Ampakine CX546 increases proliferation and neuronal differentiation in subventricular zone stem/progenitor cell cultures

Abstract

Ampakines are chemical compounds known to modulate the properties of ionotropic α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA)-subtype glutamate receptors. The functional effects attributed to ampakines involve plasticity and the increase in synaptic efficiency of neuronal circuits, a process that may be intimately associated with differentiation of newborn neurons. The subventricular zone (SVZ) is the main neurogenic niche of the brain, containing neural stem cells with brain repair potential. Accordingly, the identification of new pharmaceutical compounds with neurogenesis-enhancing properties is important as a tool to promote neuronal replacement based on the use of SVZ cells. The purpose of the present paper is to examine the possible proneurogenic effects of ampakine CX546 in cell cultures derived from the SVZ of early postnatal mice. We observed that CX546 (50 μm) treatment triggered an increase in proliferation, evaluated by BrdU incorporation assay, in the neuroblast lineage. Moreover, by using a cell viability assay (TUNEL) we found that, in contrast to AMPA, CX546 did not cause cell death. Also, both AMPA and CX546 stimulated neuronal differentiation as evaluated morphologically through neuronal nuclear protein (NeuN) immunocytochemistry and functionally by single-cell calcium imaging. Accordingly, short exposure to CX546 increased axonogenesis, as determined by the number and length of tau-positive axons co-labelled for the phosphorylated form of SAPK/JNK (P-JNK), and dendritogenesis (MAP2-positive neurites). Altogether, this study shows that ampakine CX546 promotes neurogenesis in SVZ cell cultures and thereby may have potential for future stem cell-based therapies.

Platelet-Derived Growth Factor-BB Restores HIV Tat -Mediated Impairment of Neurogenesis: Role of GSK-3β/β-Catenin

“…Our results are in agreement with previous reports implying the role of JNK activation in FGF2 (Sanalkumar et al 2010), angionenic factor angioproieth-1 (Rosa et al 2010), TNF-α (Bernardino et al 2008) and ampaline CX546(Schitine et al 2012)-mediated proliferation of NPCs.…”

Synaptic regulation of affective behaviors; role of BDNF

“…Ampakines enhance BDNF mRNA and protein levels in the hippocampus and facilitate BDNF release (Jourdi et al, 2009; Lauterborn et al, 2000). Ampakine CX546 enhances neurogenesis in SVZ cell cultures (Schitine et al, 2012). Also, LY451646 increases cell proliferation in adult rat hippocampus (Bai et al, 2003).…”

Molecular Mechanisms of Drug-Induced Cognitive Enhancement

“…Ampakines can therefore be employed to increase the availability of endogenous BDNF in the brain (Kramár et al, 2012). Probably through this effect, (Scharfman et al, 2005), ampakines also positively regulate neurogenesis (Schitine et al, 2012) that by itself can enhance cognitive function (Wezenberg et al, 2007).…”