Distinct modulation of voltage-gated and ligand-gated Ca2+ currents by PPAR-gamma agonists in cultured hippocampal neurons.
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.
Pancani
Tristano
T
Department of Molecular and Biomedical Pharmacology, University of Kentucky Medical Center, 800 Rose Street, MS 310, Lexington, Kentucky 40536-0298, USA.
Phelps
Jeremiah T
JT
Searcy
James L
JL
Kilgore
Michael W
MW
Chen
Kuey-Chu
KC
Porter
Nada M
NM
Thibault
Olivier
O
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology; D020013:Calcium Signaling / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D004622:Embryo, Mammalian; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D006624:Hippocampus / Q000166:cytology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D009457:Neuroglia; D009474:Neurons / Q000187:drug effects*; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D018408:Patch-Clamp Techniques / Q000379:methods; D000077205:Pioglitazone; D011247:Pregnancy; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D013997:Time Factors
D015220:Calcium Channels; D018691:Excitatory Amino Acid Antagonists; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D016194:Receptors, N-Methyl-D-Aspartate; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D002118:Calcium; D000077205:Pioglitazone