Distinct modulation of voltage‐gated and ligand‐gated Ca²⁺ currents by PPAR‐γ agonists in cultured hippocampal neurons

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 Ca2+ dysregulation is a pathogenic factor of brain aging/AD, we tested the hypothesis that TZDs could impact Ca2+ signaling/homeostasis in neurons. We assessed the effects of pioglitazone and rosiglitazone (TZDs) on two major sources of Ca2+ influx in primary hippocampal cultured neurons, voltage-gated Ca2+ channel (VGCC) and the NMDA receptor (NMDAR). VGCC- and NMDAR-mediated Ca2+ currents were recorded using patch-clamp techniques, and Ca2+ intracellular levels were monitored with Ca2+ 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 Ca2+-dependent pathways in the brain and have different inhibitory profiles on two major Ca2+ sources, potentially conferring neuroprotection to an area of the brain that is particularly vulnerable to the effects of aging and/or AD.

Neuroprotective mechanisms of peroxisome proliferator-activated receptor agonists in Alzheimer’s disease

“…Furthermore, some reports depict that PPARγ agonists reduce Ca +2 during Aβ-mediated insults in cortical neurons (Inestrosa et al 2005). Pioglitazone reduced NMDAR-mediated Ca +2 currents and transients, and rosiglitazone reduced the VGCC currents but not the NMDAR-mediated currents (Pancani et al 2009). Glucocorticoid administration in a mouse model of AD has shown to enhance the production of Aβ by increasing APP and beta-APP cleaving enzyme (Li et al 2010;Green et al 2006).…”

Rosiglitazone Promotes AQP2 Plasma Membrane Expression In Renal Cells Via a Ca2+-Dependent/cAMP-Independent Mechanism

“…Importantly, RGZ inhibits TRPM3 and activates TRPC5 channels expressed in HEK 293 cells with a mechanism that does not involve PPAR-γ activation but rather a direct interaction with drug binding sites on the channels. On the other hand, there is only one evidence that long-term treatment with TZD affects voltage-gated Ca 2+ currents in cultured hippocampal neurons via direct activation of PPAR-γ [77]. …”

Rosiglitazone inhibits Kv4.3 potassium channels by open‐channel block and acceleration of closed‐state inactivation

“…To our knowledge, there is only one report regarding the direct effects of PPARg on ion channels: a study of voltage-gated Ca 2+ currents in cultured hippocampal neurons, which were suppressed by thiazolidinediones via a PPARg-dependent pathway (Pancani et al, 2009). In their study, however, the neurons were treated for 24 h with the thiazolidinedione to evaluate the effects of the drug.…”