Glutamate is the predominant excitatory neurotransmitter used by primary afferent synapses and neurons in the spinal cord dorsal horn. Glutamate and glutamate receptors are also located in areas of ...the brain, spinal cord and periphery that are involved in pain sensation and transmission. Not surprisingly, glutamate receptors have been an attractive target for new pain therapies. However, their widespread distribution and array of function has often resulted in drugs targeting these sites having undesirable side-effects. This chapter will review, in general terms, the current knowledge of glutamate and its effects at various glutamate receptors with regards to nociception. In addition, we will briefly review the glutamatergic drugs currently in use as treatments for pain, as well as known novel candidates in various stages of clinical trial. Lastly, we will summarize the data supporting a novel target for pain intervention by way of GCPII inhibition, which appears devoid of the side-effects associated with direct glutamate receptor antagonists and thus holds major promise for future therapy. GCPII (glutamate carboxypeptidase II) cleaves the prevalent neuropeptide NAAG into NAA and glutamate and there is widespread evidence and belief that targeting the glutamate derived from this enzymatic action may be a promising therapeutic route.
US pediatric transplant candidates have limited access to lung transplant due to the small number of donors within current geographic boundaries, leading to assertions that the current lung ...allocation system does not adequately serve pediatric patients. We hypothesized that broader geographic sharing of pediatric (adolescent, 12–17 years; child, <12 years) donor lungs would increase pediatric candidate access to transplant. We used the thoracic simulated allocation model to simulate broader geographic sharing. Simulation 1 used current allocation rules. Simulation 2 offered adolescent donor lungs across a wider geographic area to adolescents. Simulation 3 offered child donor lungs across a wider geographic area to adolescents. Simulation 4 combined simulations 2 and 3. Simulation 5 prioritized adolescent donor lungs to children across a wider geographic area. Simulation 4 resulted in 461 adolescent transplants per 100 patient‐years on the waiting list (range 417–542), compared with 206 (range 180–228) under current rules. Simulation 5 resulted in 388 adolescent transplants per 100 patient‐years on the waiting list (range 348–418) and likely increased transplant rates for children. Adult transplant rates, waitlist mortality, and 1‐year posttransplant mortality were not adversely affected. Broader geographic sharing of pediatric donor lungs may increase pediatric candidate access to lung transplant.
This study addresses the problem of US pediatric transplant candidates’ limited access to lung transplants and shows that broader geographic sharing of pediatric donor lungs can increase pediatric transplant rates without adversely impacting adult patients.
The reversibility of chemotherapy-induced peripheral neuropathy (CIPN), a disabling and potentially permanent side effect of microtubule-targeting agents (MTAs), is becoming an increasingly important ...issue as treatment outcomes improve. The molecular mechanisms regulating the variability in time to onset, severity, and time to recovery from CIPN between the common MTAs paclitaxel and eribulin are unknown. Previously (Benbow et al. in Neurotox Res 29:299–313,
2016
), we found that after 2 weeks of a maximum tolerated dose (MTD) in mice, paclitaxel treatment resulted in severe reductions in axon area density, higher frequency of myelin abnormalities, and increased numbers of Schwann cell nuclei in sciatic nerves. Biochemically, eribulin induced greater microtubule-stabilizing effects than paclitaxel. Here, we extended these comparative MTD studies to assess the recovery from these short-term effects of paclitaxel, eribulin, and a third MTA, ixabepilone, over the course of 6 months. Paclitaxel induced a persistent reduction in axon area density over the entire 6-month recovery period, unlike ixabepilone- or eribulin-treated animals. The abundance of myelin abnormalities rapidly declined after cessation of all drugs but recovered most slowly after paclitaxel treatment. Paclitaxel- and ixabepilone- but not eribulin-treated animals exhibited increased Schwann cell numbers during the recovery period. Tubulin composition and biochemistry rapidly returned from MTD-induced levels of α-tubulin, acetylated α-tubulin, and end-binding protein 1 to control levels following cessation of drug treatment. Taken together, sciatic nerve axons recovered more rapidly from morphological effects in eribulin- and ixabepilone-treated animals than in paclitaxel-treated animals and drug-induced increases in protein expression levels following paclitaxel and eribulin treatment were relatively transient.
