ABSTRACT
Parkinson's disease (PD) is caused by dopaminergic cell death in the substantia nigra, leading to a reduced level of dopamine in the striatum. Oxidative stress is one of the causes of PD. Since symptomatic PD therapies are used, identification of compounds or proteins that inhibit oxidative stress-induced neuronal cell death is necessary. DJ-1 is a causative gene product of familial PD and plays a role in anti-oxidative stress reaction. We have identified various DJ-1-binding compounds, including compound-23, that restored neuronal cell death and locomotion defects observed in neurotoxin-induced PD models. In this study, wild-type and DJ-1-knockout mice were injected intraperitoneally with 1 mg/kg of compound-23 and then with 30 mg/kg of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at 1 h after injection. Five days after administration, the effects of compound-23 on MPTP-induced locomotion deficits, on dopaminergic cell death and on brain dopamine levels were analyzed by rotor rod tests, by staining cells with an anti-TH antibody and by an HPLC, respectively. The results showed that compound-23 inhibited MPTP-induced reduction of retention time on the rotor rod bar, neuronal cell death in the substantia nigra and striatum and dopamine content in wild-type mice but not in DJ-1-knockout mice, indicating a DJ-1-dependent effect of compound-23.
Subject(s)
Benzamides/pharmacology , Dopaminergic Neurons/drug effects , Dopaminergic Neurons/pathology , Neuroprotective Agents/pharmacology , Oncogene Proteins/physiology , Parkinson Disease/drug therapy , Parkinson Disease/genetics , Peroxiredoxins/physiology , Pyridines/pharmacology , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/pharmacology , Animals , Brain/metabolism , Cell Death/drug effects , Disease Models, Animal , Dopamine/metabolism , Mice, Inbred C57BL , Mice, Knockout , Neurotoxins/pharmacology , Oxidative Stress/genetics , Parkinson Disease/pathology , Protein Deglycase DJ-1 , Substantia Nigra/cytology , Substantia Nigra/pathologyABSTRACT
We investigated the effects of endogenous glucagon-like peptide-2 (GLP-2) on the development of intestinal mucosa in weanling rats. Three-week-old male weanling Sprague-Dawley rats were administered either anti-GLP-2 or normal rabbit serum every other day for 2 weeks. We then measured length, weight, and bromodeoxyuridine incorporation in the intestine on day 13 following the first injection. Administration of anti-GLP-2 serum significantly inhibited both epithelial proliferation in the distal ileum and elongation of the small intestine. These results suggest that intrinsic GLP-2 contributes to the growth of the small intestine during the weanling period.
Subject(s)
Glucagon-Like Peptide 2/metabolism , Ileum/growth & development , Immune Sera/pharmacology , Intestinal Mucosa/growth & development , Animals , Cell Proliferation/drug effects , Glucagon-Like Peptide 2/antagonists & inhibitors , Glucagon-Like Peptide 2/immunology , Ileum/cytology , Ileum/immunology , Ileum/metabolism , Immune Sera/immunology , Intestinal Mucosa/cytology , Intestinal Mucosa/immunology , Intestinal Mucosa/metabolism , Male , Rats , Rats, Sprague-Dawley , WeaningABSTRACT
We investigated whether bovine milk constituents influenced glucagon-like peptide (GLP)-2 secretion and intestinal growth in suckling rats. Male Sprague-Dawley rats (14 d old) received i.g. infusions of a milk protein fraction, a lactose solution, or the cream fraction of milk. The serum concentration of GLP-2, but not GLP-1, markedly increased in rats administered milk protein compared with those given the lactose solution or the cream fraction from 60 to 120 min after administration. In another experiment, both casein (CN) and whey protein isolate stimulated GLP-2 secretion at 120 min after administration, but soy protein and ovalbumin did not. Stimulation of GLP-2 secretion by several milk proteins was similar, including alpha-CN, alpha-lactalbumin (alpha-La), and beta-lactoglobulin, in a separate experiment. A hydrolysate of alpha-La obtained by incubation with protease A extracted from Aspergillus oryzae (LaHPA) caused almost twice the GLP-2 release due to intact alpha-La and other alpha-La hydrolysates. Free amino acid concentrations and molecular size distributions did not differ among alpha-La hydrolysates, including LaHPA. In rat pups reared with milk formulae containing alpha-La or LaHPA, LaHPA significantly promoted small intestinal elongation and increased the number of crypt epithelial cells compared with a formula containing intact alpha-La. LaHPA administration also increased the maltase:lactase activity ratio, a marker of maturation of the intestinal mucosa. In conclusion, milk proteins stimulate GLP-2 secretion and contribute to growth and maturation of the small intestine in suckling rats.
