Inhibition of gluconeogenesis and α-keto oxidation by 5-methoxyindole-2-carboxylic acid

Bauman, Norman; Hill, Colin

doi:10.1021/bi00844a011

Cited by 41 publications

(31 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Addition of CaI also reversed the protective effects of dld-1 gene suppression as well as DLD-1 enzyme inhibition by MICA [499,503]. CaI is believed to interfere with MICA by increasing intracellular calcium levels [486,499]. Impaired calcium homeostasis in aging brains and neurodegenerative disorders is well documented where increased levels of calcium accelerate Aβ toxicity [473,504,505].…”

Section: Discussionmentioning

confidence: 99%

“…As both AD and diabetes share many pathological features [1,51], it is possible that drugs used to lower hyperglycemia might be effective in AD treatment. MICA is a hypoglycemic agent that has been suggested as possible drug to treat T2DM [482][483][484][485][486]. MICA modifies cellular glucose levels by altering glucose metabolism but not insulin sensitivity as MICA was unable to induce glucose or galactose uptake by liver, pancreas or diaphragm peripheral tissues of the mouse [482,487,488].…”

Section: Introductionmentioning

confidence: 99%

“…Meanwhile, MICA also inhibits the carboxylation of pyruvate thus reducing glucose production from non-carbohydrate carbon sources [486,488]. MICA was found to suppress the substrate-driven decrease of α-lipoate, a cofactor in the keto acid catabolizing, DLD-1 containing enzyme complexes.…”

Section: Introductionmentioning

confidence: 99%

“…MICA was found to suppress the substrate-driven decrease of α-lipoate, a cofactor in the keto acid catabolizing, DLD-1 containing enzyme complexes. This was reflected in reduced DLD enzymatic activity in mitochondria [486,489]. The inhibitory effects of MICA could be reversed in vitro by the addition of lipoic acid in the media [486] or by increasing intracellular calcium levels using the calcium ionophore A23187 (CaI) [490,491].…”

Section: Introductionmentioning

confidence: 99%

“…This was reflected in reduced DLD enzymatic activity in mitochondria [486,489]. The inhibitory effects of MICA could be reversed in vitro by the addition of lipoic acid in the media [486] or by increasing intracellular calcium levels using the calcium ionophore A23187 (CaI) [490,491]. Although the exact mechanism in not known CaI was found to induce the levels of lactate dehydrogenase (LDH) [492,493] that ultimately increase pyruvate production from lactic acid thus induce downstream energy metabolism.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Metabolic study of Alzheimer’s disease using mutant C. elegans

Ahmad¹

View full text Add to dashboard Cite

Alzheimer's disease (AD) is associated with chronic neurodegeneration and is the cause of the most common form of dementia. The main hallmarks of AD are aggregates of amyloid beta (Aβ) and formation of hyperphosphorylated tau neurofibrillary tangles (NFTs). Unfortunately, after more than 100 years of research the exact cause(s) and mechanisms involved in AD progression remain unclarified. Evidence indicates that impaired mitochondrial bioenergetics may precede by decades, the neurodegeneration and cognitive decline associated with AD. Moreover, a genetic association of the core metabolic enzyme dihydrolipoamide dehydrogenase (DLD) with late-onset AD and reduced activity of DLD-containing enzymes suggests glucose hypo-metabolism as a possible cause of AD. Contrary to this, improvements of AD symptoms under caloric restriction or other means of reducing-glucose dependent energy metabolism supports an alternative hypothesis that a decrease in glucose metabolism may be protective. In the present study, we used mutant Caenorhabditis elegans (C. elegans) to investigate the effect of glucose metabolism on AD progression. We initially looked at the role of suppressed DLD-1, and then we focused on the effect of high glucose in AD pathogenesis.Transgenic expression of Aβ in C. elegans causes both phenotypic and behavioral defects and results in accumulation of toxic Aβ oligomers, culminating in protein aggregation as is normally associated with AD pathophysiology. Aβ expression in worm muscle causes agedependent progressive paralysis and impaired acetylcholine neurotransmission while neuronal Aβ expression results in defective chemotaxis and impaired serotonin sensitivity as well as reduced fecundity and egg hatching. Suppression of the dld-1 gene alleviated paralysis, improved acetylcholine neurotransmission, enhanced chemotaxis and restored normal sensitivity to serotonin.dld-1 gene suppression also protects vitality as indicated by improved fecundity and egg hatching.Interestingly, protective effects of dld-1 suppression could be reversed using the calcium ionophore (CaI), indicating that the protective mechanism involves calcium signaling. Each of these beneficial effects of dld-1 gene suppression could be mimicked using a specific, small molecule inhibitor of the DLD-1 enzyme, 5-methoxyindole-2-carboxylic acid (MICA).High glucose levels are associated with the metabolic disorder, diabetes, which is a major risk factor for AD. In fact, it has been suggested that AD is a neural form of diabetes, type 3 diabetes. If true, drugs used to treat diabetes could act as possible treatments for AD. In this study, I investigated the effect of elevated glucose, the glucose metabolism inhibitor, 2-deoxy-d-glucose ii (2DOG) as well as the anti-diabetes drugs, metformin and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), on AD progression. Elevated glucose in the growth medium induced hyperactivity, which interfered with the paralysis assays, but it was seen to impair cholinergic neurotransmission, egg laying and hatc...

show abstract