Loss of epidermal growth factor regulation by cobalamin in multiple sclerosis

We investigated whether the physiological regulation of cerebrospinal fluid (CSF) levels of tumor necrosis factor (TNF)-alpha, epidermal growth factor (EGF), and nerve growth factor (NGF) by cobalamin (Cbl) that is observed in rat and human central nervous system (CNS) is retained in the CSF of patients with multiple sclerosis (MS). The study involved 158 MS patients grouped on the basis of the different clinical courses (relapsing-remitting (RR), secondary-progressive (SP), and primary-progressive (PP)), and 76 gender- and age-matched control patients with other non-inflammatory and non-neoplastic neurological diseases. The MS patients were therapy-free at the time of lumbar puncture. CSF Cbl and EGF were blindly measured by means of radioimmunoassays, and CSF TNF-alpha, and NGF by means of highly sensitive enzyme-linked immunosorbent assays. Serum EGF was also measured in 38 of the MS patients and 20 healthy controls. CSF Cbl levels were significantly higher (RR patients 27.9+/-9.7 pg/ml, p<0.0001 vs. C; SP patients 25.4+/-8 pg/ml, p<0.02 vs. C), and CSF TNF-alpha and EGF levels significantly lower in the patients with the RR (TNF-alpha 28.3+/-23.4 x 10(-3) pg/ml, p<0.0001 vs. C; EGF 129.9+/-44.8 pg/ml, p<0.02 vs. C) or SP (TNF-alpha 20.5+/-20.5 x 10(-3) pg/ml, p<0.001 vs. C; EGF 116.5+/-24.8 pg/ml, p<0.05 vs. C) clinical course than in controls (Cbl 21+/-4.6 pg/ml; TNF-alpha 75.6+/-34.7 x 10(-3) pg/ml; EGF 170.2+/-54.8 pg/ml). There were no differences in CSF NGF or serum EGF levels between any of the MS clinical courses and controls. Our results indicate that: (a) the positive Cbl-mediated regulation of myelino- and oligodendrocyte-trophic EGF is lost in the CSF of RR- or SP-MS patients; (b) the decrease in EGF levels in the CSF may be one factor impeding CNS remyelination in MS; and (c) the PP clinical course may have different pathogenetic mechanism(s) also on the basis of the molecules investigated in this study.