Peripheral Infusion of IGF-I Selectively Induces Neurogenesis in the Adult Rat Hippocampus

Abstract

In several species, including humans, the dentate granule cell layer (GCL) of the hippocampus exhibits neurogenesis throughout adult life. The ability to regulate adult neurogenesis pharmacologically may be of therapeutic value as a mechanism for replacing lost neurons. Insulin-like growth factor-I (IGF-I) is a growth-promoting peptide hormone that has been shown to have neurotrophic properties. The relationship between IGF-I and adult hippocampal neurogenesis is to date unknown. The aim of this study was to investigate the effect of the peripheral administration of IGF-I on cellular proliferation in the dentate subgranular proliferative zone, which contains neuronal progenitor cells, and on the subsequent migration and differentiation of progenitor cells within the GCL. Using bromodeoxyuridine (BrdU) labeling, we found a significant increase of BrdUimmunoreactive progenitors in the GCL after 6 d of peripheral IGF-I administration. To determine the cell fate in progenitor progeny, we characterized the colocalization of BrdUimmunolabeled cells with cell-specific markers. In animals treated with IGF-I for 20 d, BrdU-positive cells increased significantly. Furthermore, the fraction of newly generated neurons in the GCL increased, as evaluated by the neuronal markers Calbindin D 28K , microtubule-associated protein-2, and NeuN. There was no difference in the fraction of newly generated astrocytes. Thus, our results show that peripheral infusion of IGF-I increases progenitor cell proliferation and selectively induces neurogenesis in the progeny of adult neural progenitor cells. This corresponds to a 78 Ϯ 17% ( p Ͻ 0.001) increase in the number of new neurons in IGF-I-treated animals compared with controls. Key words: brain; rat; IGF-I; insulin-like growth factor-I; stem cell; progenitor cell; hippocampus; neurogenesis; stereologyMost CNS neurons are terminally differentiated and are, thus, not replaced after neuronal cell death. However, self-renewing cells with multilineage potential, designated stem cells or progenitor cells, have been identified in the adult mammalian brain

Transplantation of neural progenitors enhances production of endogenous cells in the impaired brain

“…It is possible that the muscarinic signaling cascade may be part of, and/ or play a synergistic role to, the cytokine system, whose role in neurogenesis has been suggested by other investigators. [11][12][13][14][15] Whether neurogenesis was causative of biochemical recovery, most importantly of PKC, or merely parallel thereof, remains a subject of future investigation.…”

“…One possibility is the induction of cytokines by neural progenitors, [8][9][10] which enhance proliferation of endogenous neural cells. [11][12][13][14][15] Here, we aimed to examine our hypothesis by employing the prenatally heroin-damaged brain model. The heroin model was chosen because, among other effects, it induces deficits that can be related to specific synaptic functions.…”

Mechanism of stem cells in the central nervous system

“…A second approach using electrophysiology to measure from GFP-retrovirally labeled cells showed that integrated neurons exhibited neuronal morphology and displayed passive membrane properties and action potentials (Song et al, 2002;van Praag et al, 2002). Furthermore, neurogenesis in the hippocampus can be induced by exogenous factors, including peripheral administration of insulin-like growth factor-I (IGF-I) (Aberg et al, 2000) or hormones like corticosteroids (Tanapat et al, 1999;Gass et al, 2000), enriched environment (Kempermann et al, 1997;Nilsson et al, 1999), exercise (van Praag et al, 1999a,b;Gould et al, 2000), or interestingly, by hypoxia (Liu et al, 1998). Unfortunately, none of these reports has demonstrated that these signals can be used as strategies for regeneration in humans.…”

Neurobiology of mood, anxiety, and emotions as revealed by studies of a unique antidepressant: tianeptine

“…61 Selective induction of neurogenesis has also been achieved using IGF-1. 62,63 Further studies should elucidate the possible involvement of these molecules in the mechanism of action of tianeptine and other antidepressants.…”