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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. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) causes long-lasting neurodegeneration and cognitive impairments; however, the underlying mechanisms of these processes are not fully understood. Acid-sensing ion channels 1a (ASIC1a) are voltage-gated Na+- and Ca2+-channels shown to be involved in neuronal cell death; however, their role for chronic post-traumatic brain damage is largely unknown. To address this issue, we used ASIC1a-deficient mice and investigated their outcome up to 6 months after TBI. ASIC1a-deficient mice and their wild-type (WT) littermates were subjected to controlled cortical impact (CCI) or sham surgery. Brain water content was analyzed 24 h and behavioral outcome up to 6 months after CCI. Lesion volume was assessed longitudinally by magnetic resonance imaging and 6 months after injury by histology. Brain water content was significantly reduced in ASIC1a–/– animals compared to WT controls. Over time, ASIC1a–/– mice showed significantly reduced lesion volume and reduced hippocampal damage. This translated into improved cognitive function and reduced depression-like behavior. Microglial activation was significantly reduced in ASIC1a–/– mice. In conclusion, ASIC1a deficiency resulted in reduced edema formation acutely after TBI and less brain damage, functional impairments, and neuroinflammation up to 6 months after injury. Hence, ASIC1a seems to be involved in chronic neurodegeneration after TBI. [ABSTRACT FROM AUTHOR]