Catalpol Ameliorates The Pathogenesis Of EAE Animal By Increasing The Level Of Noradrenaline From Locus Coeruleus

Background:Multiple sclerosis(MS) is a chronic inflammatory disease of the central nervous system(CNS) characterized by widespread regions of focal demyelination, loss of oligodendrocytes, and axonal degeneration. The etiology and pathogenesis of the disease remain unclear. Currently, MS is widely believed to be a complex multifactorial disease involving genetic and environmental factors affecting the autoimmune responses that lead to the damage of myelin. However, increasing evidence suggests that abnormalities of the locus coeruleus noradrenaline(LC-NA) system may be a contributing factor. The endogenous neurotransmitter noradrenaline(NA) plays anti-inflammatory and neuroprotective effects in vivo and in vitro. And reduced NA levels could be permissive for increased inflammation and neuronal damage. The main source of NA in the central nervous system are tyrosine hydroxylase(TH)-positive neurons located in the Locus coeruleus(LC). TH is the rate-limiting enzyme for NA synthesis, therefore, the regulation of TH protain and intrinsic enzyme activity represents the central means for controlling the synthesis of NA. Catalpol is an iridoid glycoside purified from Rehmannia glutinosa Libosch. It showed neuroprotective effect in multiple sclerosis.Methods : In this study, we employed the experimental autoimmune encephalomyelitis(EAE) model to confirm catalpol’s neuroprotective effects. C57BL/6 mice were immunized with myelin oligodendrocyte glycoprotein peptide 35-55 to develop a chronic disease. Depletion of NA levels using the selective the LC-selective neurotoxin N-(2-chloroethyl)-N-ethyl-2- bromobenzylamine(DSP-4). The weight and disability scores of each mouse was obtained daily over the course of experiment. ELISA for noradrenaline was performed according to the manufacturer’s instructions. LC tyrosine hydroxylase protein levels in C57BL/6 mice and Sprague-Dawley rats embryos were measured by western blott analysis. TH immunofluorescence detection was used to detect TH-positive noradrenaline neurons. In the study, we also tested the effects of catalpol on LC neurons.Results:As expected, an obvious improvement of clinical scores was found in EAE mice treatment with catalpol. Catalpol increased TH expression and increased NA levels in the spinal cord. In the primary cultures, catalpol exerted a neuroprotective effect in LC neurons by increasing the generation of NA. These results suggest that treatments with drugs such as catalpol which target LC survival or function could be of benefit in MS patients.Conclusion:In conclusion, the current data suggest that abnormalities of the locus coeruleus noradrenaline(LC-NA) system may be a contributing factor, and treatment with catalpol can provide benefit in EAE, and is associated with positive effects on synthesis of noradrenaline and LC physiology. This study provides a new sight in the pathogenesis of MS.