibit all the neurites from MPGs. Accordingly, TNF-α may inhibit specific types of neurites, such as parasympathetic nerves. Further investigation is required to clarify the types of neurites inhibited by TNF-α.
This blog was written by Hotaka Matsui, a post-doctoral research fellow and graduate of the National Institute of Public Health in Japan. This work is the result of collaborative work with Johanna L. Hannan, Xiaopu Liu and Trinity J. Bivalacqua and is supported by the National Institute of Health (NIH) R03 Grant DK101701-01.
 Walsh PC and Donker PJ: Impotence following radical prostatectomy: insight into etiology and prevention. J Urol 1982;128:492.
 Walsh PC: The discovery of the cavernous nerves and development of nerve sparing radical retropubic prostatectomy. J Urol 2007;177:1632.
 Walsh PC, Lepor H and Eggleston JC: Radical prostatectomy with preservation of sexual function: anatomical and pathological considerations. Prostate 1983;4:473.
 Burnett AL, Aus G, Canby-Hagino ED et al. Erectile function outcome reporting after clinically localized prostate cancer treatment. J Urol 2007;178:597.
 Hannan JL, Kutlu O, Stopak BL et al. Valproic acid prevents penile fibrosis and erectile dysfunction in cavernous nerve-injured rats. J Sex Med 2014;11(6):1442
 Hannan JL, Weyne E, Albersen M et al. Cavernous nerve injury induced temporal increase in neuroinflammation and cytokine induction in the major pelvic ganglion of the rat. American Urological Association Annual Meeting 2014. Orlando, FL. MP43-10
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