Light- and photosensitizer-based antimicrobial photodynamic therapy (aPDI) is a very promising approach to control microbial infections. Other applications of aPDI are also being studied, for ...example, in water disinfection or food preservation. Because this technology is based on the use of light, the proper characterization of light sources is of prime importance. The aim of this study was to prepare and characterize three irradiation systems constructed for research purposes. These LED-based light sources produce visible light in the range of blue, green and red wavelengths. The efficacy and light distribution produced by the light sources were verified on a Staphylococcus aureus model sensitized with three photosensitizers: protoporphyrin IX diarginate, N-methylpyrrolidinium fullerene iodide (Full), and rose bengal. Antimicrobial blue light treatment was likewise investigated. The survival of bacterial cells after photoinactivation was determined for irradiance at three power densities. Based on the proper characterization of light emitted by each LED at each point of the illuminated area, a homogeneous distribution of light can be achieved, which is crucial for precise dosimetry.
Excitotoxic glutamate release occurs in several neurological disorders. One source is derived from the hydrolysis of the neuropeptide
N-acetyl aspartyl glutamate (NAAG) by glutamate carboxypeptidase ...II (GCPII, also known as NAALADase). Drugs that attenuate glutamate transmission have been shown to relieve neuropathic pain, however side effects have limited their clinical use. It appears that GCPII is exclusively recruited to provide a glutamate source in hyperglutamatergic, excitotoxic conditions and therefore would be devoid of such side effects. Here we report on the therapeutic effects of an orally bio-available GCP II inhibitor on established painful and sensory neuropathy in the spontaneously diabetic BB/Wor rat. It significantly improved hyperalgesia, nerve conduction velocity and underlying myelinated fiber atrophy. The data suggest that GCP II inhibition may provide a meaningful and effective approach to the treatment of painful diabetic neuropathy.
Aims/Hypothesis: Hyperglutamatergic activity induced by ischemia is believed to underlie neuronal damage in a variety of neurological disorders, including neuropathic pain. Since ischemia is believed ...to be a prominent mechanism involved in diabetic polyneuropathy (DPN), we investigated the effect of the glutamate carboxypeptidase II (GCPII, EC #3.4–17.21; previously termed NAALADase), an enzyme responsible for the hydrolysis of the neuropeptide NAAG to NAA and glutamate, on the development of DPN in type 1 diabetic BB/Wor rats.
Methods: Diabetic animals were treated with 10 mg/kg/day i.p. of the selective GCPII inhibitor GPI-5232 from onset of diabetes for 6 months. Hyperalgesia to thermal stimulation and nerve conduction velocity (NCV) were measured monthly. The effect on structural DPN was assessed by scoring of single, teased myelinated fibers, myelinated fiber morphometry and ultrastructural examination of C-fibers at 6 months.
Results: GCPII inhibition showed significant but partial effects on hyperalgesia (
p<0.001), nerve conduction slowing (
p<0.01) axonal and nodal structural changes (
p<0.001), small myelinated fiber atrophy, and degenerative changes of C-fibers.
Conclusions: GCPII inhibition has beneficial effects on hyperalgesia, nerve function, and structural degenerative changes in DPN, which are likely mediated by inhibition of ischemia-induced glutamate release.
1 Department of Anatomy and Neurobiology, Program in Neuroscience, University of Maryland School of Medicine, Baltimore 21201
2 Guilford Pharmaceuticals, Baltimore, Maryland 21224
Submitted 3 May ...2003;
accepted in final form 6 August 2003
We tested the hypothesis that endogenous N -acetylaspartylglutamate (NAAG) presynaptically inhibits glutamate release at mossy fiber-CA3 synapses. For this purpose, we made use of 2-(3-mercaptopropyl)pentanedioic acid (2-MPPA), an inhibitor of glutamate carboxypeptidase II GCP II; also known as N -acetylated alpha-linked acidic dipeptidase (NAALADase), the enzyme that hydrolyzes NAAG into N -acetylaspartate and glutamate. Application of 2-MPPA (120 µM) had no effect on intrinsic membrane properties of CA3 pyramidal neurons recorded in vitro in whole cell current- or voltage-clamp mode. Bath application of 10 µM 2-MPPA suppressed evoked excitatory postsynaptic current (EPSC) amplitudes. Attenuation of EPSC amplitudes was accompanied by a significant increase in paired-pulse facilitation (50-ms interpulse intervals), suggesting that a presynaptic mechanism is involved. The group II metabotropic glutamate receptor (mGluR) antagonist 2 S -2-amino-2-(1 S ,2 S -2-carboxycyclopropyl-1-yl)-3-(xanth-9-y l) propanoic acid (LY341495 ) prevented the 2-MPPA-dependent suppression of EPSC amplitudes. 2-MPPA reduced the frequencies of TTX-insensitive miniature EPSCs (mEPSC), without affecting their amplitudes, further supporting a presynaptic action for GCP II inhibition. 2-MPPA-induced reduction of mEPSC frequencies was prevented by LY341495 , reinforcing the role of presynaptic group II mGluR. Because GCP II inhibition is thought to increase NAAG levels, these results suggest that NAAG suppresses synaptic transmission at mossy fiber-CA3 synapses through presynaptic activation of group II mGluRs.
