title: BBB-Permeable, Neuroprotective, and Neurotrophic Polysaccharide, Midi-GAGR.
abstract: An enormous amount of efforts have been poured to find an effective therapeutic agent for the treatment of neurodegenerative diseases including Alzheimer's disease (AD). Among those, neurotrophic peptides that regenerate neuronal structures and increase neuron survival show a promise in slowing neurodegeneration. However, the short plasma half-life and poor blood-brain-barrier (BBB)-permeability of neurotrophic peptides limit their in vivo efficacy. Thus, an alternative neurotrophic agent that has longer plasma half-life and better BBB-permeability has been sought for. Based on the recent findings of neuroprotective polysaccharides, we searched for a BBB-permeable neuroprotective polysaccharide among natural polysaccharides that are approved for human use. Then, we discovered midi-GAGR, a BBB-permeable, long plasma half-life, strong neuroprotective and neurotrophic polysaccharide. Midi-GAGR is a 4.7kD cleavage product of low acyl gellan gum that is approved by FDA for human use. Midi-GAGR protected rodent cortical neurons not only from the pathological concentrations of co-/post-treated free reactive radicals and Aβ42 peptide but also from activated microglial cells. Moreover, midi-GAGR showed a good neurotrophic effect; it enhanced neurite outgrowth and increased phosphorylated cAMP-responsive element binding protein (pCREB) in the nuclei of primary cortical neurons. Furthermore, intra-nasally administered midi-GAGR penetrated the BBB and exerted its neurotrophic effect inside the brain for 24 h after one-time administration. Midi-GAGR appears to activate fibroblast growth factor receptor 1 (FGFR1) and its downstream neurotrophic signaling pathway for neuroprotection and CREB activation. Additionally, 14-day intranasal administration of midi-GAGR not only increased neuronal activity markers but also decreased hyperphosphorylated tau, a precursor of neurofibrillary tangle, in the brains of the AD mouse model, 3xTg-AD. Taken together, midi-GAGR with good BBB-permeability, long plasma half-life, and strong neuroprotective and neurotrophic effects has a great therapeutic potential for the treatment of neurodegenerative diseases, especially AD.
authors.affiliation: Department of Neurosciences, College of Medicine and Life Sciences, University of Toledo, Toledo, Ohio, United States of America.
authors.forename: Vishruti
authors.initials: V
authors.lastname: Makani
authors.affiliation: Department of Neurosciences, College of Medicine and Life Sciences, University of Toledo, Toledo, Ohio, United States of America.
authors.forename: Yong-Gil
authors.initials: YG
authors.lastname: Jang
authors.affiliation: Department of Neurosciences, College of Medicine and Life Sciences, University of Toledo, Toledo, Ohio, United States of America.
authors.forename: Kevin
authors.initials: K
authors.lastname: Christopher
authors.affiliation: Department of Neurosciences, College of Medicine and Life Sciences, University of Toledo, Toledo, Ohio, United States of America.
authors.forename: Wesley
authors.initials: W
authors.lastname: Judy
authors.affiliation: Department of Neurosciences, College of Medicine and Life Sciences, University of Toledo, Toledo, Ohio, United States of America.
authors.forename: Jacob
authors.initials: J
authors.lastname: Eckstein
authors.affiliation: Department of Pathology, College of Medicine and Life Sciences, University of Toledo, Toledo, Ohio, United States of America.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Hensley
authors.affiliation: Department of Neurosciences, College of Medicine and Life Sciences, University of Toledo, Toledo, Ohio, United States of America.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chiaia
authors.affiliation: Department of Chemical Engineering, College of Engineering, University of Toledo, Toledo, Ohio, United States of America.
authors.forename: Dong-Shik
authors.initials: DS
authors.lastname: Kim
authors.affiliation: Department of Neurosciences, College of Medicine and Life Sciences, University of Toledo, Toledo, Ohio, United States of America.
authors.forename: Joshua
authors.initials: J
authors.lastname: Park
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D002470:Cell Survival; D006801:Humans; D051379:Mice; D009410:Nerve Degeneration / Q000188:drug therapy / Q000473:pathology; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011134:Polysaccharides / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011135:Polysaccharides, Bacterial / Q000008:administration & dosage*
chemical_list: C000609620:Midi-GAGR; D018696:Neuroprotective Agents; D011134:Polysaccharides; D011135:Polysaccharides, Bacterial