NGF, TrKA,p75NTR in Men With ED and Diabetes With or Without MS (ED)

Role and Clinical Relevance of Nerve Growth Factor (NGF) and Its Receptors (TrKA and p75NTR) in Patients With Erectile Dysfunction and Diabetes With or Wothout Metabolic Syndrome

To evaluate the level of NGF,TrKA and p75NTR in patientd with erectile dysfunction and diabetes with or without metabolic syndrome

Study Overview

• Status: Unknown
• Conditions: Erectile Dysfunction
• Intervention / Treatment: Diagnostic test: A peripheral blood sample from the cubital vein

Detailed Description

Penile erection is a complex phenomenon which implies a delicate and co-ordinated equilibrium among the neurological, vascular and the smooth muscle compartment. It includes arterial dilation, trabecular smooth muscle relaxation and activation of the corporeal veno-occlusive mechanism. Erectile Dysfunction (ED) is defined as the persistent inability to attain and maintain an erection sufficient to permit satisfactory sexual performance. Erectile Dysfunction may affect physical and psychosocial health and may have a significant impact on the quality of life (QoL) of sufferers and their partner's . There is increasing evidence that ED can be an early manifestation of coronary artery and peripheral vascular disease. Erectile Dysfunction should not be regarded only as a QoL issue, but also as a potential warning sign of cardiovascular disease (CVD) .The most important organic causes of ED are vascular, metabolic, neurogenic, hormonal and pharmacological. 35-90% of diabetic patients suffer from ED In the latter metabolic disease, Dai et al. have identified as a possible etiology of ED a lack of interaction between nerve growth factor (NGF) and its TrKA receptor, resulting in a noticeable increase in NGF levels in the corpora cavernosa11. Furthermore, Hou et al. have shown that the activation of the NGF / TrKA system in the corpora cavernosa (increased expression of NGF and TrKA mRNA and upregulation of c-raf, ERK1 / 2 and CREB1) improves erectile function in mice with ED and diabetes mellitus.

The objectives of this study are:

• The primary outcome is to evaluate the systemic plasma concentration and the concentration in cavernous bodies of penis of NGF in patients with ED and diabetes with or without metabolic syndrome (a); (b) the expression of its TrKA and p75NTR receptors in the mononuclear cells taken from peripheral blood and in cavernous bodies of penis.
• The secondary outcome is to evaluate whether the levels of NGF and its receptors in the mononuclear cells can correlate with the clinical staging of ED.

Prospective pilot study. 12 patients diagnosed with ED with diabetes with or without metabolic syndrome( Mets )aged between 18 and 65 will be recruited. Each patient will undergo an initial evaluation that includes: the pathological and pharmacological anamnesis, the local objective examination and the compilation of the validated questionnaire International Index of Erectile Function Questionnaire short form (IIEF5).

Based on the IIEF5 score, patients will be divided into 4 groups (each of 10 patients):

1. mild ED (score 17-21)
2. mild to moderate ED (score 12-16)
3. Moderate ED (score 8-11)
4. Severe ED (score 5-7)

In vivo study:

Each patient will then be submitted in succession to:

1. A collection of peripheral blood from the routinary cubital vein for hormone dosage Follicle-stimulating hormone (FSH), Luteinizing hormone (LH), TESTOSTERONE FREE AND TOTAL, ESTRADIOL, PROLACTIN) and metabolic evaluation (total HDL cholesterol, LDH, glycemia, lipidemic framework); and an aliquot will be used for in vitro study
2. An introverted cavernous infiltration of Prostaglandin E1 to achieve erection (Aprostadil);
3. A blood sample from both the corpus cavernosum and the cubital vein, once the erection is achieved

Vitro study To verify a possible baseline interaction of prostaglandin E1 on the concentration of NGF released in the medium and on the expression of its receptors, an in vitro study will be performed using mononuclear cells isolated from peripheral blood (PBMC) obtained from buffy coat treated with prostaglandin E1

Evaluation of NGF and Cytokine levels A portion of each blood sample and medium conditioned by PBMC will be used for the enzyme immunoassay of NGF and pro and anti-inflammatory cytokine levels (TNF alfa and IL-10).

