title: Nanoparticle-mediated catalase delivery protects human neurons from oxidative stress.
abstract: Several neurodegenerative diseases and brain injury involve reactive oxygen species and implicate oxidative stress in disease mechanisms. Hydrogen peroxide (H2O2) formation due to mitochondrial superoxide leakage perpetuates oxidative stress in neuronal injury. Catalase, an H2O2-degrading enzyme, thus remains an important antioxidant therapy target. However, catalase therapy is restricted by its labile nature and inadequate delivery. Here, a nanotechnology approach was evaluated using catalase-loaded, poly(lactic co-glycolic acid) nanoparticles (NPs) in human neuronal protection against oxidative damage. This study showed highly efficient catalase encapsulation capable of retaining ~99% enzymatic activity. NPs released catalase rapidly, and antioxidant activity was sustained for over a month. NP uptake in human neurons was rapid and nontoxic. Although human neurons were highly sensitive to H2O2, NP-mediated catalase delivery successfully protected cultured neurons from H2O2-induced oxidative stress. Catalase-loaded NPs significantly reduced H2O2-induced protein oxidation, DNA damage, mitochondrial membrane transition pore opening and loss of cell membrane integrity and restored neuronal morphology, neurite network and microtubule-associated protein-2 levels. Further, catalase-loaded NPs improved neuronal recovery from H2O2 pre-exposure better than free catalase, suggesting possible applications in ameliorating stroke-relevant oxidative stress. Brain targeting of catalase-loaded NPs may find wide therapeutic applications for oxidative stress-associated acute and chronic neurodegenerative disorders.
authors.affiliation: Department of Cell Biology and Anatomy, University of North Texas Health Science Center, Fort Worth, TX, USA.
authors.forename: A
authors.initials: A
authors.lastname: Singhal
authors.forename: V B
authors.initials: VB
authors.lastname: Morris
authors.forename: V
authors.initials: V
authors.lastname: Labhasetwar
authors.forename: A
authors.initials: A
authors.lastname: Ghorpade
mesh_terms: D002374:Catalase / Q000008:administration & dosage / Q000378:metabolism*; D002478:Cells, Cultured; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D019344:Lactic Acid / Q000737:chemistry; D053758:Nanoparticles / Q000737:chemistry*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer
chemical_list: D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D006861:Hydrogen Peroxide; D002374:Catalase