Abstract
BackgroundCorticosteroids dominate in the treatment of chronic autoimmune neuropathies although long-term use is characterized by devastating side effects.MethodsWe introduce the intrathecal application of the synthetic steroid triamcinolone (TRIAM) as a novel therapeutic option in experimental autoimmune neuritis in Lewis ratsResultsAfter immunization with neuritogenic P2 peptide, we show a dose-dependent therapeutic effect of one intrathecal injection of 0.3 or 0.6 mg/kg TRIAM on clinical and electrophysiological parameters of neuritis with a lower degree of inflammatory infiltrates (T cells and macrophages) and demyelination in the sciatic nerve. In vitro studies in Schwann cell cultures showed an increased expression of IL-1 receptor antagonist and reduced expression of Toll-like receptor 4 after incubation with TRIAM as well as a protective effect of TRIAM against oxidative stress after H2O2 exposure.ConclusionIntrathecal TRIAM application could be a novel immunomodulatory and potentially neuroprotective option for autoimmune neuropathies with a direct effect on Schwann cells.
Highlights
Our group has previously shown that intrathecal therapeutic application of human immunoglobulins in the context of experimental autoimmune neuritis (EAN), the animal model of dysimmune neuropathies such as Guillain-Barré syndrome (GBS), or the chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) achieves a dose-dependent improvement of clinical signs, which correlate with a histological reduction of inflammatory infiltrates in the sciatic nerves and of complement activation in the sciatic nerve [10]
Intrathecal triamcinolone applied in a therapeutic concept ameliorates the clinical course of experimental autoimmune neuritis After immunization with P2 protein peptide 53–78, clinical signs of EAN begun around day 10 p.i
The major shortcoming of our in vivo study is the fact that the monophasic animal model of EAN does not reproduce the complexity of the pathophysiology of CIDP but mostly the one of GBS, for which at least intravenous corticosteroids are not effective
Summary
Corticosteroids are used as first-line therapy in the form of pulsed intravenous methylprednisolone or oral long-term prednisolone treatment for patients with CIDP and improve sensory symptoms and painful paresthesia. Their therapeutic benefits are limited by side effects such as osteoporosis, abdominal obesity, glaucoma, diabetes mellitus, and hypertension (Cushing’s syndrome) [2]. The anti-inflammatory effects of TRIAM have been widely investigated and are mediated after binding to the glucocorticoid (GR) nuclear receptors, which is widely expressed in neurons and Schwann cells. Upon binding TRIAM, the receptors undergo a conformational change and translocate in the nucleus to mediate gene transcription and induce an anti-inflammatory potential for example through inhibiting cytokine release (e.g., TNFα and IL-1β). Corticosteroids dominate in the treatment of chronic autoimmune neuropathies long-term use is characterized by devastating side effects
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