Expression analysis of TrKA and p75NTR receptors and intracellular cytokines in PBMCs.

The remaining part of each blood sample and PBMC of the in vitro experiment will be used for the cytofluorimetric evaluation of the expression of TrKA, p75NTR and the pro and anti-inflammatory cytokines and reactive oxygen species

Evaluation of the levels of NGF and its receptors in the different degrees of severity of the EDThe levels of NGF and its receptors will be stratified into the 4 groups of clinical severity of the ED

In vitro study An in vitro study will be performed using PBMC obtained from buffy coat of healthy subjects treated with prostaglandin E1.

Statistical analysis of the results The data obtained during the study will be treated with appropriate statistical tests. The results will be expressed in terms of mean ± standard error and compared by appropriate statistical tests (ANOVA or non-parametric where appropriate).

Expected results From the present study we expect to obtain more information on the impact and relevance of the NGF / TrKA / p75NTR pathway on DE in patients with Mets. Furthermore, we expect a correlation between the plasma levels of NGF and its receptors in relation to the clinical severity of the ED.

• Study Type: Interventional
• Enrollment (Anticipated): 40
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Italy
  • Terni, Italy, 05100
    • Recruiting
    • Elisabetta Costantini
    • Contact: Elisabetta Costantini, Professor; Phone Number: 3283620614; Email: elisabetta.costantini@unipg.it
    • Contact: Ester Illiano, MD; Phone Number: 3283620614; Email: ester.illiano@inwind.it
    • Sub-Investigator: Ester Illiano, MD
    • Principal Investigator: Elisabetta Costantini, Professor
    • Sub-Investigator: Mario Rende, Professor
    • Sub-Investigator: Alessandra Pistilli, Researcher
    • Sub-Investigator: Anna Stabile, Researcher

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• men with DE and metabolic syndrome

Exclusion Criteria:

• men with DE without metabolic syndrome

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Men with ED and diabetes; A peripheral blood sample from the cubital vein; A collection of peripheral blood from the routinary cubital vein for hormone dosage and metabolic evaluation; An introverted cavernous infiltration of Prostaglandin E1 to achieve erection (Aprostadil);; A blood sample from both the corpus cavernosum and the cubital vein, once the erection is achieved Baseline interaction of prostaglandin E1 on the concentration of NGF released in the medium and on the expression of its receptors Evaluation of NGF and Cytokine levels Expression analysis of TrKA and p75NTR receptors and intracellular cytokines in PBMCs

Diagnostic test: A peripheral blood sample from the cubital vein; Evaluation of NGF and Cytokine levels A portion of each blood sample and medium conditioned by PBMC will be used for the enzyme immunoassay of NGF and pro and anti-inflammatory cytokine levels (TNF alfa and IL-10). Expression analysis of TrKA and p75NTR receptors and intracellular cytokines in PBMCs The remaining part of each blood sample and PBMC of the in vitro experiment will be used for the cytofluorimetric evaluation of the expression of TrKA, p75NTR and the pro and anti-inflammatory cytokines and reactive oxygen species.; Other Names: cavernous infiltration of PGE1

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Baseline NGF	plasmatic concentration	baseline
intracavernous NGF	intracavernous concetration	15 minutes
plasmatic NGF	plasmatic concetration	15 minutes
Baseline TRka	plasmatic concetration	baseline
plasmatic TRka	plasmatic concetration	15 minutes
Intracavernous TRka	intracavernous concetration	15 minutes
Baseline p75NTR	plasmatic concentration	baseline
plasmatic p75NTR	plasmatic concentration	15 minutes
intracavernous p75NTR	intracavernous concentration	15 minutes

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
plasmatic concentration verus intracavernous concetration	to evaluate any differences between the data obtained from the systemic levy versus the intracavernous sampling.	15 minutes
clinical staging of ED and NGF,TrKa,p75NTR	is to evaluate if the levels of NGF and its receptors in the mononuclear cells can correlate with the clinical staging of ED.	15 minutes

