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IEEE Transactions on Neural Systems and... 2024Highly impaired individuals stand to benefit greatly from cutting-edge bionic technology, however concurrent functional deficits may complicate the adaptation of such...
Highly impaired individuals stand to benefit greatly from cutting-edge bionic technology, however concurrent functional deficits may complicate the adaptation of such technology. Here, we present a case in which a visually impaired individual with bilateral burn injury amputation was provided with a novel transradial neuromusculoskeletal prosthesis comprising skeletal attachment via osseointegration and implanted electrodes in nerves and muscles for control and sensory feedback. Difficulties maintaining implant hygiene and donning and doffing the prosthesis arose due to his contralateral amputation, ipsilateral eye loss, and contralateral impaired vision necessitating continuous adaptations to the electromechanical interface. Despite these setbacks, the participant still demonstrated improvements in functional outcomes and the ability to control the prosthesis in various limb positions using the implanted electrodes. Our results demonstrate the importance of a multidisciplinary, iterative, and patient-centered approach to making cutting-edge technology accessible to patients with high levels of impairment.
Topics: Humans; Bionics; Prosthesis Implantation; Artificial Limbs; Amputation, Surgical; Diazooxonorleucine
PubMed: 38363669
DOI: 10.1109/TNSRE.2024.3366530 -
Neuropsychopharmacology : Official... Mar 2019There are a number of clinically effective treatments for stress-associated psychiatric diseases, including major depressive disorder (MDD). Nonetheless, many patients...
There are a number of clinically effective treatments for stress-associated psychiatric diseases, including major depressive disorder (MDD). Nonetheless, many patients exhibit resistance to first-line interventions calling for novel interventions based on pathological mechanisms. Accumulating evidence implicates altered glutamate signaling in MDD pathophysiology, suggesting that modulation of glutamate signaling cascades may offer novel therapeutic potential. Here we report that JHU-083, our recently developed prodrug of the glutaminase inhibitor 6-diazo-5-oxo-L-norleucine (DON) ameliorates social avoidance and anhedonia-like behaviors in mice subjected to chronic social defeat stress (CSDS). JHU-083 normalized CSDS-induced increases in glutaminase activity specifically in microglia-enriched CD11b cells isolated from the prefrontal cortex and hippocampus. JHU-083 treatment also reverses the CSDS-induced inflammatory activation of CD11b cells. These results support the importance of altered glutamate signaling in the behavioral abnormalities observed in the CSDS model, and identify glutaminase in microglia-enriched CD11b cells as a pharmacotherapeutic target implicated in the pathophysiology of stress-associated psychiatric conditions such as MDD.
Topics: Animals; Behavior, Animal; CD11b Antigen; Depression; Diazooxonorleucine; Disease Models, Animal; Glutaminase; Hippocampus; Inflammation; Male; Mice; Mice, Inbred C57BL; Prefrontal Cortex; Prodrugs; Signal Transduction; Stress, Psychological
PubMed: 30127344
DOI: 10.1038/s41386-018-0177-7 -
Journal of Medicinal Chemistry Aug 2017Aberrant excitatory neurotransmission associated with overproduction of glutamate has been implicated in the development of HIV-associated neurocognitive disorders...
Aberrant excitatory neurotransmission associated with overproduction of glutamate has been implicated in the development of HIV-associated neurocognitive disorders (HAND). The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON, 14) attenuates glutamate synthesis in HIV-infected microglia/macrophages, offering therapeutic potential for HAND. We show that 14 prevents manifestation of spatial memory deficits in chimeric EcoHIV-infected mice, a model of HAND. 14 is not clinically available, however, because its development was hampered by peripheral toxicities. We describe the synthesis of several substituted N-(pivaloyloxy)alkoxy-carbonyl prodrugs of 14 designed to circulate inert in plasma and be taken up and biotransformed to 14 in the brain. The lead prodrug, isopropyl 6-diazo-5-oxo-2-(((phenyl(pivaloyloxy)methoxy)carbonyl)amino)hexanoate (13d), was stable in swine and human plasma but liberated 14 in swine brain homogenate. When dosed systemically in swine, 13d provided a 15-fold enhanced CSF-to-plasma ratio and a 9-fold enhanced brain-to-plasma ratio relative to 14, opening a possible clinical path for the treatment of HAND.
Topics: Aminocaproates; Animals; Azo Compounds; Blood; Brain; Diazooxonorleucine; Drug Stability; Female; Glutamic Acid; Glutaminase; HIV Infections; Humans; Male; Mice, Inbred C57BL; Neurocognitive Disorders; Nootropic Agents; Prodrugs; Swine; Viral Load
PubMed: 28759224
DOI: 10.1021/acs.jmedchem.7b00966 -
Analytical Biochemistry Apr 2015Glutamine is an abundant amino acid that plays pivotal roles in cell growth, cell metabolism, and neurotransmission. Dysregulation of glutamine-using pathways has been...
Glutamine is an abundant amino acid that plays pivotal roles in cell growth, cell metabolism, and neurotransmission. Dysregulation of glutamine-using pathways has been associated with pathological conditions such as cancer and neurodegenerative diseases. 6-Diazo-5-oxo-l-norleucine (DON) is a reactive glutamine analog that inhibits enzymes affecting glutamine metabolism such as glutaminase, 2-N-amidotransferase, l-asparaginase, and several enzymes involved in pyrimidine and purine de novo synthesis. As a result, DON is actively used in preclinical models of cancer and neurodegenerative disease. Moreover, there have been several clinical trials using DON to treat a variety of cancers. Considerations of dose and exposure are especially important with DON treatment due to its narrow therapeutic window and significant side effects. Consequently, a robust quantification bioassay is of interest. DON is a polar unstable molecule that has made quantification challenging. Here we report on the characterization of a bioanalytical method to quantify DON in tissue samples involving DON derivatization with 3 N HCl in butanol. The derivatized product is lipophilic and stable. Detection of this analyte by mass spectrometry is fast and specific and can be used to quantify DON in plasma and brain tissue with a limit of detection at the low nanomolar level.
Topics: 1-Butanol; Animals; Brain; Chlorine; Chromatography, High Pressure Liquid; Diazooxonorleucine; Esters; Male; Mice, Inbred C57BL; Reference Standards; Tandem Mass Spectrometry; Time Factors
PubMed: 25584882
DOI: 10.1016/j.ab.2015.01.001