Attenuation of experimental autoimmune neuritis with locally administered lovastatin‐encapsulating poly(lactic‐co‐glycolic) acid nanoparticles. Issue 2 (20th December 2016)

• Record Type: Journal Article
• Authors: Langert, Kelly A.; Goshu, Bruktawit; Stubbs, Evan B.
• Is Part Of: Journal of neurochemistry. Volume 140:Issue 2(2017)
• Page Start: 334
• Page End: 346
• Publication Date: 2016-12-20
• Subjects: Guillain–Barré syndrome -- lovastatin -- nanoparticles -- poly(lactic‐co‐glycolic) acid; Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.13892
• Languages: English
• ISSNs: 0022-3042

Abstract

Abstract: Acute inflammatory demyelinating polyneuropathy (AIDP) is an aggressive antibody‐ and T‐cell‐mediated variant of Guillain–Barré Syndrome (GBS), a prominent and debilitating autoimmune disorder of the peripheral nervous system. Despite advancements in clinical management, treatment of patients with AIDP/GBS and its chronic variant CIDP remains palliative and relies on the use of non‐specific immunemodulating therapies. Our laboratory has previously reported that therapeutic administration of statins safely attenuates the clinical severity of experimental autoimmune neuritis (EAN), a well‐characterized animal model of AIDP/GBS, by restricting the migration of autoreactive leukocytes across peripheral nerve microvascular endoneurial endothelial cells that form the blood–nerve barrier. Despite these advancements, the clinical application of systemically administered statins for the management of inflammatory disorders remains controversial as a result of disappointingly inconclusive phase trials. Here, poly(lactic‐co‐glycolic) acid (PLGA) nanoparticles were evaluated as an alternative strategy by which to locally administer statins for the management of EAN. When tested in vitro, lovastatin‐encapsulating PLGA nanoparticles elicited a marked increase in RhoB mRNA content in peripheral nerve microvascular endoneurial endothelial cells, similar to cells treated with activated unencapsulated lovastatin. Unilateral peri‐neural administration of lovastatin‐encapsulating PLGA nanoparticles, but not empty nanoparticles, to naïve Lewis rats similarly enhanced RhoB mRNA content in adjacent nerve and muscle tissue. When administered in this manner, serum levels of lovastatin were below the level of detection. Bilateral peri‐neural administration of lovastatin‐encapsulating PLGA nanoparticles to EAN‐induced Lewis rats significantly attenuated EAN clinical severity while protecting against EAN‐induced peripheral nerve morphological and functional deficits. This study provides the first proof‐of‐concept approach for the application of a nanoparticle‐based local drug delivery platform for the management of inflammatory demyelinating diseases, including AIDP/GBS. Abstract : Statins attenuate disease severity in established animal models of inflammatory autoimmune disease. When applied clinically, however, phase trials evaluating statins for the treatment of inflammatory autoimmune disease have been disappointingly inconclusive. Nanotechnology‐based drug delivery represents a relatively new and innovative approach by which to administer therapeutic compounds exhibiting low bioavailability, high systemic toxicity, and/or poor water solubility in a controlled and sustained manner. In this study, polymers of poly(lactic co‐glycolic) acid (PLGA) were used to form injectable, biodegradable nanoparticles encapsulating lovastatin. A one‐time, non‐surgical, peri‐neural administration of lovastatin‐loaded nanoparticles significantly attenuated the clinical development of experimental autoimmune neuritis (EAN), a well‐established animal model of AIDP/GBS (see graph). This study provides the first proof‐of‐concept approach for the application of a nanoparticle‐based local drug delivery platform for the management of inflammatory demyelinating diseases, including AIDP/G BS.