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In vivo EPR pharmacokinetic evaluation of the redox status and the blood brain barrier permeability in the SOD1 G93A ALS rat model
- Source :
- Free Radical Biology and Medicine. 108:258-269
- Publication Year :
- 2017
- Publisher :
- Elsevier BV, 2017.
-
Abstract
- Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder affecting the motor pathways of the central nervous system. Although a number of pathophysiological mechanisms have been described in the disease, post mortem and animal model studies indicate blood-brain barrier (BBB) disruption and elevated production of reactive oxygen species as major contributors to disease pathology. In this study, the BBB permeability and the brain tissue redox status of the SOD1 G93A ALS rat model in the presymptomatic (preALS) and symptomatic (ALS) stages of the disease were investigated by in vivo EPR spectroscopy using three aminoxyl radicals with different cell membrane and BBB permeabilities, Tempol, 3-carbamoyl proxyl (3CP), and 3-carboxy proxyl (3CxP). Additionally, the redox status of the two brain regions previously implicated in disease pathology, brainstem and hippocampus, was investigated by spectrophotometric biochemical assays. The EPR results indicated that among the three spin probes, 3CP is the most suitable for reporting the intracellular redox status changes, as Tempol was reduced in vivo within minutes (t 1/2 =2.0±0.5 min), thus preventing reliable kinetic modeling, whereas 3CxP reduction kinetics gave divergent conclusions, most probably due to its membrane impermeability. It was observed that the reduction kinetics of 3CP in vivo, in the head of preALS and ALS SOD1 G93A rats was altered compared to the controls. Pharmacokinetic modeling of 3CP reduction in vivo, revealed elevated tissue distribution and tissue reduction rate constants indicating an altered brain tissue redox status, and possibly BBB disruption in these animals. The preALS and ALS brain tissue homogenates also showed increased nitrilation, superoxide production, lipid peroxidation and manganese superoxide dismutase activity, and a decreased copper-zinc superoxide dismutase activity. The present study highlights in vivo EPR spectroscopy as a reliable tool for the investigation of changes in BBB permeability and for the unprecedented in vivo monitoring of the brain tissue redox status, as early markers of ALS.
- Subjects :
- 0301 basic medicine
chemistry.chemical_classification
Reactive oxygen species
Superoxide
SOD1
Central nervous system
Pharmacology
medicine.disease
Blood–brain barrier
Biochemistry
3. Good health
Lipid peroxidation
03 medical and health sciences
chemistry.chemical_compound
030104 developmental biology
0302 clinical medicine
medicine.anatomical_structure
chemistry
In vivo
Physiology (medical)
medicine
Amyotrophic lateral sclerosis
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 08915849
- Volume :
- 108
- Database :
- OpenAIRE
- Journal :
- Free Radical Biology and Medicine
- Accession number :
- edsair.doi...........31e5dd72953b27ccc92ecc93b8cdc84e