Development of Nano-Formulatıons Contaınıng Neuroprotectıve Actıve Ingredıent and Evaluatıon of Effıcıency in Perıpheral Nerve Injury Model

Abstract

HAIDAR Mohammad Karim, Development of Nano-formulations Containing Neuroprotective Active Ingredient and Evaluation of Efficiency in Peripheral Nerve Injury Model, Hacettepe University Graduate School of Health Sciences, Ph.D. Thesis in Department of Biopharmaceutics and Pharmacokinetics, Ankara, 2018. Peripheral nerve injury (PNI) is one of the common traumas. Causes of acquired peripheral neuropathy include physical injury, diseases or disorders, exposure to toxins etc. Depending on nature and severity of injury, several therapeutic methods have been proposed. Crush injury is the most common type (80% of PNI) of PNI and decompression is the only way for treatment. However, the outcome of this treatment method is not satisfactory. Therefore, accelerating the curative process by additional treatment is strongly required. The aim of this thesis is to develop a novel polymeric composite nanofiber which containing nanoparticles for dual and localized delivery of neuroprotective drugs for accelerating regeneration process of peripheral nerve injury. For this purpose, alpha lipoic acid (ALA) and atorvastatin calcium (ATR) were used as neuroprotective agents. At first step ATR loaded chitosan nanoparticles were prepared by Nano Spray drying method. At the second step, Nano Spray dryed ATR loaded chitosan nanoparticles were suspended into solution of poly lactic-co-glycolic acid (PLGA) and ALA. The resulting mixture was exposed to electrospinning and electrospun nanocomposites were collected for further study. After characterization of these formulations, regrading to composition of formulation, selected formulation was used subsequently and implanted into animal model of sciatic nerve trauma. Trauma was formed with the compression method in Sprague Dawley rats. The motor function and sensory tests in the post-surgery stage revealed significant improvement in the regeneration process of nerve injury in the treated animals. The ultrastructural examination of sciatic nerve tissues samples at different timepoints also implies that the number of normal myelinated axons were increased in the treatment groups. The determination of pro-inflammatory cytokines also supported the effectiveness of the developed formulation. As the conclusion of this study, we might state that ATR loaded chitosan nanoparticles that are embedded in ALA containing nanofibers could be promising drug delivery systems for neuroprotection after peripheral sciatic nerve injury, especially depending on the faster recovery within the first 15 days period after trauma.