2014 January-March; 2(1): 25–28. ISSN: 2282-4103
Published online 2014 April 30.

Capsaicin restores cutaneous microcirculation in diabetes: a capillaroscopic study

Marta Carlesimo,1 Alessandra Narcisi,1 Giovanna Marmo,1 Ilaria Beatrice Saredi,1 Chiara Gargano,1 Diego Orsini,1 and Beatrice Amorosi2

1Department of Dermatology, NESMOS Department, Sant’Andrea Hospital, “Sapienza” University of Rome, Rome, Italy
2“Istituto Dermatologico San Gallicano”, IRCCS, Rome, Italy

Address for correspondence: Alessandra Narcisi, Via di Grottarossa, 1039, 00189 Rome, Italy Phone: +39 06 33775822. Fax: +39 06 33775378. E-mail: 123alexa@virgilio.it

Summary

Background
Capsaicin (8-methyl-N-vanyllil-6-nonenamide), the active component of the chilli peppers, is able to induce receptor desensitization and defunctionalisation of peripheral nociceptors. It can induce also vascular responses by different mechanisms.

Objectives
Hypothesis that skin application of capsaicin could have beneficial effects on cutaneous microcirculatory dysfunction associated with diabetes.

Materials and methods
Videocapillaroscopic examination of periungueal vascular pattern before and after application of topical capsaicin in diabetic patients.

Results
Skin application of 15% capsaicin oleoresin caused a local improvement in microvascular function in diabetic patients.

Conclusions
Topical capsaicin application may be beneficial for the management of microvascular complications in diabetic patients.

Keywords: capsaicin, diabetes, TRPV1, cutaneous microcirculation, videocapillaroscopy, microangiopathy

Introduction

Cutaneous microangiopathy is a frequent complication of diabetes; however its pathogenesis is still unclear. Several mechanisms by which diabetes may cause microangiopathy have been hypothesised such as oxidative damage, protein kinase C overactivity, increased glycation end-products (AGEs), and excess sorbitol formation. It has been widely demonstrated that microangiopathy affects the skin in diabetic patients, with loss of capillaries and an ensuing decrease in perfusion reserve (1). Dysfunctions of C and Aδ nerve sensory fibres and endothelium play a major role in the pathogenesis of diabetic microangiopathy (2). C Fibres in particular express the TRPV1 receptor, which is a member of the TRP (Transient Receptor Potential) family of ion channels. TRPV1 receptors are activated by high temperature (> 42 °C), protons, arachidonic acid metabolites, and endocannabinoids, and is critically involved in mechanisms of peripheral nociceptive sensitization underlying the development of chronic pain (3, 4). TRPV1 activation promotes vasomotor responses by stimulating the release of vasoactive molecules, such as Calcitonin Gene-Related Peptide (CGRP) from nerve endings (5).

Capsaicin (8-methyl-N-vanyllil-6-nonenamide), the active component of the chilli peppers, behaves as a superagonist of TRPV1 receptors, causing an initial activation followed by receptor desensitization and defunctionalisation of peripheral nociceptors. These properties set the ground for the use of capasaicin patch in the treatment of chronic pain (6). TRPV1 activation causes neurovascular responses, characterized by vasodilation and increased vascular permeability (7), and can also cause cell cycle arrest and apoptotic cell death (8). Hence, we hypothesized that skin application of capsaicin could have beneficial effects on cutaneous microcirculatory dysfunction associated with diabetes. We examined this possibility with the aid of a videocapillaroscopy technique.

Materials and methods

A group of 10 patients (7 females, 3 males) who were hospitalized in the Dermatology department, aged 50 to 70 years, with a 2–5 year history of diabetes mellitus type II with no clinically evident complications were selected for the study. All patients were undergoing treatment with variable doses of insulin. The patients underwent an accurate clinical examination before testing. The videocapillaroscopic machine was a Zeiss OMP1.

Each patient was examined while in sitting posture after an acclimatisation of 30 minutes at a room temperature of 20–26°C. Videocapillaroscopy at 50x and 200x magnification was performed on the nailfold of the fourth finger of the left hand (Figure 1). The following parameters were evaluated: number of vessels (increased, decreased, normal), distribution, morphology, length, presence of volutes and tortuosities and flow rate. To increase initial transparency during morphological videocapillaroscopic examination, a drop of immersion oil was placed on the nailfold.

