Identification of Potentially Neuroprotective Genes Upregulated by Neurotrophin Treatment of CA3 Neurons in the Injured Brain

Abstract

Specific neurotrophic factors mediate histological and/or functional improvement in animal models of traumatic brain injury (TBI). In previous work, several lines of evidence indicated that the mammalian neurotrophin NT-4/ 5 is neuroprotective for hippocampal CA3 pyramidal neurons after experimental TBI. We hypothesized that NT-4/5 neuroprotection is mediated by changes in the expression of specific sets of genes, and that NT-4/5-regulated genes are potential therapeutic targets for blocking delayed neuronal death after TBI. In this study, we performed transcription profiling analysis of CA3 neurons to identify genes regulated by lateral fluid percussion injury, or by treatment with the trkB ligands NT-4/5 or brain-derived neurotrophic factor (BDNF). The results indicate extensive overlap between genes upregulated by neurotrophins and genes upregulated by injury, suggesting that the mechanism behind neurotrophin neuroprotection may mimic the brain's endogenous protective response. A subset of genes selected for further study in vitro exhibited neuroprotection against glutamate excitotoxicity. The neuroprotective genes identified in this study were upregulated at 30 h post-injury, and are thus expected to act during a clinically useful time frame of hours to days after injury. Modulation of these factors and pathways by genetic manipulation or small molecules may confer hippocampal neuroprotection in vivo in preclinical models of TBI.

Engineering mesenchymal stem cells to improve their exosome efficacy and yield for cell‐free therapy

“…Sequences such as DNA or RNA have been shown to display neuroprotective or angiogenic properties. They can be packed inside exosomes or directed to the exosomes [9,68–74]. For example, protein kinase b (Akt) has been shown to display angiogenic properties so when the AKT1 gene was transfected into MSCs, the exosomes derived from Akt‐modified MSCs promoted endothelial cell proliferation, migration and new blood vessel formation in the rat model of myocardial infarction [69].…”

The Role of BDNF in Experimental and Clinical Traumatic Brain Injury

“…Three of the studies reported increased BNDF mRNA expression in the first 1 to 6 h after injury [ 44 , 46 , 47 ], whereas one reported a decreased mRNA expression at 20 h after trauma in both TBI and sham groups [ 45 ]. At all other subsequent time points, BDNF mRNA expression in the ipsilateral hippocampus was reported to be decreased or not affected compared to the sham ( Figure 3 a) [ 9 , 47 , 48 , 49 , 50 , 51 , 52 ]. Interestingly, BDNF protein expression did not show any significantly increased expression in the first day after trauma and showed decreased or not altered expression in the following weeks ( Figure 3 b).…”

Prevention of streptozotocin‑induced Neuro‑2a cell death by C8‑B4 microglia transformed with repetitive low‑dose lipopolysaccharide

“…nT-4/5 is a neurotrophic factor with neuroprotective effects (20)(21)(22)(23). in our previous study, nT-4/5 gene expression was promoted in lPSx3-microglia, suggesting that lPSx3-microglia have a neuroprotective potential (19).…”

“…to its high-affinity receptor, tyrosine receptor kinase B (TrkB) and supports neuronal survival and growth (20)(21)(22)(23). Hence, lPSx3-microglia might have a neuroprotective effect.…”