The discovery of palmitoylethanolamide and NGF as players in inflammation and pain

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In 1986 Rita Levi-Montalcini received a Nobel Prize for Medicine with his collaborator, Prof. S. Cohen, for their research on NGF, that as reported by the Nobel Committee,

“is a fascinating example how an argute observer may extrapolate useful hypothesis from an apparent caos”.

From 1983 to 1986, Levi-montalcini was President of the Italian Association for Multiple Sclerosis and after she was Honorary President, showing a great interest for the problems of patients with this and other neurodegenerative disorders. In the full video, quoted above, she mentioned MS in relation to mast cells and autocoids.

In an interview with Rita by G. Giudice, to the answers regarding the consequences of her discovery for Developmental Biology and about its applications, she told that “The discovery of NGF has demonstrated that the protein factors which are released by all the cells in an organism play an essential role in the development of every system (in the case of my factor, the nervous system).” And that “NGF has found unhoped-for possibilities of clinical application to the most varied pathological conditions of a degenerative nature and to those belonging to homeodynarnic systems (nervous, immune and endocrine). A recent discovery has been that NGF may play an important role in Alzheimer’s disease, in disorders of viral origin such as immune deficiency disorder (the HIV virus), and in afflictions of an autoimmune nature (multiple sclerosis). One clinical application with great potential for development—which has recently been discovered by some young researchers working in my own group and in a team at the Venice Eye Clinic—is the use of NGF as a collyrium with which to treat lesions of the cornea (of either traumatic, viral or toxic origin) that ìnevitably cause the cornea’s destruction and, therefore, blindness. lf administered topically, NGF induces the permanent regeneration of the damaged cornea and its total functional repair.” (Rita Levi-Montalcini, one of the most prominent Italian personalities of the twentieth century, by Federico, A, in:Neurological sciences, Volume: 34, Issue: 2 (February 1, 2013), pp: 131-133)

In the picture we show her description of the discovery of NGF in 1956 (In vitro and in vivo Effects of a Nerve Growth-Stimulating Agent Isolated from Snake Venom, by Rita Levi-Montalcini and Stanley Cohen:Proceedings of the National Academy of Sciences of the United States of America (PNAS), Volume: 42, Issue: 9 (September 15, 1956), pp: 695-699)

NGF discovery

How important NGF started to become in various inflammatory disorders, we can see for instance in the abstract of a dissertation of 2000 on asthma:

Nerve growth factor (NGF) is known for years for its properties to induce neurite outgrowth. Its role in inflammation has recently been discovered. In this thesis the role of NGF in allergic asthma is shown. In chapter 2 we showed that NGF can induce airway hyperresponsiveness in guinea pigs. Simply injecting 8-80 ng NGF intravenously resulted in an airway hyperresponsiveness within 1 hr after administration. Sensory nerves in the aiwarys signal to the central nervous system. A subtype of these neurons express tachykinins, e.g. substance P and neurokinin A. Tachykinins can induce airway hyperresponsiveness. It seems NGF acts by sensitizing the sensory neurons. A neurokinin-1 receptor antagonist can prevent the induction of airway hyperresponsiveness by NGF. The neurokinin-1 receptor is the preferred receptor for the ligand substance P. In chapter 3 we show that NGF can sensitize the sensory nerve endings, and this either results in the release of more substance P or sensitization of the neurokinin-1 receptor, but does not involve an increased synthesis of substance P. Furthermore, cannabinoids can prevent the NGF-induced hyperresponsiveness in isolated tracheal ring as well as in the guinea pig in vivo. Cannabinoids induce an inhibitory signal in sensory neurons and thereby proof again that sensory nerve endings are involved in the induction of airway hyperresponsiveness by NGF. In a model for allergic asthma, using ovalbumin as an allergen, antibodies against NGF can prevent the acutely induced bronchoconstriction by inhalation of ovalbumin (chapter 4). This model for allergic asthma shows airway hyperresponsiveness as well, and this coincides with an increased content of tachykinins in the sensory neuronal cell bodies. In chapter 5 we show that this coincides with an increase in NGF in the airways as well. When the signal transduction pathway of the high affinity receptor for NGF, trkA, is blocked, the airway hyperresponsiveness can be prevented. Furthermore, the increase in substance P in the airways and neurons is prevented as well. Neurons as well as immune cells can release NGF. One of these cells is the mast cell. It has been suggested sensory neurons and mast cells interact. In chapter 6 we co-cultured bone marrow derived mast cells and dorsal root ganglion neurons to study whether these cells would affect each others function. The cells specifically adhered to each other. They only affect each other’s function, though this seems not to be of any significant physiological importance. Concluding, NGF affects airway function by affecting sensory nerve function. This thesis shows NGF is involved in the development of airway pathology in a model for allergic asthma. This could lead to the development of a new class of therapeutics against allergic asthma. (Nerve growth factor: a novel mediator in asthma, by Vries, Annick de. Source: Farmaceutische Wetenschappen Proefschriften, Utrecht (2001)

One response

  1. Reblogged this on Mastopedia Research Feed and commented:
    The link between NGF and the mast cell driving up inflammatory processes in patients…

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