Professor Rita Levi-Montalcini did not only discover the nerve growth factor, she also had the courage to see that this neurotrophic factor could be a inducer of pathology, especially in chronic states of inflammation. In her paper Nerve growth factor: from neurotrophin to neurokine she and her colleagues discuss the pathological role of NGF in inflammation and the counteracting funtion of the ‘superman’ molecule, the endogenous lipid palmitoylethanolamide (PEA).
Montalcini et al start with the remark:
In the past decade, considerable progress has been made towards a better understanding of not only the ‘classical’ actions of NGF in the nervous system but also how this molecule maintains a balanced interplay between the nervous, immune and endocrine systems.
Especially the mast cells, Montalcini often referred to these cells as the Cinderella cells of our immune system, are especially important:
Mast cells, in particular, are highly complex in their multipotentiality and hetero- geneity. These cells can be influenced by humoral, immune and physical factors, and are ideally situated to survey and respond to a wide spectrum of micro- environmental cues.
Levi-Montalcini points out the importantce of NGF in inflammatory pain and upregulation physiology, the hypersensitivity:
A key feature of inflammation is pain and hyperalgesia. In the periphery, inflammatory mediators in- crease the sensitivity of high-threshold nociceptors so that a lower stimulus intensity is required to activate them; this is the phenomenon of peripheral sensitiz- ation20. Nerve growth factor has recently been shown to be a major contributor to the production of inflammatory hypersensitivity.
In the paper the network of interleukines is described, and its relation to NGF and lateron to the mast cells:
Cytokines are important regulatory factors in immune processes. Among these potent inflammatory agents are IL1-beta, IL6, interferon-gamma and tumour necrosis factor-alpha. The cytokine network represents a major bidirectional communication link between the nervous and immune systems. Cytokines involved in inflammation and immune responses, such as IL1-beta and TNF-alpha, are strong inducers of NGF synthesis.
The subtle interplay of all these factors become even more clear as she points out to both NGF and cytokines which are synthesized and released by neurones, astrocytes, kera- tinocytes, lymphocytes and mast cells.
In a separate chapter, Mast cells and nervous system homeostasis, Levi-Montalcini discusses in greater detail the relation between NGF, the mast cell and pathological conditions of pain and chronic inflammation. The authors point our that mast cells can be stimulated by NGF and can secrete NGF, thus creating a positive feedback loop of inflammation and hyperalgesia. Here comes in the regulating function of palmitoylethanolamide (PEA), which has been made clear by a simple diagram. PEA is defined my Levi-Montalcini as an ALIAmide molecule (involved in autacoid local injury antagonism). Hereunder she explains the PEA- ALIAmide diagram:
As our website focusses on palmitoylethanolamide, we herewith quote the entire paragraph on PEA:
It has recently been proposed that saturated N-acylethanolamides like palmitoylethanolamide, which accumulate in tissues following injury and which downmodulate mast-cell activation in vitro, exert a local, autacoid, anti-injury function via mast cells. Palmitoylethanolamide is orally active in reducing tissue inflammation and mast-cell degranulation in vivo, in decreasing hyperalgesia that accompanies peripheral nerve compression86, and in limiting the neurological deficits of experimental allergic encephalomyelitis. Moreover, palmitoylethanolamide appears to protect against excitotoxic neuronal death in vitro and to be produced by cultured CNS neurones upon excitatory amino acid receptor activation.
The mechanism of this action of N-acyl-ethanolamides has been termed autacoid local injury antagonism (ALIA) (Figure above). The observed pharmacological effects of palmi- toylethanolamide appear to reflect the consequences of supplying the tissue with a sufficient quantity of its physiological regulator of cellular homeostasis.
There is now evidence that mast cells express functional cannabinoid receptors of the so-called peripheral type (designated CB2); CB2 receptors bind palmitoylethanolamide, which then downregulates the activation of mast cells.
Palmitoylethanolamide does not interact with the cannabinoid receptor CB1 that is expressed in the brain. Conceivably, palmitoylethanolamide and its congeners (‘ALIAmides’) might play a role in modulating cellular defence mechanisms by act- ing at non-CB1 cannabinoid recep- tors. The activation of such receptors might downmodulate deleterious cellular processes following pathological events or noxious stimuli in both the immune and nervous systems (see figure above).