An ester of many uses ...

Proprionyl L-Carnitine
Enhances Wound Healing

And also Counteracts Endothelial Cell Dysfunction
By Will Block

We have written before about the enhancement of wound healing (see “Arginine Improves Wound Healing” in the November 2011 issue, “Accelerated Wound Healing with Flavonoids” in the July 2001 issue, “Arginine Heals Bedsores” in the June 2015 issue, “Depression and Anxiety Slow Wound Healing” in the June 2001 issue). So why write another article on the same topic? Because there’s new evidence and future technologies have not arrived yet.

New Research for a Natural Derivative of Carnitine

Propionyl-L-carnitine (PLC) is a natural derivative of carnitine that has been reported to improve post-ischemic blood flow recovery. Ischemia is an inadequate blood supply to an organ or part of the body, especially the heart muscles; when blood flow is restored damage occurs.

PLC is an ester of L-carnitine, required for the transport of fatty acids into the mitochondria. L-carnitine is an endogenous (made in the body) substance that acts as a carrier for fatty acids across the inner mitochondrial membrane necessary for subsequent β-oxidation and ATP production. PLC has also been recognized to be an antioxidant agent, so protecting tissues from oxidative damage.

In particular, PLC has been documented to be capable to reduce membrane lipid peroxidation and the effects of hypoxia in cardiomyocytes (heart cells), endothelial dysfunction in ischemic rabbit limbs and in human inflammatory bowel diseases (such as Crohn’s disease and ulcerative colitis). A preliminary study reported PLC as clinically effective in the healing of arterial or venous cutaneous chronic ulcers in 14 of 18 vasculopathic (any disorder of the blood vessels) patients unmanageable to all other forms of therapy.2 The beneficial effect was associated with an improved blood flow recovery.


So why write another article on the
same topic? Because there’s new
evidence and future technologies
have not arrived yet.


In a new study, Italian researchers sought to document any beneficial effect of PLC on the healing process to determine whether it is exclusively related to blood flow recovery or also depends from other mechanisms.1 The researchers tested the efficacy of PLC in two models of cutaneous wound healing in rat: the skin flap and full-thickness skin wound.

Since PLC was also documented to ameliorate serum-deprived dysfunction of human umbilical vein endothelial cells, the researchers aimed to investigate if beneficial effects of PLC can be extended to cutaneous microcirculation. The in vivo studies and in vitro data gathered by using human dermal microvascular endothelial cells strongly support that—in addition to its vasodilatative capacity—PLC accelerates dermal wound healing through its beneficial anti-oxidant effects on microvascular endothelial dysfunction and reparative angiogenesis.


L-carnitine is an endogenous (made in
the body) substance that acts as
a carrier for fatty acids across the
inner mitochondrial membrane
necessary for subsequent β-oxidation
and ATP production.


In the Italian study, researchers evaluated the effects of PLC in rat skin flap (healthy skin and tissue that is partly detached and moved to cover a nearby wound) and cutaneous (skin) wound healing.

A daily oral PLC treatment improved (100 mg/kg/day) skin flap viability and this was attributed to a reduction in ROS levels, along with increased activity of inducible nitric oxide synthase (iNOS) and the up-regulation of nitric oxide (NO). The human equivalent dose would be about 1.3 g of PLC for a 176 lb human. PLC accelerated wound healing and increased capillary density, likely favoring dermal angiogenesis by upregulation of iNOS, vascular endothelial growth factor (VEGF), placental growth factor (PlGF) and reduction of NADPH-oxidase 4 (Nox4) expression. Nox4 is a member of the NADPH oxidase family with an important role in cellular physiology, including regulation of signaling, cell differentiation and cell proliferation. Nox4 induces mitochondrial dysfunction.


The findings: PLC treatment improved
rat skin flap viability, accelerated
wound healing and dermal
angiogenesis (the growth of new
blood vessels needed for healing).


In serum-deprived human dermal microvascular endothelial cell cultures, PLC improved endothelial dysfunction by increasing iNOS, PlGF, VEGF receptors 1 and 2 expression and NO levels. Additionally, PLC counteracted serum deprivation-induced impairment of mitochondrial β-oxidation, Nox4 and cellular adhesion molecule (CAM) expression, ROS generation and leukocyte adhesion.

