ABSTRACT
Alzheimer's disease (AD) is the most common proteinopathy, which is accompanied by a steady decrease in the patient's cognitive functions with a simultaneous accumulation of amyloid plaques in brain tissues. Amyloid plaques are extracellular aggregates of amyloid ß (Aß) and are associated with neuroinflammation and neurodegeneration. Unlike humans and all other mammals, rats and mice do not reproduce AD-like pathology because there are three amino acid substitutions in their Aß. Amyloid plaques form in the brains of transgenic mice with overexpression of human Aß, and such mice are therefore possible to use in biomedicine to model the key features of AD. The transgenic mouse line APPswe/PS1dE9 is widely used as an animal model to study the molecular mechanisms of AD. A study was made to characterize the APPswe/PS1dE9/Blg subline, which was obtained by crossing APPswe/PS1dE9 mice on a CH3 genetic background with C57Bl6/Chg mice. No difference in offspring's survival and fertility was observed in the subline compared to wild-type control mice. Histological analysis of the brain in the APPswe/PS1dE9/Blg line confirmed the main neuromorphological features of AD and showed that amyloid plaques progressively increase in number and size during aging. The APPswe/PS1dE9/Blg line was assumed to provide a convenient model for developing therapeutic strategies to slow down AD progression.
Subject(s)
Alzheimer Disease , Cerebral Amyloid Angiopathy , Mice , Humans , Rats , Animals , Alzheimer Disease/genetics , Alzheimer Disease/pathology , Mice, Transgenic , Amyloid beta-Peptides/genetics , Amyloid beta-Peptides/metabolism , Plaque, Amyloid/genetics , Cerebral Amyloid Angiopathy/genetics , Cerebral Amyloid Angiopathy/complications , Cerebral Amyloid Angiopathy/metabolism , Brain/metabolism , Disease Models, Animal , MammalsABSTRACT
Multimerin-1 (Mmrn-1) is a soluble protein, also known as elastin microfibril interfacer 4 (EMILIN-4), found in platelets and in the endothelium of blood vessels. Its function and role in pathology are still not fully understood. Genetic modifications in alpha-synuclein gene (Snca) locus that mapped 160 Kb apart from Mmrn-1 in mouse genome, could weigh with regulatory elements of Mmrn-1 gene. We have studied the Mmrn-1 expression in brain cortex of three mouse lines with Snca knock-out: B6(Cg)-Sncatm1.2Vlb/J, B6;129-Sncatm1Sud/J, and B6;129X1-Sncatm1Rosl/J. The 35-fold increase for Mmrn-1 mRNA level have been found in B6;129X1-Sncatm1Rosl/J mice that carry in their genome foreign sequences including bacterial gene neo and a strong promoter of a mouse phosphoglycerate kinase (Pgk1) oriented towards Mmrn-1 gene. This effect on regulatory elements of Mmrn-1 gene as a result of modifications in Snca locus should be taken into consideration when using B6;129X1-Sncatm1Rosl/J line, that is widely applied for study of neurodegeneration mechanisms.
Subject(s)
Blood Proteins/genetics , Brain/metabolism , Cell Adhesion Molecules/genetics , alpha-Synuclein/genetics , Animals , Gene Expression Regulation/genetics , Mice , Mice, KnockoutABSTRACT
We performed correction of endothelial dysfunction with phenol derivatives KUD-259 and KUD-974 containing heteroatomic and heterocyclic structures. Pharmacological activity of KUD-259 and KUD-974 surpassed that of L-norvaline, a non-selective arginase inhibitor.
Subject(s)
Arginase/antagonists & inhibitors , Phenol/chemistry , Thrombin/chemistry , Animals , Endothelium, Vascular/drug effects , Endothelium, Vascular/metabolism , Male , NG-Nitroarginine Methyl Ester/pharmacology , Nitric Oxide/pharmacology , Rats , Rats, Wistar , Signal Transduction/drug effects , Valine/analogs & derivatives , Valine/pharmacologyABSTRACT
The ADMA-like pre-eclampsia in pregnant rats was modeled by daily introduction of L-NAME in a dose of 25 mg/kg for 7 days. L-arginine (200 mg/kg) prevented the development of arterial hypertension and a decrease in placentary microcirculation and microalbuminuria. The possibility of using L-arginine for the prevention of competitive eNOS inhibition by ADMA is discussed.
Subject(s)
Arginine/administration & dosage , Endothelium/drug effects , Hypertension/prevention & control , Placenta/drug effects , Pre-Eclampsia/drug therapy , Albuminuria/prevention & control , Animals , Arginine/therapeutic use , Blood Pressure/drug effects , Endothelium/physiology , Female , Humans , Injections, Intraperitoneal , Microcirculation/drug effects , Microcirculation/physiology , NG-Nitroarginine Methyl Ester/administration & dosage , NG-Nitroarginine Methyl Ester/adverse effects , Nitric Oxide Synthase Type III/metabolism , Placenta/blood supply , Pre-Eclampsia/chemically induced , Pre-Eclampsia/metabolism , Pregnancy , RatsABSTRACT
L-arginine (200 mg/kg), vitamin B(6) (2 mg/kg), and folic acid (0.2 mg/kg) exert a protective effect on endothelial function in L-NAME-induced NO deficiency in male and pregnant female Wistar rats. Combined administration of these agents effectively prevented the development of endothelial dysfunction and L-NAME-induced preeclampsia.
Subject(s)
Arginine/pharmacology , Endothelium/physiopathology , Folic Acid/pharmacology , Nitric Oxide/deficiency , Placenta/blood supply , Vitamin B 6/pharmacology , Animals , Arginine/therapeutic use , Drug Therapy, Combination , Endothelium/drug effects , Endothelium/metabolism , Female , Folic Acid/therapeutic use , Male , Microcirculation/drug effects , NG-Nitroarginine Methyl Ester , Nitric Oxide Synthase Type III/metabolism , Placenta/drug effects , Placenta/metabolism , Pre-Eclampsia/chemically induced , Pre-Eclampsia/drug therapy , Pre-Eclampsia/metabolism , Pregnancy , Rats , Rats, Wistar , Vitamin B 6/therapeutic useABSTRACT
Intragastric methionine (3 g/kg daily for 7 days) elevates homocysteine concentration and increases the endothelial dysfunction coefficient. This protocol of methionine treatment is an adequate model of hyperhomocysteine-induced endothelial dysfunction and can be used for studies of the endothelio- and cardioprotective effects of drugs.
Subject(s)
Endothelium, Vascular/pathology , Hyperhomocysteinemia/physiopathology , Vascular Diseases/physiopathology , Animals , Endothelium, Vascular/drug effects , Hyperhomocysteinemia/complications , Hyperhomocysteinemia/drug therapy , Methionine/therapeutic use , Rats , Vascular Diseases/drug therapy , Vascular Diseases/etiologyABSTRACT
Experimental NO deficiency induced by L-NAME injection led to the development of arterial hypertension, endothelial dysfunction, and cardiomyocyte hypertrophy and reduced blood content of nitrates and nitrites. Impaza, NO donors, activators of NO-synthase, antioxidants, and antihypertensive preparations produced endothelium-protective effect of different degree.
