title: Dendrimer-based postnatal therapy for neuroinflammation and cerebral palsy in a rabbit model.
abstract: Cerebral palsy (CP) is a chronic childhood disorder with no effective cure. Neuroinflammation, caused by activated microglia and astrocytes, plays a key role in the pathogenesis of CP and disorders such as Alzheimer's disease and multiple sclerosis. Targeting neuroinflammation can be a potent therapeutic strategy. However, delivering drugs across the blood-brain barrier to the target cells for treating diffuse brain injury is a major challenge. We show that systemically administered polyamidoamine dendrimers localize in activated microglia and astrocytes in the brain of newborn rabbits with CP, but not healthy controls. We further demonstrate that dendrimer-based N-acetyl-l-cysteine (NAC) therapy for brain injury suppresses neuroinflammation and leads to a marked improvement in motor function in the CP kits. The well-known and safe clinical profile for NAC, when combined with dendrimer-based targeting, provides opportunities for clinical translation in the treatment of neuroinflammatory disorders in humans. The effectiveness of the dendrimer-NAC treatment, administered in the postnatal period for a prenatal insult, suggests a window of opportunity for treatment of CP in humans after birth.
authors.affiliation: Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Detroit, MI 48201, USA. skannan3@jhmi.edu
authors.forename: Sujatha
authors.initials: S
authors.lastname: Kannan
authors.forename: Hui
authors.initials: H
authors.lastname: Dai
authors.forename: Raghavendra S
authors.initials: RS
authors.lastname: Navath
authors.forename: Bindu
authors.initials: B
authors.lastname: Balakrishnan
authors.forename: Amar
authors.initials: A
authors.lastname: Jyoti
authors.forename: James
authors.initials: J
authors.lastname: Janisse
authors.forename: Roberto
authors.initials: R
authors.lastname: Romero
authors.forename: Rangaramanujam M
authors.initials: RM
authors.lastname: Kannan
mesh_terms: D000111:Acetylcysteine / Q000627:therapeutic use; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002547:Cerebral Palsy / Q000188:drug therapy*; D050091:Dendrimers / Q000737:chemistry*; D011073:Polyamines / Q000737:chemistry; D011817:Rabbits
chemical_list: D050091:Dendrimers; C531249:Poly(amidoamine); D011073:Polyamines; D000111:Acetylcysteine