The reaction of gold reagents [HAuCl 4 •3H 2 O], [AuCl(tht)], or cyclometalated gold(III) precursor, [C^NAuCl 2 ] with chiral ((R,R)-(-)-2,3-bis(t-butylmethylphosphino) quinoxaline) and non-chiral phosphine (1,2-Bis(diphenylphosphino)ethane, dppe) ligands lead to distorted Au(I), ( 1 , 2 , 4 , 5 ) and novel cyclometalated Au(III) complexes ( 3 , 6) . These gold compounds were characterized by multinuclear NMR, microanalysis, mass spectrometry, and X-ray crystallography. The inherent electrochemical properties of the gold complexes were also studied by cyclic voltammetry and theoretical insight of the complexes was gained by density functional theory and TD-DFT calculations. The complexes effectively kill cancer cells with IC 50 in the range of ~0.10–2.53 μΜ across K562, H460, and OVCAR8 cell lines. In addition, the retinal pigment epithelial cell line, RPE-Neo was used as a healthy cell line for comparison. Differential cellular uptake in cancer cells was observed for the compounds by measuring the intracellular accumulation of gold using ICP-OES. Furthermore, the compounds trigger early – late stage apoptosis through potential disruption of redox homeostasis. Complexes 1 and 3 induce predominant G1 cell cycle arrest. Results presented in this report suggest that stable gold-phosphine complexes with variable oxidation states hold promise in anticancer drug discovery and need further development.

Traumatic brain injury (TBI) is a large-scale public health problem. Mild TBI is the most prevalent form of neurotrauma and accounts for a large number of medical visits in the United States. There are currently no FDA-approved treatments available for TBI. The increased incidence of militaryrelated, blast-induced TBI further accentuates the urgent need for effective TBI treatments. Therefore, new preclinical TBI animal models that recapitulate aspects of human blast-related TBI will greatly advance the research efforts into the neurobiological and pathophysiological processes underlying mild to moderate TBI as well as the development of novel therapeutic strategies for TBI. Here we present a reliable, reproducible model for the investigation of the molecular, cellular, and behavioral effects of mild to moderate blast-induced TBI. We describe a step-by-step protocol for closed-head, blast-induced mild TBI in rodents using a bench-top setup consisting of a gasdriven shock tube equipped with piezoelectric pressure sensors to ensure consistent test conditions. The benefits of the setup that we have established are its relative low-cost, ease of installation, ease of use and high-throughput capacity. Further advantages of this non-invasive TBI model include the scalability of the blast peak overpressure and the generation of controlled reproducible outcomes. The reproducibility and relevance of this TBI model has been evaluated in a number of downstream applications, including neurobiological, neuropathological, neurophysiological and behavioral analyses, supporting the use of this model for the characterization of processes underlying the etiology of mild to moderate TBI.

Traumatic brain injury (TBI) in various forms affects millions in the United States annually. There are currently no FDA-approved therapies for acute injury or the chronic comorbidities associated with TBI. Acute phases of TBI are characterized by profound neuroinflammation, a process that stimulates the generation and release of proinflammatory cytokines including interleukin-1α (IL-1α) and IL-1β. Both forms of IL-1 initiate signaling by binding with IL-1 receptor type 1 (IL-1R1), a receptor with a natural, endogenous antagonist dubbed IL-1 receptor antagonist (IL-1Ra). The recombinant form of IL-1Ra has gained FDA approval for inflammatory conditions such as rheumatoid arthritis, prompting interest in repurposing these pharmacotherapies for other inflammatory diseases/injury states including TBI. This review summarizes the currently available preclinical and clinical literature regarding the therapeutic potential of inhibiting IL-1-mediated signaling in the context of TBI. Additionally, we propose specific research areas that would provide a greater understanding of the role of IL-1 signaling in TBI and how these data may be beneficial for the development of IL-1-targeted therapies, ushering in the first FDA-approved pharmacotherapy for acute TBI.

Traumatic brain injury (TBI) is a large-scale public health problem. Mild TBI is the most prevalent form of neurotrauma and accounts for a large number of medical visits in the United States. There are currently no FDA-approved treatments available for TBI. The increased incidence of militaryrelated, blast-induced TBI further accentuates the urgent need for effective TBI treatments. Therefore, new preclinical TBI animal models that recapitulate aspects of human blast-related TBI will greatly advance the research efforts into the neurobiological and pathophysiological processes underlying mild to moderate TBI as well as the development of novel therapeutic strategies for TBI. Here we present a reliable, reproducible model for the investigation of the molecular, cellular, and behavioral effects of mild to moderate blast-induced TBI. We describe a step-by-step protocol for closed-head, blast-induced mild TBI in rodents using a bench-top setup consisting of a gasdriven shock tube equipped with piezoelectric pressure sensors to ensure consistent test conditions. The benefits of the setup that we have established are its relative low-cost, ease of installation, ease of use and high-throughput capacity. Further advantages of this non-invasive TBI model include the scalability of the blast peak overpressure and the generation of controlled reproducible outcomes. The reproducibility and relevance of this TBI model has been evaluated in a number of downstream applications, including neurobiological, neuropathological, neurophysiological and behavioral analyses, supporting the use of this model for the characterization of processes underlying the etiology of mild to moderate TBI.

