RESUMEN
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.
Asunto(s)
Cauda Equina/patología , Lisofosfatidilcolinas/metabolismo , Lisofosfolípidos/metabolismo , Médula Espinal/patología , Animales , Constricción Patológica , Modelos Animales de Enfermedad , Femenino , Regulación de la Expresión Génica , Lisofosfatidilcolinas/sangre , Lisofosfatidilcolinas/líquido cefalorraquídeo , Lisofosfolípidos/sangre , Lisofosfolípidos/líquido cefalorraquídeo , Neuralgia/metabolismo , Neuralgia/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas Sprague-Dawley , Receptores del Ácido Lisofosfatídico/genética , Receptores del Ácido Lisofosfatídico/metabolismoRESUMEN
HIV infiltrates the CNS soon after an individual has become infected with the virus, and can cause dementia and encephalitis in late-stage disease. Here, a global metabolomics approach was used to find and identify metabolites differentially regulated in the cerebrospinal fluid (CSF) of rhesus macaques with SIV-induced CNS disease, as we hypothesized that this might provide biomarkers of virus-induced CNS damage. The screening platform used a non-targeted, mass-based metabolomics approach beginning with capillary reverse phase chromatography and electrospray ionization with accurate mass determination, followed by novel, nonlinear data alignment and online database screening to identify metabolites. CSF was compared before and after viral infection. Significant changes in the metabolome specific to SIV-induced encephalitis were observed. Metabolites that were increased during infection-induced encephalitis included carnitine, acyl-carnitines, fatty acids, and phospholipid molecules. The elevation in free fatty acids and lysophospholipids correlated with increased expression of specific phospholipases in the brains of animals with encephalitis. One of these, a phospholipase A2 isoenzyme, is capable of releasing a number of the fatty acids identified. It was expressed in different areas of the brain in conjunction with glial activation, rather than linked to regions of SIV infection and inflammation, indicating widespread alterations in infected brains. The identification of specific metabolites as well as mechanisms of their increase illustrates the potential of mass-based metabolomics to address problems in CNS biochemistry and neurovirology, as well as neurodegenerative diseases.
Asunto(s)
Sistema Nervioso Central/metabolismo , Fosfolipasas/genética , Síndrome de Inmunodeficiencia Adquirida del Simio/líquido cefalorraquídeo , Virus de la Inmunodeficiencia de los Simios , Animales , Carnitina/análogos & derivados , Carnitina/líquido cefalorraquídeo , Sistema Nervioso Central/enzimología , Sistema Nervioso Central/virología , Ácidos Grasos/líquido cefalorraquídeo , Regulación Enzimológica de la Expresión Génica , Fosfolipasas A2 Grupo IV/genética , Fosfolipasas A2 Grupo IV/metabolismo , Hipocampo/metabolismo , Hibridación in Situ , Lisofosfatidilcolinas/líquido cefalorraquídeo , Macaca mulatta , Fosfolipasas/metabolismo , Fosfolipasas A1/genética , Fosfolipasas A1/metabolismo , Síndrome de Inmunodeficiencia Adquirida del Simio/metabolismo , Espectrometría de Masa por Ionización de Electrospray , Regulación hacia Arriba/genéticaRESUMEN
Choline containing phospholipids are essential for the integrity of the'cell'membrane. Minor changes in the lysophosphatidylcholine (lyso-PC)/phosphatidylcholine (PC) ratio may lead to neuronal damage and cell loss. Several studies have shown protein and lipid oxidation in Alzheimer's disease (AD) affected brain regions. Amyloid-beta peptides may induce free-radical oxidative stress which normally is counteracted by anti-oxidant defense mechanisms. We hypothesize that oxidation may lead to changed concentrations of choline containing phospholipids in cerebrospinal fluid (CSF) of AD patients, because of the susceptibility of the unsaturated acyl-chains of PC for oxidation. PC and lyso-PC were determined in CSF of AD patients (n=19) and subjects with subjective memory complaints without dementia (n=19) by tandem mass spectrometry. No differences in total PC concentrations were observed between both study groups. Furthermore, we could not demonstrate different concentrations of PC species containing linoleic acid and PC species containing arachidonic acid. Interestingly, lyso-PC concentrations tended to be lower while the lyso-PC/PC ratio was significantly decreased in CSF of AD patients compared to controls (0.36% versus 0.54%; P=0.017). A comparable decrease was found for the lyso-PC/PC ratio for PC containing linoleic acid (P=0.022) or arachidonic acid (P=0.010), respectively. The lower lyso-PC/PC ratio in CSF of patients with AD may reflect alterations in the metabolism of choline-containing phospholipids in the brain in AD, and suggests that PC species containing linoleic acid or arachidonic acid are equally involved.