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Distinct modulation of voltage‐gated and ligand‐gated Ca 2+ currents by PPAR‐γ agonists in cultured hippocampal neurons
Author(s) -
Pancani Tristano,
Phelps Jeremiah T.,
Searcy James L.,
Kilgore Michael W.,
Chen KueyChu,
Porter Nada M.,
Thibault Olivier
Publication year - 2009
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2009.06107.x
Subject(s) - pioglitazone , rosiglitazone , neuroprotection , endocrinology , hippocampal formation , medicine , nmda receptor , neuroscience , insulin resistance , cognitive decline , chemistry , insulin , diabetes mellitus , biology , type 2 diabetes , receptor , disease , dementia
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.