Brain-derived neurotrophic factor delivered to the brain using poly (lactide-co-glycolide) nanoparticles improves neurological and cognitive outcome in mice with traumatic brain injury.
Currently, traumatic brain injury (TBI) is the leading cause of death or disabilities in young individuals worldwide. The multi-complexity of its pathogenesis as well as impermeability of the blood-brain barrier (BBB) makes the drug choice and delivery very challenging. The brain-derived neurotrophic factor (BDNF) regulates neuronal plasticity, neuronal cell growth, proliferation, cell survival and long-term memory. However, its short half-life and low BBB permeability are the main hurdles to be an effective therapeutic for TBI. Poly (lactic-co-glycolic acid) (PLGA) nanoparticles coated by surfactant can enable the delivery of a variety of molecules across the BBB by receptor-mediated transcytosis. This study examines the ability of PLGA nanoparticles coated with poloxamer 188 (PX) to deliver BDNF into the brain and neuroprotective effects of BNDF in mice with TBI. C57bl/6 mice were subjected to weight-drop closed head injuries under anesthesia. Using enzyme-linked immunosorbent assay, we demonstrated that the intravenous (IV) injection of nanoparticle-bound BDNF coated by PX (NP-BDNF-PX) significantly increased BDNF levels in the brain of sham-operated mice (p < 0.001) and in both ipsi- (p < 0.001) and contralateral (p < 0.001) parts of brain in TBI mice compared to controls. This study also showed using the passive avoidance (PA) test, that IV injection of NP-BDNF-PX 3 h post-injury prolonged the latent time in mice with TBI thereby reversing cognitive deficits caused by brain trauma. Finally, neurological severity score test demonstrated that our compound efficiently reduced the scores at day 7 after the injury indicating the improvement of neurological deficit in animals with TBI. This study shows that PLGA nanoparticles coated with PX effectively delivered BDNF into the brain, and improved neurological and cognitive deficits in TBI mice, thereby providing a neuroprotective effect.
a Faculty of Medicine and Defence Health , National Defence University of Malaysia , Kuala Lumpur , Malaysia.
Igor
I
Khalin
b Scientific Centre for Expertise of Medical Application Products , Moscow , Russia.
Renad
R
Alyautdin
c iPROMISE, Non-Destructive Biomedical and Pharmaceutical Research Centre, Universiti Teknologi MARA , Selangor , Malaysia.
Tin Wui
TW
Wong
a Faculty of Medicine and Defence Health , National Defence University of Malaysia , Kuala Lumpur , Malaysia.
Justin
J
Gnanou
d Ophthalmic Microsurgery Department, International Medical Center Oftalmika , Kharkiv , Ukraine , and.
Ganna
G
Kocherga
e Institute of Pharmaceutical Technology, Goethe University , Frankfurt , Germany.
Jörg
J
Kreuter
D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000187:drug effects*; D000070642:Brain Injuries, Traumatic / Q000188:drug therapy*; D019208:Brain-Derived Neurotrophic Factor / Q000008:administration & dosage* / Q000737:chemistry; D003071:Cognition / Q000187:drug effects*; D006207:Half-Life; D019344:Lactic Acid / Q000737:chemistry*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000737:chemistry; D020442:Poloxamer / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D013501:Surface-Active Agents / Q000737:chemistry
D019208:Brain-Derived Neurotrophic Factor; D018696:Neuroprotective Agents; D013501:Surface-Active Agents; D020442:Poloxamer; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid
Blood–brain barrier; brain-derived neurotrophic factor; drug-delivery; nanoparticles; traumatic brain injury