Figure 1Figure 1
Capillaroscopic images of a patient of the study.

After the initial videocapillaroscopic evaluation, AIS-PES 15% Capsaicin oleoresin (2ml) was applied topically on the nailfold and the same parameters were examined at 5 and 15 minutes from application. 15% Capsaicin oleoresin was applied to all patients once a day during 7 days with a dropper, directly on the nail-fold of the fourth finger of the left hand. In order to verify the vasoactive effect of a one week application of topical Capsaicin, all patients were examined by Lunedei’s Test and CO2 Cryotest after 7 days of capsaicin oleoresin application. Lunedei’s Test is performed by applying a tourniquet above the elbow and waiting 2 minutes at 5mmHg above the patients systolic pressure, then 5 minutes at 5 mmHg below patient’s systolic pressure. The tourniquet is then removed and the presence of ecchymoses using videocapillaroscopy is examined, cronometering and recording the time taken for normal microcirculation to appear. CO2 Cryotest consisted in application of a balloon filled with cold water (12 or 15°C) to the left hand, until the skin temperature of 26°C was reached. The cold water balloon was subsequently removed and the reactive vasodilatation was observed. The time taken for the vasodilatation to disappear was then cronometered and recorded.

Results

In the 10 diabetic patients evaluated at time 0, the following morpho-functional aspects were found by capillaroscopic evaluation (Table 1): (i) decrease in capillary number, (ii) dilatation and tortuosity of capillaries in all nailfolds, (iii) decreased flow rate, and (iv) several volutes in capillary morphology. At 5 min from the application of 2 ml of 15% capsaicin oleoresin, we observed a reduction of capillary calibre and an increase in flow rate in both venous and arterial branches of capillaries, while we did not find changes in the number or distribution of vessels. At 15 min from capsaicin application, we found a marked reduction of capillary calibre and disappearance of venous stasis because of reduced vessel diameter. Finally, a 7-day treatment with capsaicin caused an almost complete disappearance of the abnormal vascular response to the Lunedei’s test and normalized the recovery time to CO2 cryotest.

Table 1Table 1
Patient characteristics and capillaroscopic features.

Discussion

Capsaicin is widely studied for its role in pain transmission and in mechanisms of nociceptive sensitization. However, a large body of evidence suggests that TR-PV1 receptors, the molecular targets of capsaicin, are expressed not only in neurons but also in non-neuronal cells, such as smooth muscle cells and endothelial cells of blood vessels (9). Capsaicin causes vascular responses, which result from neurogenic mechanism (vasodilation, increase in vascular permability) (5), as well as from a direct action of capsaicin on TRPV1 receptors expressed by the endothelium (vasodilation) or smooth mucle cells (vasoconstriction) (10).

We have shown here that skin application of 15% capsaicin oleoresin caused a local improvement in microvascular function in diabetic patients. The precise mechanisms underlying this beneficial effect of capsaicin in diabetic patients remain to be determined. Diabetic neuropathy is known to be associated with a reduced production of CGRP, a vasoactive molecule that is under the control of TRPV1 receptors in nerve terminals, and causes neurogenic vasodilation (11). Activation of TRPV1 by capsaicin may cause an increased CGRP release, thereby restoring the blood vessel response to stimulation of sensory nerve endings (12). However, this mechanism cannot explain the beneficial effect seen after 7-day treatment with capsaicin, which should result into TRPV1 desensitization and a lower secretion of CGRP and other vasoactive compounds from nerve terminals. It is possible that TRPV1 receptors expressed on endothelial cells are refractory to capsaicin-induced desensitization (for example, because of a high receptor reserve), and their activation stimulates nitric oxide formation (with resultant vasodilation and vasoprotection) during the 7-day treatment with capsaicin. This hypothesis warrants further investigation on isolated capillary vessels or cultured endothelial cells obtained from control or diabetic patients.

This study may be biased for the absence of a group control of patients. Further studies are needed to better clarify the pathogenetic mechanism that correlate the topical capsaicin in the management of microvascular complications in diabetic patients.

Further studies are needed to establish whether, and to what extent, this particular approach can be applied to the treatment of diabetes complications.

Footnotes

Disclosure. The Authors declare no conflict of interests.

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