4th International Conference on Neurology and Brain Disorders

September 09-11, 2021

September 09 -11, 2021 | Virtual Event
INBC 2017

Giuseppe Scalabrino

Speaker at International Conference on Neurology and Brain Disorders 2017 - Giuseppe Scalabrino
University of Milan, Italy
Title : Cobalamin, normal prions, and epidermal growth factor. A three-cornered hat

Abstract:

Cobalamin (Cbl), epidermal growth factor (EGF), and normal prions (PrPCs) are key molecules for myelin maintenance in the central (CNS) and peripheral nervous system (PNS). We have previously shown that Cbl deficiency causes an imbalance in some cytokines (e.g. tumour necrosis factor(TNF)-alpha and interleukin-6) and growth factors (e.g. EGF and nerve growth factor) in the CNS and PNS of the rat, and in serum and cerebrospinal fluid (CSF) of adult Cbl-deficient (Cbl-D) patients.More in detail, we demonstrated that the neurotrophic of Cbl in the CNS of Cbl-D rats is mediated by stimulation of the EGF synthesis in the CNS itself. It is conceivable that this imbalance triggers subsequent cellular events. We posited the working hypothesis that there may be a link between Cbl and PrPCs, and that this link is deranged in Cbl-D neuropathy because of the Cbl deficiency-induced imbalance in CNS and/or PNS cytokines and/or growth factors.

We demonstrated that:

(1) bothCbl and EGF up-regulate PrPC synthesis independently in rat spinal cord (SC)

(2) Cbl deficiency induces excess PrPC in rat SC and PNS, concomitantly with myelin damage and PNS electrophysiological abnormalities

(3) the SC increase is mediated by a local Cbl deficiency-induced excess of TNF-alpha

(4) intracerebroventricular (icv) treatment with anti-PrPCoctapeptide repeat region antibodies normalizes the ultrastructure of the Cbl-D rat SC and PNS myelins, and the PNS electrophysiological abnormalities, without modifying their Cbl-D status

(5) icvPrPC administration to otherwise normal rats causes SC and PNS myelin lesions and PNS electrophysiological abnormalities, similar to those of Cbl-D neuropathy, and increases in SC and liver TNF-alpha concentrations

(6) CSF and serum PrPC concentrations in adult Cbl-D patients are significantly higher than in the corresponding controls

(7) the concentrations significantly correlate with their CSF and serum Cbl concentrations; and

(8) no increases have been observed in PrPC levels of serum of patients with non-Cbl-D anemias, and CSF of patients with ALS or AD.

Therefore, we can conclude that:

(a) Cbl deficiency causes a vicious circle, because the Cbl deficiency-induced increase in SC and PNS TNF-alpha levels contributes to the local increase in PrPC levels and vice versa;

(b) we were the first to demonstrate that the experimental Cbl-D neuropathy is also caused by a local excess of PrPCs that do not show any apparent conformational change;

(c) our clinical data of Cbl-D patients and the myelinotoxic effects of exogeneous PrPCs appear to confirm this notion;

(d) all of the myelinotrophic agents (i.e. Cbl, EGF, and anti-TNF-alpha antibodies) markedly increased the PrPC-mRNA levels of the SC and duodenal mucosa (but not the liver) of the Cbl-D rats; and

(e) the myelinotrophic effect of Cbl takes many inter-related routes, and that of EGF may be both Cbl-independent and Cbl-dependent.

Biography:

Dr. Giuseppe Scalabrino studied at the School of Medicine of the University of Milan and received his M.D. degree magna cum laude in 1968. Since 1969, Dr. Scalabrino has held a number of academic positions in the Institute of General Pathology of the Faculty of Medicine and Surgery. He was Associate Professor of General Pathology between 1971 and 1985; from 1986 till 2014 has been full Professor of General Pathology. Over the course of his distinguished career, Dr. Scalabrino has been involved as invited speaker in various professional conferences, mainly dealing with the role of polyamines in oncology and subsequently with the role of vitamin B12 (cobalamin) in mammalian central nervous system. Among Dr. Scalabrino’s numerous honors is the International Award “Roentgen” from Italian Accademia dei Lincei in Rome, which he received for oncological research in 1983. Reviewer of International Scientific Journals and author of more than 100 scientific papers published in journals with impact factors. Dr. Scalabrino’s studies of cobalamin neurotrophism have been mentioned in 12 american textbook of neurology, hematology, biochemistry, and vitaminology.

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