PRECLINICAL DEVELOPMENT OF A CURCUMIN-LOADED NANOPARTICLE FOR THE TREATMENT OF CMT1A DISEASE

Abstract

CMT type 1A is the most prevalent form of Charcot-Marie-Tooth disease and is characterized by a duplication of the PMP22 gene, leading to peripheral demyelination and ultimate sensorimotor loss. Pathological alterations in oxidative, ER stress and inflammation were reported as common features in CMT patients. Curcumin, which associates with a wide range of biological properties including antioxidant and anti-inflammatory activities, has shown beneficial effects on peripheral nerve function in several types of neuropathies. However, this compound presents with unfavorable pharmacokinetics. For this purpose, we have developed curcumin loaded cyclodextrin/cellulose nanocrystals (NanoCur) to bypass this limitation. In our current study, we aim to assess the effect of NanoCur treatment in CMT1A rodent models and compare its efficacy to Theracurmin, a commercially available curcumin formulation. In addition, an elaboration on the potential toxicity and the mechanism of action of the compound are sought. For that, daily injections of low doses of NanoCur were administered intraperitoneally for rats and mice for 12 weeks and 8 weeks, respectively. Neuropathy was assessed through nerve conduction velocity (NCV), Catwalk gait analysis, Beam Balance, Grip strength and Rotarod. Biochemical and histological analyses related to myelin phenotype and markers of inflammation, oxidative and ER stress were also performed on the sciatic nerves of the different experimental groups using electron microscopy, histochemistry, western blot and qPCR. Our results show an improved motor function in the CMT1A rats, associated with an improvement in the myelin phenotype within the nerve. Furthermore, NanoCur treatment appears to perform its effect through concomitant alleviation of oxidative, ER and inflammatory pathways. All of this is combined with no apparent systemic toxicity of the compound. To our interest, these effects are not significant upon treatment with a similar dose of Theracurmin. Therefore, NanoCur significantly associates with therapeutic benefits at the cellular and functional levels in CMT1A with minimal systemic toxicity, promoting it as a potential therapeutic candidate for CMT1A disease and, possibly, other forms of neuropathies.