Collaborators and Investigators

• Sponsor: University Of Perugia
• Collaborators: Ester Illiano, MD; Mario Rende,Full Professor; Alessandra Psitilli, Researcher; Anna Stabile, Researcher
• Investigators: Study Director: Ester Illiano, MD, University Of Perugia

Publications and helpful links

General Publications

• Rask-Madsen C, King GL. Mechanisms of Disease: endothelial dysfunction in insulin resistance and diabetes. Nat Clin Pract Endocrinol Metab. 2007 Jan;3(1):46-56. doi: 10.1038/ncpendmet0366.
• Teng KK, Hempstead BL. Neurotrophins and their receptors: signaling trios in complex biological systems. Cell Mol Life Sci. 2004 Jan;61(1):35-48. doi: 10.1007/s00018-003-3099-3.
• Arcidiacono P, Stabile AM, Ragonese F, Pistilli A, Calvieri S, Bottoni U, Crisanti A, Spaccapelo R, Rende M. Anticarcinogenic activities of sulforaphane are influenced by Nerve Growth Factor in human melanoma A375 cells. Food Chem Toxicol. 2018 Mar;113:154-161. doi: 10.1016/j.fct.2018.01.051. Epub 2018 Jan 31.
• Pistilli A, Rende M, Crispoltoni L, Montagnoli C, Stabile AM. LY294002 induces in vitro apoptosis and overexpression of p75NTR in human uterine leiomyosarcoma HTB 114 cells. Growth Factors. 2015;33(5-6):376-83. doi: 10.3109/08977194.2015.1118096. Epub 2015 Dec 10.
• Pula G, Pistilli A, Montagnoli C, Stabile AM, Rambotti MG, Rende M. The tricyclic antidepressant amitriptyline is cytotoxic to HTB114 human leiomyosarcoma and induces p75(NTR)-dependent apoptosis. Anticancer Drugs. 2013 Oct;24(9):899-910. doi: 10.1097/CAD.0b013e328364312f.
• Rende M, Pistilli A, Stabile AM, Terenzi A, Cattaneo A, Ugolini G, Sanna P. Role of nerve growth factor and its receptors in non-nervous cancer growth: efficacy of a tyrosine kinase inhibitor (AG879) and neutralizing antibodies antityrosine kinase receptor A and antinerve growth factor: an in-vitro and in-vivo study. Anticancer Drugs. 2006 Sep;17(8):929-41. doi: 10.1097/01.cad.0000224459.13651.fd.
• Jackson G. The importance of risk factor reduction in erectile dysfunction. Curr Urol Rep. 2007 Nov;8(6):463-6. doi: 10.1007/s11934-007-0049-x.
• Kaya E, Sikka SC, Gur S. A comprehensive review of metabolic syndrome affecting erectile dysfunction. J Sex Med. 2015 Apr;12(4):856-75. doi: 10.1111/jsm.12828. Epub 2015 Feb 11.
• Dai YT, Chen Y, Yao LS, Yang R, Sun ZY, Wen DG. [Expression of nerve growth factor in cavernous tissue and its effects on the treatment of rats with diabetic erectile dysfunction]. Zhonghua Nan Ke Xue. 2005 Oct;11(10):748-51, 754. Chinese.

Study record dates

Study Major Dates

• Study Start (Actual): January 30, 2019
• Primary Completion (Anticipated): December 30, 2019
• Study Completion (Anticipated): January 30, 2020

Study Registration Dates

• First Submitted: February 14, 2019
• First Submitted That Met QC Criteria: March 2, 2019
• First Posted (Actual): March 5, 2019

Study Record Updates

• Last Update Posted (Actual): March 5, 2019
• Last Update Submitted That Met QC Criteria: March 2, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Keywords: Erectile Dysfunction; NGF; TrKA; p75NTR
• Additional Relevant MeSH Terms: Mental Disorders; Sexual Dysfunctions, Psychological; Sexual Dysfunction, Physiological; Erectile Dysfunction
• Other Study ID Numbers: DE1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No