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

Abstract

Primary objective Neurotrophin levels are elevated after TBI yet there is minimal regeneration. It was hypothesized that the pro-neurotrophin/p75NTR pathway is induced more than the mature neurotrophin/Trk pathway and that interfering with p75 signaling improves recovery following TBI. Research design Lateral Fluid Percussion (LFP) injury was performed on wildtype and p75 mutant mice. In addition, TrkB agonist 7,8 Dihydroxyflavone or p75 antagonist TAT-Pep5 were tested. Western blot and immunohistochemistry revealed biochemical and cellular changes. Morris Water Maze and Rotarod tests demonstrated cognitive and vestibulomotor function. Main outcomes and results p75 was upregulated and TrkB is downregulated 1 day post LFP. p75 mutant mice as well as mice treated with the p75 antagonist or the TrkB agonist exhibited reduced neuronal death and degeneration and less astrocytosis. The cells undergoing apoptosis appear to be neurons rather than glia. There was improved motor function and spatial learning in p75 mutant mice and mice treated with the p75 antagonist. Conclusions Many of the pathological and behavioural consequences of TBI might be due to activation of the pro-neurotrophin/p75 toxic pathway overriding the protective mechanisms of the mature neurotrophin/Trk pathway. Targeting p75 can be a novel strategy to counteract the damaging effects of TBI.

Osthole Upregulates BDNF to Enhance Adult Hippocampal Neurogenesis in APP/PS1 Transgenic Mice

“…37,38) One possibility is that TrkB activity is compromised while its level of expression is unaltered. To evaluate this, we used an antibody that recognizes phosphorylated TrkB, which corresponds to the inactive form of TrkB 145 kDa.…”

The Pathways Involved in TLQP-62 Mediated Biological Functions

“…It was also activated in NPCs after TLQP-62 treatment. From these findings it was evident that both the mGluR5 and NMDA receptors are required for TLQP-62-induced proliferation of NPCs [6].…”

“…The role of TLQP-62, as bioactive VGF derived bioactive peptides includes the following: modulation of insulin secretion and glucose homeostasis, improving glucose tolerance in vivo, regulation of gene expression [5], regulation of memory formation [4], determining phases of neurogenesis, enhancing synaptic activity, proliferation of neural progenitor cells (NPCs) or TLQP-62 induced neurogenesis [6]. Table 3.…”

“…induced proliferation of Neural Progenitor Cells (NPCs) by activating the signalingpathways downstream of the glutamate receptor [6].…”

“…Other behavioral and physiological roles of this neuropeptide includes the following: stimulation of insulin secretion in insulinoma cells, regulation of gene expression in INS1E cells, activation of the intracellular signaling pathways, enhancement of intracellular calcium mobilization in INS1E cells, trophic and proliferative effects on insulinoma cell lines, in the act of improving glucose tolerance in vivo, determination of phases of neurogenesis, enhancing synaptic activity [4][5][6].…”