| Abstract |
Obesity is an exponentially rising detrimental condition characterized by abnormal fat accumulation. Obesity has been linked with the onset of several diseases and syndromes. Lately, it has been found that obesity is associated with delayed wound healing both in humans and rodents.
The process of wound healing is characterized by high complexity and acquires the participation of several cell types. Furthermore, it is a stepped process that includes the: inflammation, epithelialization and remodeling, stages that may be overlapping but are still distinct. Delay or deterrence in any of these stages leads to impaired wound healing.
Inflammation is regulated by a variety of factors, such as corticotropin releasing hormone (CRH), which is the major regulator of hypothalamic-pituitary-adrenal axis (HPA axis). Activation of the axis leads to release from the adrenal cortex of glucocorticoids, which are potent anti-inflammatory agents. CRH and its receptors except of being present in the central nervous system have been identified in a variety of peripheral tissues and organs, including the skin. In previous studies, we have shown that CRH and its receptors are present in wounded skin however, their role in the wound healing process remains unclear yet.
Dehydroepiandrosterone (DHEA) is a hormone produced by the adrenal gland, which has neurosteroid and immunoregulative properties and which, nowadays has been identified as a new ligand for TrkA receptors of the family of nerve growth factor (NGF). Treatment with DHEA has beneficial effects in inflammation in mouse models, including the reduction of inflammation and destruction of the tissue after induction of cutaneous thermal injury. In addition, topical use of DHEA significantly improves the process of aging in the skin. Recent studies have shown that, DHEA can prevent human keratinocytes from apoptosis in cultures via activation of membrane signaling pathways. These studies suggest that DHEA is a candidate molecule for possible clinical use in pathological conditions of the skin. However, its use is limited due to its immediate conversion to estrogens and androgens. For that purpose, efforts have been made in order to develop synthetic derivatives of DHEA, which lack these endocrine properties. Recently, one such derivative has been designed and synthesized (BNN27 (Patent number: WO 2008/155534)), which lacks the ability to convert to estrogens and androgens. BNN27, a microneurotrophin as it is now called, has neuroprotective and powerful immuroregulative properties, as well.
The aim of the present work was the elucidation of the function of neurosteroids and stress neuropeptides in cutaneous wound healing of lean and obese mice. Towards this direction, we used wild type and corticotropin releasing hormones (CRH) knockout (Crh-/-) mice. After three months, which was the duration of the obesity protocol that was applied, we performed wounds in the back of the mice. In parallel, mice were treated (ip) with the DHEA analogue, BNN27, for three days after the induction of the wound. Next, we measured both the total wound area and perimeter, the visceral adipose tissue mass and the food intake of the animals. In addition, factors that affect or/and are induced or inhibited during wound healing process were studied, such as, cytokines, the receptors of the neurosteroid used and the nerve growth factor, collagen and, finally.
We found that wild type animals under high fat diet (HFD) exhibited higher adipose tissue accumulation compared to their normally fed littermates (SC) and the size of their adipocytes was bigger as well. Paradoxically, the healing rates tended to be the same in all the animal groups with a slight difference in the group that was treated with SC and DMSO which showed a faster healing process (no statistical significance). HFD caused a reduction to the mRNA levels of collagen type I. The cytokines under study were unaffected by BNN27 treatment. Obesity induced the expression of TrkA receptor mRNA which has the highest affinity for BNN27.
As far as it concerns, the experiments done with main purpose the identification of the role of neuropeptides in the process of wound healing, demonstrated that lack of CRH reduced both food intake and the total fasting blood glucose levels. Furthermore, deficiency of CRH resulted in increased collagen mRNA levels.
Our data confirm the inhibitory role of obesity in wound healing and further suggest that the neurosteroid BNN27 also negatively affects this process. In our previous studies, we have shown that while CRH deficiency accelerates wound healing in non-obese mice, the effect is not the same in mice treated with HFD. However, CRH deficiency positively affects wound healing by triggering the expression of wound healing acceleration-related-factors. Future studies are designed to shed light in the precise role of BNN27 and the mechanism through which it regulates obesity and wound healing.
|
Μελέτη του ρόλου των νευροπεπτιδίων του στρες και των συνθετικών νευροστεροειδών στην τραυματική επούλωση φυσιολογικών και παχύσαρκων μυών
