< Back to previous page

Publication

TRP kanalen als farmacologische doelwitten voor symptomen van de lagere urinewegen

Book - Dissertation

Lower urinary tract symptoms are a common complaint in the adult population with a major impact on the quality of life and substantial personal and societal expenditures. On the other hand, the management of LUTS remains troublesome; different treatment modalities are available with different success rates, considerable adverse events and discontinuation rates. TRP ion channels are promising pharmacological targets since they are key players in LUT physiology and pathophysiology. Members of this ion channel family contribute to mechano- or chemosensation and signal transduction, making them important players in the LUT sensory system. TRPV4 and TRPM4 are among the highest expressed TRP channels in the urothelium and detrusor muscle. Targeting this bladder sensory system represents a promising new pathway to treat LUTS. Despite many excellent studies about TRPV4 and TRPM4 in the LUT, our current understanding about these ion channels is still limited and many questions remain about their exact location, structure and function, hampering the further development of TRPV4 and TRPM4 as pharmacological targets to treat LUTS. Firstly, we studied the benefit of TRPV4 activation as a target to treat detrusor underactivity. We characterized a novel rat model for detrusor underactivity after iatrogenic nerve injury. Using a combination of immunohistochemistry, PCR, bladder strip contractility and cystometry, we provided evidence that intravesical TRPV4 activation is a valuable therapeutic target to improve cystometric parameters after nerve injury. Also, we used for the first time genetically modified TRPV4 knock-out rats to confirm our experiments, providing solid negative controls.In a second part, we focussed on the expression and function of TRPM4 in DSM contractility. We showed that TRPM4 is highly expressed in urothelium and detrusor smooth muscle, although a clear functional role could not be established in detrusor strip contractility and cystometry experiments. Furthermore, 9-Phenanthrol proves to be a TRPM4 aspecific pharmacological tool since it affects experimental parameters in both WT and Trpm4-/- rats, hereby casting a shadow on previous studies. In summary, our data indicate a TRPM4-independent mode of action of 9-phenanthrol in the rat lower urinary tract and could not confirm the postulated role of TRPM4 in detrusor contractility.In a final chapter, we established a small-animal (18F)FDG-PET protocol in an effort to develop a novel method to better understand afferent bladder signalling and supraspinal brain control in a small-animal model. We demonstrate that volume induced voiding as well as bladder fullness in rats provoke changes in brain metabolism similar to the changes detected in humans, including activation of the insular and cingulate cortex, which is consistent with their role in the mapping of bladder afferent activity. Our results provide a basis for further research into the brain control of the LUT in small laboratory animals. In conclusion, we have confirmed TRPV4 as a valuable therapeutic target to treat a variety of LUT dysfunctions, including detrusor underactivity, while the role of TRPM4 in the LUT, although highly expressed in urothelium and detrusor, has become even more enigmatic. Furthermore, we have tried to contribute to the complex understanding of LUT brain control by designing small-animal PET brain imaging experiments during the micturition cycle. Little by little, the mysteries TRP channels in the LUT are being unravelled and compounds modulating these channels in the LUT are being tested in pre-clinical studies and clinical trials. Although the road ahead is still long and dark, we hope that we have made it a little bit shorter and somewhat brighter so TRP channel modulators can live up to the myth of becoming Truly Revolutionary Pharmacotherapies.
Publication year:2020
Accessibility:Open