ABSTRACT
Alzheimer's disease (AD) patients exhibit neuropathological features, such as amyloid-beta (Aß) plaques and neurogenic fibrillary tangles. These features are thought to play important pathogenic roles, including neuronal dysfunction and apoptosis in the disease progression. Herein, we systematically evaluated a previously reported dual-target isoquinoline inhibitor (9S) for cholinesterase and Aß aggregation in in vitro and in vivo models of AD. 9S exhibited neuroprotective effects in Aß-induced and PHF6-induced PC12 cell models as well as in an okadaic acid-induced SH-SY5Y cell model, which were due to attenuated neuronal apoptosis through modulations of GSK-3ß phosphorylation and reactive oxygen species. One-month administration of 9S to triple transgenic AD (3 × Tg-AD) female mice (aged 6 months) led to significant improvement in cognitive deficits. Whereas similar treatment regimens for older 3 × Tg-AD female mice (aged 10 months) showed negligible neuroprotective effects. These findings suggest the importance of therapeutic intervention at the early stage of the disease.
Subject(s)
Alzheimer Disease , Neuroblastoma , Neuroprotective Agents , Mice , Humans , Female , Animals , Alzheimer Disease/pathology , Mice, Transgenic , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Glycogen Synthase Kinase 3 beta , Neuroblastoma/drug therapy , Amyloid beta-Peptides , Isoquinolines/therapeutic use , Disease Models, Animal , Repressor ProteinsABSTRACT
Renal fibrosis is an inevitable outcome of all kinds of progressive chronic kidney disease (CKD). Recently, asiatic acid (AA), a triterpenoid compound from Chinese medicine Centella asiatica, has been found to attenuate renal fibrosis. In the current study, we explored the mechanisms underlying antifibrotic effect of AA on UUO model. SD rats and ICR mice were subjected to unilateral ureteral occlusion (UUO) surgery. Prior the surgery, rats were administered AA (10 mg·kg-1 per day, ig) for 7 days, whereas the mice received AA (15 mg·kg-1 per day, ig) for 3 days. UUO group displayed significant degree of renal dysfunction, interstitial fibrosis, oxidative stress, and activation of the TGF-ß/Smad and Wnt/ß-catenin signaling pathway in the kidney, these pathological changes were greatly ameliorated by pretreatment with AA. In addition, we found that co-treatment with GW9662, a selective PPAR-γ antagonist (1 mg·kg-1 per day, ip) for 7 days, abolished the protective effects of AA. We further revealed that AA pretreatment did not significantly change the expression levels of PPAR-γ in the kidney, but markedly increase the plasma levels of 15d-PGJ2, an endogenous ligand of PPAR-γ. In UUO mice, pretreatment with 15d-PGJ2 (24 µg·kg-1 per day, ip, for 7 days) produced similar protective effect as AA. Moreover, AA pretreatment upregulated the expression levels of active, nuclear-localized SREBP-1 (nSREBP-1), whereas fatostatin, a specific inhibitor of SREBP-1, decreased the expression of nSREBP-1, as well as the level of 15d-PGJ2. These results provide new insight into the antifibrotic mechanism of AA and endogenous metabolites might become a new clue for investigation of drug mechanism.
Subject(s)
Fibrosis/drug therapy , Kidney Diseases/drug therapy , PPAR gamma/metabolism , Pentacyclic Triterpenes/pharmacology , Prostaglandin D2/analogs & derivatives , Ureteral Obstruction/drug therapy , Administration, Oral , Anilides/pharmacology , Animals , Disease Models, Animal , Dose-Response Relationship, Drug , Fibrosis/metabolism , Fibrosis/pathology , Kidney Diseases/metabolism , Kidney Diseases/pathology , Ligands , Male , Mice , Mice, Inbred ICR , Molecular Structure , PPAR gamma/antagonists & inhibitors , Pentacyclic Triterpenes/administration & dosage , Pentacyclic Triterpenes/antagonists & inhibitors , Prostaglandin D2/administration & dosage , Prostaglandin D2/biosynthesis , Prostaglandin D2/blood , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Ureteral Obstruction/metabolism , Ureteral Obstruction/pathologyABSTRACT
Chronic kidney disease (CKD) has become a major public health problem worldwide and has a great impact on the quality of life of millions of people. Long-term obstructive uropathy is an important cause of CKD. We hypothesized diagnostic biomarkers for early stage obstructive nephropathy can be discovered by metabolomic profiling of biofluid. Unilateral ureteral occlusion (UUO) surgery was performed on rats to induce renal interstitial fibrosis. Sham-operated rats were used as controls. Plasma and urine metabolites were analyzed by UPLC-MS based metabolomic approach. Significant metabolic profiling separations were found between UUO rats and controls at different time points. 13 differential plasma metabolites and 14 differential urine metabolites were identified at the first postoperative day. The altered metabolic pathways included glycerophospholipid metabolism, tryptophan metabolism, glutamate metabolism and purine metabolism. We further identified a panel of five plasma biomarkers which offer good diagnostic performance (areas under the curve of 1.0 in the discovery set and validation set) for early diagnosis of obstructive nephropathy. These findings demonstrate that early stage obstructive nephropathy can be diagnosed in an animal model based on plasma metabolomics which is a powerful tool for characterizing metabolic disturbances. This method has strong potential for clinical translation.
