NIDA Boosts Research and Development of Medical Devices for Substance use Disorder via the NIH Blueprint MedTech Initiative.

: Deaths from drug overdose have reached a crisis level, with more than 100,000 reported from April 2020 to April 2021. Novel approaches to address it are urgently needed. : National Institute on Drug Abuse (NIDA) is leading novel comprehensive efforts to develop safe and effective products that address the needs of the citizens affected by SUD.

The preclinical data forum network: A new ECNP initiative to improve data quality and robustness for (preclinical) neuroscience.

Current limitations impeding on data reproducibility are often poor statistical design, underpowered studies, lack of robust data, lack of methodological detail, biased reporting and lack of open data sharing, coupled with wrong research incentives. To improve data reproducibility, robustness and quality for brain disease research, a Preclinical Data Forum Network was formed under the umbrella of the European College of Neuropsychopharmacology (ECNP). The goal of this network, members of which met for the first time in October 2014, is to establish a forum to collaborate in precompetitive space, to exchange and develop best practices, and to bring together the members from academia, pharmaceutical industry, publishers, journal editors, funding organizations, public/private partnerships and non-profit advocacy organizations.

Hepatoprotection and lethality rescue by histone deacetylase inhibitor valproic acid in fatal hemorrhagic shock.

Background: Pharmacological histone deacetylase (HDAC) inhibitors, such as known anticonvulsant valproic acid (VPA), demonstrate cytoprotective effects and increase acetylation of nuclear histones, promoting transcriptional activation of deregulated genes. Therefore, we examined protective effects of VPA administration in lethal hemorrhage and analyzed the patterns of hepatic histone acetylation.

Methods: Male Wistar Kyoto rats were pretreated with VPA (n = 10) and 2-methyl-2-pentenoic acid (2M2P), structural VPA analog with limited HDAC inhibiting activity (2M2P; n = 8), at 300 mg/kg/dose, administered subcutaneously, 24 hour and immediately before lethal, if untreated, hemorrhage was induced by removing the 60% of total blood volume.

Impact of resuscitation strategies on the acetylation status of cardiac histones in a swine model of hemorrhage.

Background: Chromatin remodeling through histone acetylation is a key control mechanism in gene transcription. We have shown previously that fluid resuscitation in rodents is coupled with highly structured post-translational modifications of cardiac histones. The current experiment was performed to validate this concept in a clinically relevant large animal model of hemorrhage and resuscitation, and to correlate the changes in histone acetylation with altered expression of immediate-early response genes.

Histone deacetylase as therapeutic target in a rodent model of hemorrhagic shock: effect of different resuscitation strategies on lung and liver.

Background: DNA transcription is regulated in part by acetylation of nuclear histones, controlled by 2 groups of enzymes: histone deacetylases (HDAC) and histone acetyl transferases (HAT). We have shown previously that hemorrhage and resuscitation are associated with HDAC/HAT imbalance, which influences the acetylation status of cardiac histones. The goals of this study were to determine whether: (1) resuscitation after hemorrhage affects histone acetylation in a fluid- and organ-specific fashion; and (2) administration of HDAC inhibitors influences histone acetylation and subsequent gene expression.

Differential effect of resuscitation on Toll-like receptors in a model of hemorrhagic shock without a septic challenge.

Unlabelled: It has been shown that the inflammatory response and cellular damage after hemorrhagic shock are influenced by resuscitation strategies. Toll-like receptors (TLRs) play an important role in signal transduction in inflammatory conditions. However, alterations in TLR expression following hemorrhagic shock and resuscitation have not been well documented.

Characterization of the antinociceptive actions of bicifadine in models of acute, persistent, and chronic pain.

Bicifadine (1-p-tolyl-3-azabicyclo[3.1.0]hexane) inhibits monoamine neurotransmitter uptake by recombinant human transporters in vitro with a relative potency of norepinephrine > serotonin > dopamine (approximately 1:2:17).

Valproic acid prevents hemorrhage-associated lethality and affects the acetylation pattern of cardiac histones.

Pharmacological inhibitors of histone deacetylases (HDAC) demonstrate cytoprotective effects both in vitro and in vivo. In this study, we investigated whether valproic acid (VPA), a known mood stabilizer and anticonvulsant with HDAC-inhibiting activity, improves survival following otherwise lethal hemorrhage in rats. We found that preinsult injection of VPA (300 mg/kg, twice) prolonged the survival of severely hypotensive animals up to 5 times.

Identification of expression patterns associated with hemorrhage and resuscitation: integrated approach to data analysis.

Background: Although transcriptional profiling is a well-established technique, its application to systematic studying of various biological phenomena is still limited because of problems with high-volume data analysis and interpretation. This research project's objective was to create a comprehensive summary of changes in gene expression after hemorrhagic shock (HS), reliant and impartial of multiple variables, such as resuscitation treatments, organ analyzed, and time after impact.

Methods: Rat model of severe (40% total blood loss) HS was employed.

Cardiac histones are substrates of histone deacetylase activity in hemorrhagic shock and resuscitation.

Background: DNA transcription is regulated, in part, by acetylation of nuclear histones that are controlled by 2 groups of enzymes: histone deacetylases (HDAC) and histone acetyl transferases (HAT). Whether an imbalance in HDAC/HAT system plays a role in hemorrhage/resuscitation is unknown. The goals of this study were to determine whether hemorrhage results in deacetylation of cardiac histones and whether this can be corrected through the application of different resuscitation strategies or specific HDAC inhibitors.

