scholarly journals Understanding the Mechanism of Action of NAI-112, a Lanthipeptide with Potent Antinociceptive Activity

Molecules ◽  
2021 ◽  
Vol 26 (22) ◽  
pp. 6764
Author(s):  
Arianna Tocchetti ◽  
Marianna Iorio ◽  
Zeeshan Hamid ◽  
Andrea Armirotti ◽  
Angelo Reggiani ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Phosphatidic Acid ◽  
Lysophosphatidic Acid ◽  
Antibacterial Activities ◽  
Pain Sensation ◽  
Pain Model ◽  
Lipid Ii ◽  
Pain Models ◽  
Resistant Mutants ◽  
Weak Antibacterial Activity

NAI-112, a glycosylated, labionine-containing lanthipeptide with weak antibacterial activity, has demonstrated analgesic activity in relevant mouse models of nociceptive and neuropathic pain. However, the mechanism(s) through which NAI-112 exerts its analgesic and antibacterial activities is not known. In this study, we analyzed changes in the spinal cord lipidome resulting from treatment with NAI-112 of naive and in-pain mice. Notably, NAI-112 led to an increase in phosphatidic acid levels in both no-pain and pain models and to a decrease in lysophosphatidic acid levels in the pain model only. We also showed that NAI-112 can form complexes with dipalmitoyl-phosphatidic acid and that Staphylococcus aureus can become resistant to NAI-112 through serial passages at sub-inhibitory concentrations of the compound. The resulting resistant mutants were phenotypically and genotypically related to vancomycin-insensitive S. aureus strains, suggesting that NAI-112 binds to the peptidoglycan intermediate lipid II. Altogether, our results suggest that NAI-112 binds to phosphate-containing lipids and blocks pain sensation by decreasing levels of lysophosphatidic acid in the TRPV1 pathway.

scholarly journals Massive Edema of the Lower Limbs in Patients after Spinal Cord Injury—One Picture, Different Diagnoses

2021 ◽  
Vol 18 (8) ◽  
pp. 4219
Author(s):  
Magdalena Mackiewicz-Milewska ◽  
Małgorzata Cisowska-Adamiak ◽  
Katarzyna Sakwińska ◽  
Iwona Szymkuć-Bukowska ◽  
Iwona Głowacka-Mrotek
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Heterotopic Ossification ◽  
Lower Limb ◽  
Bone Fractures ◽  
Lower Limbs ◽  
University Hospital ◽  
Pain Sensation ◽  
Vein Thrombosis ◽  
Cord Injury

Diagnosis of the cause of massive edema of the lower limbs in patients after spinal cord injury (SCI) can be difficult because of loss of pain sensation, commonly occurring in this group of patients. This paper reviews several different pathologies that can lead to lower-limb edema and the associated diagnostic difficulties. We present four cases of patients with massive edemas of lower limbs at different times after SCI undergoing treatment in the Department of Rehabilitation, University Hospital in Bydgoszcz, Poland. All patients had a lack of pain sensation in the lower limbs and significantly elevated levels of D-dimer. In two cases, deep vein thrombosis (DVT) and intramuscular hematomas (IHs) were diagnosed. IHs were probably a consequence of antithrombotic treatments implemented due to the occurrence of DVT. Heterotopic ossification (HO) was diagnosed in a third case, and, in another patient, who was hospitalized for the longest period after injury, we found humeral bone fractures. Heterotopic ossification, intramuscular haematomas, and bone fractures of the lower limb can mimic DVT. Careful observation of the edema evolution is recommended, as the onset of new symptoms may indicate a different cause of edema from that initially established.

scholarly journals Blockage of Lysophosphatidic Acid Signaling Improves Spinal Cord Injury Outcomes

2012 ◽  
Vol 181 (3) ◽  
pp. 978-992 ◽  
Author(s):  
Yona Goldshmit ◽  
Rosalia Matteo ◽  
Tamar Sztal ◽  
Felix Ellett ◽  
Frisca Frisca ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Lysophosphatidic Acid ◽  
Cord Injury ◽  
Injury Outcomes ◽  
Lysophosphatidic Acid Signaling

