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  • Enhancement of Adult Hippocampal Neurogenesis by a Neurotrophic Peptide in Traumatic Brain Injury

    Final Number:
    163

    Authors:
    Muhammad Omar Chohan MD; Khalid Iqbal PhD; Howard Yonas MD; Edwin Nemoto PhD

    Study Design:
    Laboratory Investigation

    Subject Category:

    Meeting: Congress of Neurological Surgeons 2013 Annual Meeting

    Introduction: Selective hippocampal vulnerability to trauma is the cause of long-term cognitive impairment in survivors of traumatic Brain Injury (TBI). Following TBI, there is up-regulation of neurotrophic factors in the hippocampus to preserve volume and function of the granule cell layer. Therefore, increasing adult hippocampal neurogenesis and stimulating neuronal plasticity pharmacologically could be a very useful strategy towards inhibiting cognitive decline following TBI. We recently discovered an 11-mer peptide (Peptide 6) corresponding to an active region of human ciliary neurotrophic factor (amino acid residues 146 to 156) which, when given peripherally, increased numbers of proliferating and differentiating adult hippocampal neural progenitor cells (AHPs) with improvement of reference memory in mouse models of Down syndrome and Alzheimer’s disease. We therefore, hypothesized a similar effect in traumatic brain injury.

    Methods: Normal adult C57Bl6 mice were subjected to TBI using controlled cortical impact (CCI) device with 1.5 mm of cortical penetration. The animals were treated with 50nmol/animal/day of Peptide 6 or saline given as daily intraperitoneal injections for 30 days. Dentate gyrus neurogenesis was assessed by stereological analysis of cells expressing neuronal markers, doublecortin and NeuN, and BrdU uptake.

    Results: We found that, compared to saline, Peptide 6 treatment significantly increased number of proliferating progenitors in the dentate gyrus by 50% (BrdU-IR cells, mean ± SEM: 3303 ± 217 control, 4850 ± 265, p = 0.037) and enhanced neuronal commitment (BrdU-NeuN IR cells: 1057 ± 217 control; 1901 ± 265 Peptide 6, p = 0.004) by 80%.

    Conclusions: Our results suggest that long-term treatment with Peptide 6 enhanced the pool of neural progenitor cells in the hippocampus and increased the numbers of newborn neurons in TBI mice. Further studies examining the effect of Peptide 6 on hippocampus dependent memory tasks will further elucidate its role in developing potential therapy for severe traumatic brain injury.

    Patient Care: We demonstrate enhancement of neural progenitor cell proliferation and differentiation into mature neurons by a small molecule, based on human CNTF, in a mouse model of TBI. The fact that this molecule is neurogenic and is given peripherally and non-invasively, demonstrates its potential in hippocampal regeneration in the posttraumatic brain. Further studies describing its effects on hippocampal dependent memory tasks are underway and will be crucial in determining its potential of as a novel biological molecule to treat patients with TBI.

    Learning Objectives: By the conclusion of this session, participants should be able to: 1) Describe the effect of severe traumatic brain injury on hippocampus and its effect on cognition on survivors 2) Describe the role of neurotrophic factors in enhancing adult hippocampal neurogenesis for maintenance of hippocampal cytoarchitecture. 3) Describe the potential therapeutic role of a novel small molecule based on human ciliary neurotrophic factor (CNTF) in enhancing hippocampal neurogenesis in the post traumatic brain

    References: Blanchard, J. et al. Pharmacologic reversal of neurogenic and neuroplastic abnormalities and cognitive impairments without affecting Abeta and tau pathologies in 3xTg-AD mice. Acta neuropathologica 120, 605-621 (2010) Chirumamilla, S., Sun, D., Bullock, M. R. & Colello, R. J. Traumatic brain injury induced cell proliferation in the adult mammalian central nervous system. Journal of neurotrauma 19, 693-703 (2002). Chohan, M. O. et al. Enhancement of dentate gyrus neurogenesis, dendritic and synaptic plasticity and memory by a neurotrophic peptide. Neurobiology of aging 32, 1420-1434 (2011). Emsley, J. G. & Hagg, T. Endogenous and exogenous ciliary neurotrophic factor enhances forebrain neurogenesis in adult mice. Experimental neurology 183, 298-310 (2003) Oyesiku, N. M. et al. Regional changes in the expression of neurotrophic factors and their receptors following acute traumatic brain injury in the adult rat brain. Brain research 833, 161-172 (1999).

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