Abstract
Recent findings showing that epidermal growth factor (EGF) is significantly decreased in the cerebrospinal fluid (CSF) and spinal cord (SC) of living or deceased multiple sclerosis (MS) patients, and that its repeated administration to rodents with chemically- or virally-induced demyelination of the central nervous system (CNS) or experimental allergic encephalomyelitis (EAE) prevents demyelination and inflammatory reactions in the CNS, have led to a critical reassessment of the MS pathogenesis, partly because EGF is considered to have little or no role in immunology. EGF is the only myelinotrophic factor that has been tested in the CSF and spinal cord of MS patients, and it has been shown there is a good correspondence between liquid and tissue levels. This review: (a) briefly summarises the positive EGF effects on neural stem cells, oligodendrocyte cell lineage, and astrocytes in order to explain, at least in part, the biological basis of the myelin loss and remyelination failure in MS; and (b) after a short analysis of the evolution of the principle of cause-effect in the history of Western philosophy, highlights the lack of any experimental immune-, toxin-, or virus-mediated model that precisely reproduces the histopathological features and “clinical” symptoms of MS, thus underlining the inapplicability of Claude Bernard's crucial sequence of “observation, hypothesis, and hypothesis testing.” This is followed by a discussion of most of the putative non-immunologically-linked points of MS pathogenesis (abnormalities in myelinotrophic factor CSF levels, oligodendrocytes (ODCs), astrocytes, extracellular matrix, and epigenetics) on the basis of Popper's falsification principle, and the suggestion that autoimmunity and phologosis reactions (surely the most devasting consequences of the disease) are probably the last links in a chain of events that trigger the reactions. As it is likely that there is a lack of other myelinotrophic growth factors because myelinogenesis is controlled by various CNS and extra-CNS growth factors and other molecules within and outside ODCs, further studies are needed to investigate the role of non-immunological molecules at the time of the onset of the disease. In the words of Galilei, the human mind should be prepared to understand what nature has created.
Highlights
Epidermal growth factor (EGF) was first isolated from mouse submaxillary glands in 1962 [1], but it was not until 20 years later that it was identified in human cerebrospinal fluid (CSF) [2], and in rat brain [3]
We found that chronic EGF treatment during the development of myelin ODC glycoprotein (MOG)-induced EAE prevents the onset of the disease and strongly reduces the phlogistic reaction, and its “therapeutic” results are even better than those observed in MOG-induced EAE mice chronically treated with dexamethasone [68]
We found that the levels of EGF, Cbl, and normal cellular prion (PrPc) in postmortem spinal cord (SC) samples of multiple sclerosis (MS) patients are significantly lower than in post-mortem SC samples taken from patients with other neurological or non-neurological diseases, and the negative Cbl control of PrPc levels in the normal CSF is lost in MS SC, in which the levels of both the molecules are markedly decreased [11]
Summary
Epidermal growth factor (EGF) was first isolated from mouse submaxillary glands in 1962 [1], but it was not until 20 years later that it was identified in human cerebrospinal fluid (CSF) [2], and in rat brain [3]. The various experimental MS-like models (EAE, chemicallyor virally-induced CNS demyelination, and transgenic animals) do not entirely reproduce the histopathological features, clinical course, or abnormalities in cerebrospinal fluid (CSF) typical of MS, but only mirror some of its characteristics [55,56,57,58] This has raised substantial doubts as to whether the experimental and human diseases have the same pathogenesis [59]. Given that EGF does not seem to have any immunological role [77], the findings of studies of EGF in experimental MS-like models (i.e., those in which it has been administered) and in MS itself support the view that the autoimmune reaction in the SC of EAE mice may be caused by damage to or abnormalities in the structure of CNS myelin and/or an ODC disease rather than the other way round as is traditionally believed. Impulse conduction along demyelinated axons requires considerably more energy than along myelinated axons, but inflammation, demyelination, and reduced mitochondrial gene expression in MS contribute to energy failure [115,116,117]
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