At the same time, dermal microvascular endothelial cell dysfunction was prevented by Nox4 inhibition. Interestingly, inhibition of β-oxidation counteracted the beneficial effects of PLC on oxidative stress and endothelial dysfunction.

In summary of the researchers findings, PLC treatment improved rat skin flap viability, accelerated wound healing and dermal angiogenesis (the growth of new blood vessels needed for healing). The beneficial effects of PLC likely resulted from improvement of mitochondrial β-oxidation and reduction of Nox4-mediated oxidative stress and endothelial dysfunction. This type of antioxidant therapy and targeting of endothelial dysfunction is thought to present a promising tool for the treatment of delayed wound healing or chronic ulcers.

References

  1. Scioli MG, Lo Giudice P, Bielli A, Tarallo V, De Rosa A, De Falco S, Orlandi A. Propionyl-L-carnitine enhances wound healing and counteracts microvascular endothelial cell dysfunction. PLoS One. 2015 Oct 16;10(10):e0140697. doi:10.1371/journal.pone.0140697. eCollection 2015. PubMed PMID: 26473356; PubMed Central PMCID: PMC4608702.
  2. Pola P, Flore R, Serricchio M, Tondi P. New carnitine derivatives for the therapy of cutaneous ulcers in vasculopathics. Drugs Exp Clin Res. 1991; 17: 277–282.

Wound Healing

Figure 1 The three classic stages of wound repair. Inflammation (a), New Tissue Formation (b) and Remodelling (c).

The Inflammation stage lasts until about 48 hours after injury. Depicted is a skin wound from 24–48 hours after injury. The wound is characterized by a hypoxic environment in which a fibrin clot has formed. Bacteria, neutrophils and platelets are abundant in the wound. Normal skin appendages (such as hair follicles and sweat glands) are present in the skin outside the wound.

The New Tissue Formation stage occurs about 2–10 days after injury. Portrayed is a skin wound at about 5–10 days after injury. An eschar (scab) has formed on the surface of the wound. Most cells from the previous stage of repair have migrated from the wound, and new blood vessels now populate the area. The migration of epithelial cells can be observed under the eschar.

The Remodelling stage lasts for a year or more. Shown is a skin wound about 1–12 months after repair. Disorganized collagen has been laid down by fibroblasts that have migrated into the wound. The wound has contracted near its surface, and the widest portion is now the deepest. The re-epithelialized wound is slightly higher than the surrounding surface, and the healed region does not contain normal skin appendages. (see Gurtner GC, Werner S, Barrandon Y, Longaker MT. Wound repair and regeneration. Nature. 2008 May 15;453(7193):314-21.)

LEM1512skin274.jpg

(click on thumbnail for full sized image)

Despite the goal to make any needed (or elective) surgery as minimally-invasive as possible, it’s the recovery process that creates the most undesirable consequences, when the body’s resources marshal all of its efforts to heal the wounds created by the surgical knife.

More than 3 million patients worldwide have employed da Vinci robotic surgery approved by the FDA in 2005. Since then, its use for hysterectomy has been widely advertised. Surgeons avow that the da Vinci robotic device yields better results and makes for easier recovery. Also, many hospitals claim that patients experience less pain and fewer complications, getting back on their feet faster. Is it true?

A Study that Challenges the da Vinci Claims

While da Vinci “surgeons” operate through just a few small incisions, a study comparing the outcomes in 264,758 women receiving hysterectomies found no overall difference in complication rates between two groups—laparoscopic or robotically assisted hysterectomy.1 Laparoscopic surgery also makes small incisions and claims to be minimally invasive. The surgeries were performed at 441 hospitals between 2007 and 2010. However, there was also no difference in the rates of blood transfusion, even though one of the claims regarding robotic surgery is that it causes less blood loss.

As to superior recovery, there was no evidence presented in the above study. Even so, it is difficult to tell from the literature given that many robot surgeries are provided with “an enhanced recovery programme including the following elements should be implemented: patient education, preoperative carbohydrate drinks, spinal or local analgesia, goal-directed fluid therapy, early feeding and intensive early mobilization [and more …].”2

The Promise of Disruptive Technologies

Those who follow “disruptive” medical technologies know that the innovative process of 3D bio-printing of living human cells—for use as implants or grafts targeting use in reconstructive surgery and wound care—will eventually prevail. Even organs will be printable.

Also, new research has brought wound-healing dressings closer to reality by establishing a method of electrical stimulation that kills off the majority of multi-drug resistant bacteria commonly found in difficult-to-treat infections.

