Adult neural stem/progenitor cells reduce NMDA‐induced excitotoxicity via the novel neuroprotective peptide pentinin

Abstract

J. Neurochem. (2009) 109, 858–866. Abstract Although the potential of adult neural stem cells to repair damage via cell replacement has been widely reported, the ability of endogenous stem cells to positively modulate damage is less well studied. We investigated whether medium conditioned by adult hippocampal stem/progenitor cells altered the extent of excitotoxic cell death in hippocampal slice cultures. Conditioned medium significantly reduced cell death following 24 h of exposure to 10 μM NMDA. Neuroprotection was greater in the dentate gyrus, a region neighboring the subgranular zone where stem/progenitor cells reside compared with pyramidal cells of the cornis ammonis. Using mass spectrometric analysis of the conditioned medium, we identified a pentameric peptide fragment that corresponded to residues 26–30 of the insulin B chain which we termed ‘pentinin’. The peptide is a putative breakdown product of insulin, a constituent of the culture medium, and may be produced by insulin‐degrading enzyme, an enzyme expressed by the stem/progenitor cells. In the presence of 100 pM of synthetic pentinin, the number of mature and immature neurons killed by NMDA‐induced toxicity was significantly reduced in the dentate gyrus. These data suggest that progenitors in the subgranular zone may convert exogenous insulin into a peptide capable of protecting neighboring neurons from excitotoxic injury.

The stem cell secretome and its role in brain repair

“…Mass spectrometry (MS) analyses on NPC-CM identified the novel neuroprotective peptide pentitin, a putative breakdown product of the insulin B chain [104]. Pentitin prevented NMDA-mediated toxicity of both mature and immature neurons, thus confirming a role of this secreted factor in part of the neuroprotection observed with NPC-CM [104]. Human NPCs transplanted in the rat cortex 1 week post-stroke successfully engrafted and migrated towards the lesion.…”

“…NPC-CM also reduced the extent of N-methyl- d -aspartate (NMDA)-induced excitotoxic cell death in hippocampal slice cultures. Mass spectrometry (MS) analyses on NPC-CM identified the novel neuroprotective peptide pentitin, a putative breakdown product of the insulin B chain [104]. Pentitin prevented NMDA-mediated toxicity of both mature and immature neurons, thus confirming a role of this secreted factor in part of the neuroprotection observed with NPC-CM [104].…”

Identification of ApoE as an autocrine/paracrine factor that stimulates neural stem cell survival via MAPK/ERK signaling pathway

“…2006), and plays a role in cell fate determination and neuroprotection (Llado et al. 2004; Faijerson et al. 2009).…”

Oxidative-Signaling in Neural Stem Cell-Mediated Plasticity: Implications for Neurodegenerative Diseases

“…Further, the secretome derived from adult NSC was shown to protect hippocampal neurons from NMDA-induced excitotoxicity. This was shown to be mediated by a novel neuroprotective peptide, pentitin, a putative breakdown product of the insulin B chain [157]. Another study investigated the effects of hNSCs-derived secretome in a rat model of PD.…”