A small molecule p75NTR ligand protects neurogenesis after traumatic brain injury

Abstract

The p75 neurotrophin receptor (p75 NTR ) influences the proliferation, survival, and differentiation of neuronal precursors and its expression is induced in injured brain, where it regulates cell survival. Here, we test the hypotheses that pharmacologic modulation of p75 NTR signaling will promote neural progenitor survival and proliferation, and improve outcomes of traumatic brain injury (TBI). LM11A-31, an orally available, blood-brain barrier-permeant small-molecule p75 NTR signaling modulator, significantly increased proliferation and survival, and decreased JNK phosphorylation, in hippocampal neural stem/progenitor cells in culture expressing wild-type p75 NTR , but had no effect on cells expressing a mutant neurotrophinunresponsive form of the receptor. The compound also enhanced the production of mature neurons from adult hippocampal neural progenitors in vitro. In vivo, intranasal administration of LM11A-31 decreased postinjury hippocampal and cortical neuronal death, neural progenitor cell death, gliogenesis, and microglial activation, and enhanced long-term hippocampal neurogenesis and reversed spatial memory impairments. LM11A-31 diminished the postinjury increase of SOX2-expressing early progenitor cells, but protected and increased the proliferation of endogenous polysialylated-neural cell adhesion molecule positive intermediate progenitors, and restored the long-term production of mature granule neurons. These findings suggest that modulation of p75 NTR actions using small molecules such as LM11A-31 may constitute a potent therapeutic strategy for TBI. STEM CELLS

VGF (TLQP-62)-induced neurogenesis targets early phase neural progenitor cells in the adult hippocampus and requires glutamate and BDNF signaling

“…Treatment with LM11A-31 following contusion injury results in an increase in the number of surviving oligodendrocytes and myelinated axons through inhibition of apoptosis via JNK3 [115]. The LM11A-31 compound also increases neurogenesis, inhibits neuronal death, and prevents activation of astrocytes and microglia following Controlled Cortical Impact model of TBI [116]. In contrast, LM11A-31 has been found to lack protective effects following pilocarpine-induced seizures [117].…”

The p75 neurotrophin receptor: at the crossroad of neural repair and death

“…Nanomolar concentrations of the experimental compound, LM11A-31, a non-peptide structural mimetic of loop1 of NGF, have been shown to have neurotropic properties and to offer potent neuroprotection from Aβ induced damage in mouse and culture models of AD Nguyen et al, 2014), spinal cord injury (Tep et al, 2013), traumatic brain injury (Shi et al, 2013), virus-induced inflammation (Meeker et al, 2012) and chemotherapeutic toxicity (James et al, 2008) in the absence of pro-apoptotic effects. This therapeutic approach was based, in part, on the concept that small molecules might regulate neurotrophin receptor dimerization, activation and/or interactions with co-receptors in ways that do not necessarily recapitulate the full actions of the naturally occurring peptides.…”

Dynamic Nature of the p75 Neurotrophin Receptor in Response to Injury and Disease

“…Promising results have recently been published that demonstrate the therapeutic utility of compounds that target the p75 NTR . Nanomolar concentrations of the experimental compound, LM11A-31, a non-peptide structural mimetic of loop1 of NGF, have been shown to have neurotropic properties and to offer potent neuroprotection from Aβ induced damage in mouse and culture models of AD(Yang et al, 2008; Knowles et al, 2009; Nguyen et al, 2014), spinal cord injury(Tep et al, 2013), traumatic brain injury(Shi et al, 2013), virus-induced inflammation(Meeker et al, 2011), chemotherapeutic toxicity(James et al, 2008) as well as protection against apoptotic effects normally induced in oligodendrocytes by p75 NTR ligation(Massa et al, 2006). A structurally unrelated compound similarly modeled after loop 1of NGF and targeted to the p75 NTR , LM11A-24, also protected against motor neuron degeneration(Pehar et al, 2006).…”