Multipl Sklerozun Progresif Sürecinin Dişi Wistar Sıçanlarda Deneysel Otoimmün Ensefalomiyelit Modeli ile İncelenmesi ve Pentoksifilinin Etkileri

Abstract

Multiple sclerosis (MS) is a primary demyelinating chronic disease of the central nervous system with neurodegenerative, inflammatory, and autoimmune components. Experimental autoimmune encephalomyelitis (EAE) is a widely used animal model of MS. The progressive process of MS is associated with cortical demyelination and neuropsychiatric symptoms (NPSs). Lipopolysaccharide (LPS) is a Toll-like receptor 4 (TLR4) agonist and a bacterial endotoxin that can increase blood brain barrier (BBB) permeability. Pentoxifylline, in addition to its nonspecific phosphodiesterase inhibition, can also exhibit TLR4 antagonism. In this study, we aimed to create a chronic progressive MS model characterized by cortical demyelination and NPSs in Wistar albino female rats by increasing BBB permeability through LPS injection after immunization with myelin oligodendrocyte glycoprotein (MOG) and to reveal the effects of pentoxifylline in treatment. The immunization of the rats was performed by subcutaneous injection at the base of the tail with an emulsion of 20 µg MOG antigen in a volume of 100 µL and an equal volume of CFA (Complete Freund Adjuvant). BBB permeability was assessed using the evans blue assay, NPSs were evaluated through behavioral tests, demyelination and microglial activation were examined by immunohistochemistry, and peripheral nerve involvement was assessed via compound action potential (CAP) recordings in in vivo electrophysiology. 4 mg/kg LPS was shown to increase BBB permeability. MOG-immunized rats were injected with LPS at week 3, resulting in chronic progressive MS model that persisted until day 70. Depression-like and anxiety-like behaviors, cognitive dysfunction, motor dysfunction and mechanical allodynia were detected in the model. Widespread grey matter demyelination, predominantly severe in the subpial cortex and hippocampus, accompanied by microglial activation, were identified. Serum TNF-α levels were found to be increased and peripheral nerve electrophysiology showed a prolonged refractory period during the chronic process. Daily intraperitoneal dose of 100 mg/kg of pentoxifylline for 2 weeks was found to be effective in the treatment of allodynia, depression-like and anxiety-like behaviors. This thesis study demonstrated that the addition of LPS injection at week 3 to the classical EAE model can create a chronic progressive MS model with prominent cortical demyelination and NPSs, and pentoxifylline had a therapeutic effect on the NPSs of our model, especially depression, anxiety and pain.