RESUMEN
High glycine (GLY) levels have been suggested to induce neurotoxic effects in the central nervous system of patients with nonketotic hyperglycinemia (NKH). Since the mechanisms involved in the neuropathophysiology of NKH are not totally established, we evaluated the effect of a single intracerebroventricular administration of GLY on the content of proteins involved in neuronal damage and inflammatory response, as well as on the phosphorylation of the MAPK p38, ERK1/2, and JNK in rat striatum and cerebral cortex. We also examined glial fibrillary acidic protein (GFAP) staining, a marker of glial reactivity. The parameters were analyzed 30 min or 24 h after GLY administration. GLY decreased Tau phosphorylation in striatum and cerebral cortex 30 min and 24 h after its administration. On the other hand, synaptophysin levels were decreased in striatum at 30 min and in cerebral cortex at 24 h after GLY injection. GLY also decreased the phosphorylation of p38, ERK1/2, and JNK 30 min after its administration in both brain structures. Moreover, GLY-induced decrease of p38 phosphorylation in striatum was attenuated by N-methyl-D-aspartate receptor antagonist MK-801. In contrast, synuclein, NF-κB, iκB, inducible nitric oxide synthase and nitrotyrosine content, and GFAP immunostaining were not altered by GLY infusion. It may be presumed that the decreased phosphorylation of MAPK associated with alterations of markers of neuronal injury induced by GLY may contribute to the neurological dysfunction observed in NKH.
Asunto(s)
Encéfalo/patología , Glicina/administración & dosificación , Hiperglicinemia no Cetósica/patología , Hiperglicinemia no Cetósica/fisiopatología , Sistema de Señalización de MAP Quinasas , Neuronas/patología , Animales , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/enzimología , Cuerpo Estriado/patología , Cuerpo Estriado/fisiopatología , Maleato de Dizocilpina/farmacología , Proteína Ácida Fibrilar de la Glía/metabolismo , Proteínas I-kappa B/metabolismo , Inyecciones Intraventriculares , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , FN-kappa B/metabolismo , Neuronas/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Fosforilación/efectos de los fármacos , Ratas Wistar , Sinaptofisina/metabolismo , Tirosina/análogos & derivados , Tirosina/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Proteínas tau/metabolismoRESUMEN
The association of pulmonary hypertensive vascular disease with nonketotic hyperglycinemia is rare. We describe 5 infants diagnosed with nonketotic hyperglycinemia, in whom pulmonary hypertensive vascular disease was the main presenting feature, and who developed severe pulmonary edema in response to pulmonary vasodilators.
Asunto(s)
Hiperglicinemia no Cetósica/diagnóstico , Hipertensión Pulmonar/etiología , Edema Pulmonar/inducido químicamente , Vasodilatadores/efectos adversos , Femenino , Humanos , Hiperglicinemia no Cetósica/complicaciones , Hiperglicinemia no Cetósica/mortalidad , Hiperglicinemia no Cetósica/fisiopatología , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/patología , Hipertensión Pulmonar/fisiopatología , Lactante , Pulmón/patología , Masculino , Edema Pulmonar/diagnóstico por imagen , Edema Pulmonar/mortalidad , Radiografía , Insuficiencia Respiratoria/etiología , Estudios RetrospectivosRESUMEN
Patients affected by nonketotic hyperglycinemia (NKH) usually present severe neurological symptoms and suffer from acute episodes of intractable seizures with leukoencephalopathy. Although excitotoxicity seems to be involved in the brain damage of NKH, the mechanisms underlying the neuropathology of this disease are not fully established. The objective of the present study was to investigate the in vitro effects of glycine (GLY), that accumulate at high concentrations in the brain of patients affected by this disorder, on important parameters of oxidative stress, such as lipid peroxidation (thiobarbituric acid-reactive substances (TBA-RS) and chemiluminescence) and the most important non-enzymatic antioxidant defense reduced glutathione (GSH) in cerebral cortex from 30-day-old rats. GLY significantly increased TBA-RS and chemiluminescence values, indicating that this metabolite provokes lipid oxidative damage. Furthermore, the addition of high doses of the antioxidants melatonin, trolox (soluble vitamin E) and GSH fully prevented GLY-induced increase of lipid peroxidation, indicating that free radicals were involved in this effect. GLY also decreased GSH brain concentrations, which was totally blocked by melatonin treatment. Finally, GLY significantly reduced sulfhydryl group content from a commercial GSH solution, but did not oxidize reduced cytochrome C. Our data indicate that oxidative stress elicited in vitro by GLY may possibly contribute at least in part to the pathophysiology of the neurological dysfunction in NKH.