Moreover, gene and stem cell therapy combinations are slated to aid wound healing—not to mention the possible use of ultrasound to promote faster healing of wounds. But that’s only part of the future, which is here right now, though unevenly distributed (Jokingly, but true). The big question is, what to do now?

What Is Wound Healing?

Wound repair is one of the most complex biological processes that occur during human life. Following an injury, multiple biological pathways immediately become activated and are synchronized. Wound healing is a dynamic process orchestrated by the body, requiring coordination of various events and signaling networks to provide a protective barrier against further external stimuli or infections.

Importance of the Immune System

To restore tissue integrity and homeostasis, the healing process involves cellular components of the immune system, the blood coagulation cascade, and inflammatory pathways, including many interactions between extracellular matrix, multiple soluble mediators, connective tissue contraction, blood cells, endothelial cells, keratinocytes, and angiogenesis.

The Role of the Endothelium

Normally, the endothelium provides a semi-permeable membrane for the transfer of nutrients and retrieval of waste products. It also regulates monocyte adhesion and subsequent infiltration at the site of injury, while it promotes vasodilatation and inhibits inflammation and thrombosis (see Fig. 1).

When wound healing is underway, angiogenesis leads to the formation of a dense network of small blood vessels in the granulation tissue. Endothelial dysfunction contributes to microangiopathy that impairs cutaneous microvascular blood flow, hypoxia and accelerated inflammation, causing delayed healing or chronic wounds (see Fig. 1).

The management of wounds presents a significant burden to healthcare services, consuming a large amount of resources. Experimental data suggest that wound healing associates with endothelial aberrations suggestive of localized dysfunction.

Animal models of impaired cutaneous wound healing reveal a reduction in NO production, which associates with reduced collagen accumulation and wound breaking strengths. Since the amino acid arginine increases NO, it stands to reason that there is an important usage in wound healing. See the subhead “Many Nutrients Help Healing” below.

Endothelial Cell Dysfunction Impairs Wound Repair

Reduction in cutaneous blood flow, and oxygen tension, abnormal angiogenesis and increased levels of matrix metalloproteinases (MMPs) and reactive oxygen species (ROS) further support the hypothesis that endothelial cell dysfunction is responsible for impaired wound repair. Vascular inflammation and increased production of ROS play a pivotal role in endothelial dysfunction.

ROSs are produced by several enzyme systems, including NADPH oxidase (Nox), xanthine oxidase, endothelial nitric oxide synthase, lipoxygenases and myeloperoxidase. Although all those enzymes can potentially contribute to the oxidative stress, Nox is the predominant source of ROS in the vasculature and Nox4 the major endothelial isoform.

The cellular fueling system, in particular the mitochondrial β-oxidation pathway, is a target for various noxious stimuli, including oxidative stress. Inflammatory stimuli can induce the increase of cellular oxidative stress driven by increasing mitochondrial oxidative stress and Nox activity, with a consequent mitochondrial dysfunction and impairment of β-oxidation. Endothelial dysfunction is also accompanied by increased expression of cell adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and inflammatory cytokine secretion.

Adhesion molecules are critical because they mediate inflammatory cell recruitment into the subendothelial space. There are clinical reports that therapy with antioxidants and free radical scavengers are efficacious in patients with endothelial dysfunction.

The High Cost of Healing

Economically, impaired wound healing represents a high cost for health and medical care. That’s because endothelial dysfunction predisposes dermal microangiopathy (small vessel disease affecting the skin). Surgery is typically performed through the skin or through blood conduits that result in damage to endothelial cells. This contributes to delayed wound healing and chronic ulcers.

Endothelial dysfunction impairs cutaneous microvascular blood flow by inducing an imbalance between vasorelaxation and vasoconstriction as a consequence of reduced nitric oxide (NO) production and increased oxidative stress and inflammation.

References

  1. Wright JD, Ananth CV, Lewin SN, Burke WM, Lu YS, Neugut AI, Herzog TJ, Hershman DL. Robotically assisted vs laparoscopic hysterectomy among women with benign gynecologic disease. JAMA. 2013 Feb 20;309(7):689-98.
  2. Iavazzo C, Gkegkes ID. Enhanced recovery programme in robotic hysterectomy. Br J Nurs. 2015 Sep 10-23;24(16):S4-8.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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