Hepatic and pulmonary apoptosis after hemorrhagic shock in swine can be reduced through modifications of conventional Ringer's solution.

Background: Cytotoxic properties of racemic (D-,L-isomers) lactated Ringer's solution detected in vitro and in small animal experiments, have not been confirmed in large animal models. Our hypothesis was that in a clinically relevant large animal model of hemorrhage, resuscitation with racemic lactated Ringer's solution would induce cellular apoptosis, which can be attenuated by elimination of d-lactate.

Methods: Yorkshire swine (n = 49, weight 40-58 kg) were subjected to uncontrolled (iliac arterial and venous injuries) and controlled hemorrhage, totaling 40% of estimated blood volume.

Energy substrate-supplemented resuscitation affects brain monocarboxylate transporter levels and gliosis in a rat model of hemorrhagic shock.

Background: Monocarboxylate (MC)-supplemented resuscitation has been shown to attenuate cellular injury after hemorrhagic shock. However, little is known about its effect on the central nervous system. The brain can use MCs such as lactate, pyruvate, and beta-hydroxybutyrate as energy substrates.

Hepatic apoptosis after hemorrhagic shock in rats can be reduced through modifications of conventional Ringer's solution.

Background: Resuscitation with racemic lactated Ringer's solution induces cellular apoptosis. This study was conducted to determine if the elimination of D-lactate isomer would attenuate apoptosis in the liver, and to investigate the possible mechanisms.

Study Design: Sprague Dawley rats (n=30, 5 per group) were subjected to modified volume-controlled hemorrhage and randomized to the following groups: no hemorrhage (sham); no resuscitation (NR); resuscitation with racemic lactated Ringer's (DL-LR); L-isomer LR (L-LR); ketone (beta-hydroxybuturate) Ringer's (KR); or pyruvate Ringer's (PR).

Induction of profound hypothermia modulates the immune/inflammatory response in a swine model of lethal hemorrhage.

Unlabelled: Profound hypothermic arrest ("suspended animation") is a new strategy to improve outcome following uncontrolled lethal hemorrhage (ULH). However, the impact of this approach on the immune/inflammatory response is unknown. This experiment was conducted to test the influence of profound hypothermia on markers of immune/inflammatory system.

Profound hypothermia protects neurons and astrocytes, and preserves cognitive functions in a Swine model of lethal hemorrhage.

Background: Lethal injuries can be repaired under asanguineous hypothermic arrest (suspended animation) with excellent survival. This experiment was designed to test the impact of this strategy on neuronal and astroglial damage in a swine model of lethal hemorrhage. Furthermore, our goal was to correlate the histological changes in the brain with neurological outcome, and the levels of circulating brain specific markers.

Combat casualty care research: from bench to the battlefield.

Hemorrhagic shock is the leading cause of death in civilian and combat trauma. Effective hemorrhage control and better resuscitation strategies have the potential of saving lives. The Trauma Readiness and Research Institute for Surgery (TRRI-Surg) was established to address the core mission of the Uniformed Services University, "Learning to Care for Those in Harm's Way," by conducting research to improve the outcome of combat casualties.

Differential expression of extracellular matrix remodeling genes in rat model of hemorrhagic shock and resuscitation.

Background: Matrix metalloproteinases (MMPs) and their specific physiological inhibitors, tissue inhibitors of metalloproteinases (TIMPs), are thought to play an essential role in tissue repair, cell death and morphogenesis. We have previously discovered unexpected up-regulation of genes coding for multiple MMP/TIMP family members in a rat model of hemorrhagic shock and resuscitation. However, the effect of different resuscitation protocols at the level of protein expression and function remains unknown.

The rate of induction of hypothermic arrest determines the outcome in a Swine model of lethal hemorrhage.

Background: Lethal injuries can be surgically repaired under asanguineous hypothermic condition (suspended animation) with excellent outcome. However, the optimal rate for the induction of hypothermic metabolic arrest following uncontrolled lethal hemorrhage (ULH) is unknown.

Methods: ULH was induced in 32 female swine (80-120 lbs) by creating an iliac artery and vein injury, followed 30 minutes later by laceration of the descending thoracic aorta.

M2 muscarinic acetylcholine receptor knock-out mice show deficits in behavioral flexibility, working memory, and hippocampal plasticity.

Muscarinic acetylcholine receptors are known to play key roles in facilitating cognitive processes. However, the specific roles of the individual muscarinic receptor subtypes (M1-M5) in learning and memory are not well understood at present. In the present study, we used wild-type (M2+/+) and M2 receptor-deficient (M2-/-) mice to examine the potential role of M2 receptors in learning and memory and hippocampal synaptic plasticity.

D-lactate increases pulmonary apoptosis by restricting phosphorylation of bad and eNOS in a rat model of hemorrhagic shock.

Unlabelled: Resuscitation with racemic lactated Ringer's solution (containing equal amounts of D and L isomers of lactate) has been shown to induce pulmonary apoptosis. Substitution of DL-isomer lactate with ketone bodies (beta-hydroxybutyrate, BHB), sodium pyruvate, or L-isomer of lactate decrease this injury without changing the energy status of the tissues or the expression of apoptotic genes. These modified solutions however alter the function of apoptotic proteins through an unknown mechanism.