A Rat Chronic Pain Model of Spinal Cord Contusion Injury

2012 ◽  
pp. 195-203 ◽  
Author(s):  
Kelli Sharp ◽  
Amin Boroujerdi ◽  
Oswald Steward ◽  
Z. David Luo
Keyword(s):  
Spinal Cord ◽  
Chronic Pain ◽  
Pain Model ◽  
Contusion Injury ◽  
Spinal Cord Contusion

Growth factor-like phospholipids generated after corneal injury

1998 ◽  
Vol 274 (4) ◽  
pp. C1065-C1074 ◽  
Author(s):  
Károly Liliom ◽  
Zhiwei Guan ◽  
Jih-Lie Tseng ◽  
Dominic M. Desiderio ◽  
Gábor Tigyi ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Growth Factor ◽  
Phosphatidic Acid ◽  
Aqueous Humor ◽  
Lysophosphatidic Acid ◽  
Xenopus Oocyte ◽  
Two Dimensional ◽  
Corneal Injury ◽  
Rabbit Eye ◽  
Cellular Regeneration

The present study provides evidence that growth factor-like glycerophosphate mediators of the lysophosphatidic acid (LPA) family are present in the aqueous humor and the lacrimal gland fluid of the rabbit eye. By use of a combination of HPLC, two-dimensional TLC, mass spectrometry, and the Xenopus oocyte bioassay, the LPA-like phospholipids LPA, cyclic PA, alkenyl-glycerophosphate (GP), lysophosphatidylserine, and phosphatidic acid were detected as physiological constituents of the fluids bathing the cornea. Corneal injury resulted in an increased production of some of these mediators. Alkenyl-GP, a novel member of the LPA family, has been identified in postinjury aqueous humor, establishing that it is generated endogenously. LPA and its homologues were found to be mitogenic in freshly dissociated keratocytes from uninjured corneas. There appears to be a link between the occurrence of LPA responsiveness in keratocytes activated by injury and the increase in LPA-like activity in aqueous humor. These data suggest that LPA and its homologues are involved in maintaining the integrity of the normal cornea and in promoting cellular regeneration of the injured cornea.

scholarly journals Alteration of the lysophosphatidic acid and its precursor lysophosphatidylcholine levels in spinal cord stenosis: A study using a rat cauda equina compression model

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Baasanjav Uranbileg ◽  
Nobuko Ito ◽  
Makoto Kurano ◽  
Daisuke Saigusa ◽  
Ritsumi Saito ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Lysophosphatidic Acid ◽  
Mass Spectrometry Imaging ◽  
Cauda Equina ◽  
Motor Dysfunction ◽  
Lipid Mediator ◽  
Neurogenic Claudication ◽  
Imaging Analysis ◽  
Cauda Equina Compression ◽  
Tissue Damages

Abstract Cauda equina compression (CEC) is a major cause of neurogenic claudication and progresses to neuropathic pain (NP). A lipid mediator, lysophosphatidic acid (LPA), is known to induce NP via the LPA1 receptor. To know a possible mechanism of LPA production in neurogenic claudication, we determined the levels of LPA, lysophosphatidylcholine (LPC) and LPA-producing enzyme autotaxin (ATX), in the cerebrospinal fluid (CSF) and spinal cord (SC) using a CEC as a possible model of neurogenic claudication. Using silicon blocks within the lumbar epidural space, we developed a CEC model in rats with motor dysfunction. LPC and LPA levels in the CSF were significantly increased from day 1. Importantly, specific LPA species (16:0, 18:2, 20:4) were upregulated, which have been shown to produce by ATX detected in the CSF, without changes on its level. In SC, the LPC and LPA levels did not change, but mass spectrometry imaging analysis revealed that LPC was present in a region where the silicon blocks were inserted. These results propose a model for LPA production in SC and CSF upon neurogenic claudication that LPC produced locally by tissue damages is converted to LPA by ATX, which then leak out into the CSF.

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