Gold nanoparticle-4-(4-aminophenyl)butyric acid ameliorates endoplasmic reticulum stress and improves outcomes after traumatic brain injury

Traumatic brain injury (TBI) remains a leading cause of morbidity and mortality in children. Dysregulation of endoplasmic reticulum (ER) stress and neuroinflammation following TBI contribute to abnormal protein accumulation, cell loss, and cognitive deficits. Histone deacetylase (HDAC) inhibitors exert rapid and reversible neuroprotective effects; however, poor brain bioavailability hinders their effectiveness. Here, we conjugated gold nanoparticle (GNP) with 4-(4-aminophenyl)butyric acid (4-APB; a HDAC inhibitor) (GNP-4-APB) with imaging tag, and evaluated GNP-4-APB brain bio-distribution and therapeutic efficacy in a juvenile mouse model of TBI. On postnatal day 20-21 (P20-21), male and female littermates were randomized into seven treatment groups: sham, TBI + saline, TBI+4-APB (high dose), TBI + GNP alone, TBI + GNP-4-APB (low, median, high doses). Mice in the TBI groups underwent TBI and received intraperitoneal injection of a single dose of therapeutic drugs at 6h (h) post-injury according to the designated treatment groups. Sham animals did not receive any intervention. Animals underwent behavioral testing at 24 h post-treatment and euthanized after behavioral testing. We found that GNP-4-APB crossed the blood-brain-barrier and localized with neurons and microglia at the site of injury. A single dose of GNP-4-APB (median and high doses) significantly improved sensorimotor functions, ameliorated ER stress, and decreased the levels of pro-inflammatory cytokines in a sex-dependent manner. Moreover, at the same dose, GNP-4-APB exhibited a significantly higher effectiveness, compared with the 4-APB free drug. In conclusion, GNP-4-APB targeted the neurons and microglia at the injured brain regions, exhibited significantly higher efficacy than free drug, and improved TBI outcomes in a sex-dependent manner.