Address for reprint requests and other correspondence: A. Keller, Dept. Anatomy and Neurobiology, Univ. Maryland School of Medicine, 685 W. Baltimore St., Baltimore, MD 21201 (E-mail: akeller{at}umaryland.edu ).
Nearly two decades ago, Joe Coyle published a single-authored review with the provocative title, The Nagging Question of the Function of N-Acetylaspartylglutamate (Coyle, 1997). In this review, Coyle ...documented NAAG's localization to subpopulations of glutamatergic, cholinergic, GABAergic, and noradrenergic neurons, Ca(2+)-dependent release, mGlu3 receptor agonist and NMDA receptor antagonist activity, and cleavage by the glial enzyme glutamate carboxypeptidase II (GCPII). However, at the time of his review, NAAG's physiological function as a neurotransmitter remained elusive. Ironically his review was published months following the discovery of the first potent and selective GCPII inhibitor, 2-(phosphonomethyl)pentanedioc acid (2-PMPA) (Jackson et al., 1996). Over the ensuing decades, over a dozen independent laboratories used 2-PMPA and other GCPII inhibitors to elucidate two distinct neurotransmitter functions for NAAG. Under basal conditions, when GCPII activity is relatively low, intact NAAG dampens synaptic activity via presynaptic mGlu3 receptor activation and NMDA receptor blockade. However, under stimulated conditions, NAAG release and GCPII activity are enhanced resulting in excess glutamate generation, activating NMDA and other glutamate receptors, often pathologically. Diverse classes of GCPII inhibitors have been synthesized and shown to increase NAAG, decrease glutamate, and provide robust efficacy in many disease models wherein abnormal glutamatergic transmission is presumed pathogenic. In addition, over the past 20 years, basic questions regarding NAAG's synthesis, packaging into vesicles, and receptor selectivity profile have been eloquently elucidated. The purpose of this chapter is to summarize these advances and the promise of regulating NAAG metabolism through GCPII inhibition as a therapeutic strategy.
Advances in treating the injured neonatal brain have given rise to neuro-intensive care services for newborns. This study assessed the impact of one such service in a cohort of newborns treated with ...therapeutic hypothermia.
Our newborn neuro-intensive care service was started in November 2012. From January 2008 to October 2016, a cohort of 158 newborns was treated with therapeutic hypothermia, 29 before and 129 after the inception of the service. This study compared the outcomes of newborns treated by the service with those of newborns treated before. Multivariate regression analysis associating length-of-stay and treatment pre- or post-service was adjusted for five-minute Apgar score, time-to-target temperature, seizures, and mortality.
The neuro-intensive care service was also associated with a decrease in mortality (17% before service to 5.4% with the service, p = 0.03), though this association is likely multifactorial and reflects the application of therapeutic hypothermia to a wider variety of patients. However, the service was independently associated with decreased length-of-stay (mean 22 pre-service to 13 days with the service, p < 0.0005.)CONCLUSIONS:The service educated referring hospitals in recognizing therapeutic hypothermia candidates, which increased the number of treated newborns, and created a number of procedures to streamline the delivery of treatment. While the increasing number and variety of patients treated could spuriously reduce length-of-stay, length-of-stay was still significantly reduced after adjustment, providing evidence that neuro-intensive care services for newborns can improve hospital outcomes.
During the past 10 years, substantial progress has been made in the discovery and development of small molecule glutamate carboxypeptidase II (GCP II) inhibitors. These inhibitors have provided the ...necessary tools to investigate the physiological role of GCP II as well as the potential therapeutic benefits of its inhibition in neurological disorders of glutamatergic dysregulation. This review article details key GCP II inhibitors discovered in the last decade and important findings from preclinical and clinical studies.
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