Traumatic brain injury (TBI) is a leading cause of mortality and morbidity. In the United States alone, TBI accounts for 2.8 million emergency department visits and an economic cost of nearly $80 billion annually. The lack of any FDA‐approved therapies for treatment of acute or chronic symptoms of TBI necessitates the identification and characterization of novel drug targets. TBI often results in the generation of neuropsychiatric disorders including major depressive disorder (MDD), anxiety, aggression, and social withdrawal within the first 12 months following injury, disorders linked to altered serotonin (5‐HT) signaling. Currently, the effects of TBI on physiologic function of the 5‐HT signaling system within the CNS are poorly understood. We hypothesize that TBI drives the formation of aberrant behavioral states linked to neuropsychiatric disorders through alterations of normal, physiologic 5‐HT signaling. To test this hypothesis, adult, wild type C57Bl/6J mice were subjected to a single, blast‐induced TBI or sham treatment, followed by behavioral and/or molecular analyses 0–30 days post‐injury (dpi). High performance liquid chromatography (HPLC) revealed a time‐dependent increase and subsequent decrease in total 5‐HT and 5HIAA levels within the dorsal raphe nucleus (DRN) 10 and 30 dpi, respectively. No effect of TBI on 5‐HT levels was found in prefrontal cortex (PFC) or somatosensory cortex (SSC), areas of high 5‐HT innervation. Using the tube test for social dominance, time‐dependent alterations in DRN 5‐HT levels were found to correlate with altered social dominance behavior. TBI resulted in decreased social dominance/aversion 10 dpi, but an increase in dominance behavior 30 dpi. Using the Crawley Three Chamber Sociability Assay, TBI‐induced decreases in sociability were observed 10 dpi, an effect not present at 30 dpi. To investigate alterations in 5‐HT receptor pharmacology associated with TBI, 5‐HT2A receptor sensitivity was determined using DOI‐induced head twitch response (HTR) assays. TBI rapidly increased 5‐HT2A receptor sensitivity, effects persisting for 10 dpi. TBI‐elicited increases in DOI‐induced HTR were attenuated by administration of the 5‐HT2A antagonist M100907, indicating a dependence on intact 5‐HT2A receptor signaling. [3H]Ketanserin receptor binding studies revealed an increase in cortical 5‐HT2A receptor binding at 3 and 10 dpi. Collectively, these data provide evidence that TBI elicits time‐dependent alterations in the 5‐HT architecture of the CNS, effects that coincide with altered social function. A more thorough understanding of specifically how neurotrauma alters 5‐HT signaling will allow for the informed clinical utilization of available 5‐HT‐oriented pharmacotherapies and may provide drug discovery targets for TBI‐elicited neuropsychiatric sequelae. Support or Funding Information Studies were supported by the Brain & Behavior Research Foundation, PhRMA Foundation, and the University of Cincinnati

With the evolution of modern warfare and the increased use of improvised explosive devices (IEDs), there has been an increase in blast-induced traumatic brain injuries (bTBI) among military personnel and civilians. The increased prevalence of bTBI necessitates bTBI models that result in a properly scaled injury for the model organism being used. The primary laboratory model for bTBI is the shock tube, wherein a compressed gas ruptures a thin membrane, generating a shockwave. To generate a shock wave that is properly scaled from human to rodent subjects the shock wave must have a short duration and high peak overpressure while fitting a Friedlander waveform, the ideal representation of a blast wave. A large variety of factors have been experimentally characterized in attempts to create an ideal waveform, however we found current research on the gas composition being used to drive shock wave formation to be lacking. To better understand the effect the driver gas has on the waveform being produced, we utilized a previously established murine shock tube bTBI model in conjunction with several distinct driver gasses. In agreement with previous findings, helium produced a shock wave most closely fitting the Friedlander waveform in contrast to the plateau-like waveforms produced by some other gases. The peak pressure at the exit of the shock tube and 5 cm from the exit have a strong negative correlation with the density of the gas being used: helium the least dense gas used produces the highest peak overpressure. Density of the driver gas also exerts a strong positive effect on the duration of the shock wave, with helium producing the shortest duration wave. Due to its ability to produce a Friedlander waveform and produce a waveform following proper injury scaling guidelines, helium is an ideal gas for use in shock tube models for bTBI.

The monoamine neurotransmitter serotonin (5-HT) is important for the regulation of behavior, and aberrations in 5-HT signaling are linked to several neuropsychiatric and neurodevelopmental disorders. 5-HT signaling is dependent on and tightly regulated by the functional activity of the 5-HT transporter (SERT). Neurotrauma is known to structurally and functionally impact 5-HT neuronal tracts and 5-HT signaling; however, the extent to which various forms of neurotrauma alter homeostatic 5-HT signaling through the modulation of SERT expression and/or functional uptake capacity is currently not well characterized. We aimed to better characterize the protein expression and uptake activity of SERT following mild traumatic brain injury (mTBI). A murine model of blast-induced mTBI was utilized to characterize alterations in SERT expression and function following injury. mTBI was found to decrease (≈26%) the protein levels of SERT 3 days postinjury (DPI) in the dorsal raphe nucleus (DRN), the primary locale of 5-HT neuronal cell bodies within the central nervous system. Concomitant reductions in midbrain SERT-dependent radiolabeled 5-HT uptake were observed 3 DPI (≈24%). No alterations in SERT expression were observed 10 DPI in the DRN. Additionally, no alterations in SERT expression or function were observed in prefrontal cortex samples at any time point observed. This data reveals time- and location-dependent alterations in SERT expression and function following mTBI. These studies illustrate the critical importance of ongoing research efforts to characterize the molecular effects of various forms of neurotrauma on SERT protein expression and function, which may yield novel drug targets within 5-HT systems.

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