Lipopolysaccharide Modified Liposomes for Amyotropic Lateral Sclerosis Therapy: Efficacy in SOD1 Mouse Model

Nicholas J. Wiley, A. B. Madhankumar, Ryan M. Mitchell, Elizabeth B. Neely, Elias Rizk, Gregory L. Douds, Zachary Simmons, James R. Connor

Department of Neurology, Pennsylvania State University College of Medicine/Milton S. Hershey Medical Center, Hershey, USA.
George M. Leader Family Laboratory, Department of Neurosurgery, Pennsylvania State University College of Medicine/Milton S. Hershey Medical Center, Hershey, USA.

DOI: 10.4236/anp.2012.13007                

Abstract

Activation of microglia is a histological feature observed in neurodegenerative diseases like ALS. The oral administration of minocycline has been demonstrated to have minimal neuroprotection ability in the animal models and is also associated with inadvertent toxicity due to non-specific oral absorption of the drug. Nonetheless, the drug itself shows promise in a number of disease models suggesting it could be effective if delivered optimally. Thus, we utilized LPS modified liposomes to target TLR4 receptor on the microglia in SOD1^G93A mice and compared its efficacy with non- targeted nanoliposomes. The in vitro results indicate that targeting the TLR4 receptor on microglia significantly increases (p < 0.01) the uptake of drug by 29% compared to non-targeted liposomes. In the SOD1^G93A mouse model of ALS, targeted and non-targeted minocycline treatment significantly increased (p < 0.05) latency to endpoint stages compared to control mice. Targeting liposomes to microglia significantly delayed disease progression. Both targeted and non-targeted liposomes administration in SOD1 mice resulted in decreased TNF-α secretion in activated BV-2 microglial cells as compared to activated cells receiving no treatment. The non-targeted liposomes had a greater effect than the targeted liposomes in reducing the levels of TNF-α released by the BV-2 cells. In SOD1^G93A mice, the non- targeted nanovesicles significantly increased the latency to rotarod failure and both targeted and non-targeted nanovesicles significantly delayed disease endpoints.

Keywords

Amyotrophic Lateral Sclerosis; Minocycline; Liposomes; Microglia; TLR4; Lipopolysaccharides

Conflicts of Interest

The authors declare no conflicts of interest.

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