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Distinct modulation of voltage-gated and ligand-gated Ca2+currents by PPAR-γ agonists in cultured hippocampal neurons
- Source :
- Journal of Neurochemistry. 109:1800-1811
- Publication Year :
- 2009
- Publisher :
- Wiley, 2009.
-
Abstract
- Type 2 diabetes mellitus is a metabolic disorder characterized by hyperglycemia and is especially prevalent in the elderly. Because aging is a risk factor for type 2 diabetes mellitus, and insulin resistance may contribute to the pathogenesis of Alzheimer's disease (AD), anti-diabetic agents (thiazolidinediones-TZDs) are being studied for the treatment of cognitive decline associated with AD. These agents normalize insulin sensitivity in the periphery and can improve cognition and verbal memory in AD patients. Based on evidence that Ca(2+) dysregulation is a pathogenic factor of brain aging/AD, we tested the hypothesis that TZDs could impact Ca(2+) signaling/homeostasis in neurons. We assessed the effects of pioglitazone and rosiglitazone (TZDs) on two major sources of Ca(2+) influx in primary hippocampal cultured neurons, voltage-gated Ca(2+) channel (VGCC) and the NMDA receptor (NMDAR). VGCC- and NMDAR-mediated Ca(2+) currents were recorded using patch-clamp techniques, and Ca(2+) intracellular levels were monitored with Ca(2+) imaging techniques. Rosiglitazone, but not pioglitazone reduced VGCC currents. In contrast, NMDAR-mediated currents were significantly reduced by pioglitazone but not rosiglitazone. These results show that TZDs modulate Ca(2+)-dependent pathways in the brain and have different inhibitory profiles on two major Ca(2+) sources, potentially conferring neuroprotection to an area of the brain that is particularly vulnerable to the effects of aging and/or AD.
- Subjects :
- medicine.medical_specialty
Patch-Clamp Techniques
Time Factors
endocrine system diseases
Enzyme-Linked Immunosorbent Assay
Hippocampus
Receptors, N-Methyl-D-Aspartate
Biochemistry
Neuroprotection
Article
Rosiglitazone
Cellular and Molecular Neuroscience
Pregnancy
Internal medicine
medicine
Animals
Hypoglycemic Agents
Drug Interactions
Calcium Signaling
Cognitive decline
Cells, Cultured
6-Cyano-7-nitroquinoxaline-2,3-dione
Neurons
Dose-Response Relationship, Drug
Pioglitazone
business.industry
Glutamate receptor
Embryo, Mammalian
Electric Stimulation
Rats
PPAR gamma
Endocrinology
medicine.anatomical_structure
NMDA receptor
Ligand-gated ion channel
Calcium
Female
Thiazolidinediones
Calcium Channels
Neuron
business
Excitatory Amino Acid Antagonists
Neuroglia
Protein Binding
medicine.drug
Subjects
Details
- ISSN :
- 14714159 and 00223042
- Volume :
- 109
- Database :
- OpenAIRE
- Journal :
- Journal of Neurochemistry
- Accession number :
- edsair.doi.dedup.....2cbace1761fe652dabec4a838fd30a05