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ABSTRACT: Neural progenitor cell (NPC) transplantation offers great potential to treat spinal cord injury (SCI), but their efficiency is limited by poor survival and neuronal differentiation after transplantation. In the injury site, microglia may become activated and participate in the inflammation reaction. In vitro studies indicated that activated microglia might impair NPC survival and neuronal differentiation, but resting microglia did not. This study investigated the potential of minocycline to modify the negative effects of activated microglia on NPCs in vitro. First, the direct effects of minocycline on NPCs were tested. The results showed that at the concentration of 10μg/ml or lower, minocycline did not affect NPC survival and proliferation, but impaired neuronal differentiation. Then microglia were activated with lipopolysaccharide (LPS) or treated with LPS plus minocycline (LPSMC), and the effects of conditioned media on NPC apoptosis and differentiation were studied. The results showed that, compared with LPS treatment group, the microglia conditioned media of LPSMC treatment group resulted in a significantly lower apoptotic rate of NPCs, and increased the neuronal differentiation of NPCs. This suggested that minocycline may inhibit the negative effects of microglia on NPCs, and have the potential to support the survival and neuronal differentiation of transplanted NPCs for SCI.
Neuroscience Letters 03/2013; · 2.11 Impact Factor
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ABSTRACT: It is well known that glial cell line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor for motoneurons. We have previously shown that it greatly enhanced motoneuron survival and axon regeneration after implantation of peripheral nerve graft following spinal root avulsion. Aims: In the current study, we explore whether injection of GDNF promotes axon regeneration in decellularized nerve induced by repeated freeze-thaw cycles. Methods: We injected saline or GDNF into the decellularized nerve after root avulsion in adult Sprague-Dawley rats and assessed motoneuron axon regeneration and Schwann cell migration by retrograde labeling and immunohistochemistry. Results: We found that no axons were present in saline-treated acellular nerve whereas Schwann cells migrated into GDNF-treated acellular nerve grafts. We also found that Schwann cells migrated into the nerve grafts as early as 4 days after implantation, coinciding with the first appearance of regenerating axons in the grafts. Application of GDNF outside the graft did not induce Schwann cell infiltration nor axon regeneration into the graft. Application of pleiotrophin, a trophic factor which promotes axon regeneration but not Schwann cell migration, did not promote axon infiltration into acellular nerve graft. Conclusions: We conclude that GDNF induced Schwann cell migration and axon regeneration into the acellular nerve graft. Our findings can be of potential clinical value to develop acellular nerve grafting for use in spinal root avulsion injuries. © 2012 The Authors. Neuropathology and Applied Neurobiology © 2012 British Neuropathological Society.
Neuropathology and Applied Neurobiology 01/2012; · 3.80 Impact Factor
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ABSTRACT: Neuronal nitric oxide synthase (nNOS) is induced after axonal injury. The role of induced nNOS in injured neurons is not well established. In the present study, we investigated the co-expression of nNOS with GAP-43 in spinal motoneurons following axonal injury. The role of induced nNOS was discussed and evaluated. In normal rats, spinal motoneurons do not express nNOS or GAP-43. Following spinal root avulsion, expression of nNOS and GAP-43 were induced and colocalized in avulsed motoneurons. Reimplantation of avulsed roots resulted in a remarkable decrease of GAP-43- and nNOS-IR in the soma of the injured motoneurons. A number of GAP-43-IR regenerating motor axons were found in the reimplanted nerve. In contrast, the nNOS-IR was absent in reimplanted nerve. These results suggest that expression of GAP-43 in avulsed motoneurons is related to axonal regeneration whereas nNOS is not.
Nitric Oxide 12/2010; 23(4):258-63. · 3.55 Impact Factor
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ABSTRACT: This study aims to address if phosphorylation of the transcription factor c-Jun is associated with lesion-induced death of spinal motoneurons, and if this cellular response is modulated by glial-cell-line-derived neurotrophic factor (GDNF). We found that after both distal axotomy and root avulsion, spinal motoneurons in neonatal rats expressed phosphorylated c-Jun (p-c-Jun) and almost all injured motoneurons in these animals died. Similarly, root avulsion in adult rats also induced p-c-Jun expression that preceded the loss of motoneurons. In contrast, neither motoneuron death nor p-c-Jun induction was found after distal axotomy of spinal nerves in adult rats. Application of GDNF after distal axotomy in the neonatal model prevented motoneuron death but did not alter the expression of p-c-Jun in the surviving motoneurons. We conclude that c-Jun phosphorylation correlates with the cellular events leading to motoneuron death and that its expression cannot be modulated by GDNF. We further showed that expression of p-c-Jun was not correlated with the expression of growth-associated protein-43 (GAP-43), whose expression was closely correlated both temporally and spatially with periods of axonal outgrowth, suggesting that p-c-Jun may not be related with axonal regeneration of injured motoneurons.
Brain research 03/2010; 1320:7-15. · 2.46 Impact Factor
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Jiasong Guo,
Ka Kit Gilberto Leung,
Huanxing Su,
Qiuju Yuan,
Li Wang, Tak-Ho Chu,
Wenming Zhang,
Jenny Kan Suen Pu,
Gloria Kowk Po Ng,
Wai Man Wong,
Xiang Dai,
Wutian Wu
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ABSTRACT: Traumatic brain injury (TBI) or brain surgery may cause extensive loss of cerebral parenchyma. However, no strategy for reconstruction has been clinically effective. Our previous study had shown that self-assembling peptide nanofiber scaffold (SAPNS) can bridge the injured spinal cord, elicit axon regeneration, and eventually promote locomotor functional recovery. In the present study we investigated the effect of SAPNS for the reconstruction of acutely injured brain. The lesion cavity of the injured cortex was filled with SAPNS or saline immediately after surgically induced TBI, and the rats were killed 2 days, 2 weeks, or 6 weeks after the surgery for histology, immunohistochemistry, and TUNEL studies. Saline treatment in the control animals resulted in a large cavity in the injured brain, whereas no cavity of any significant size was found in the SAPNS-treated animals. Around the lesion site in control animals were many macrophages (ED1 positive) but few TUNEL-positive cells, indicating that the TBI caused secondary tissue loss mainly by means of necrosis, not apoptosis. In the SAPNS-treated animals the graft of SAPNS integrated well with the host tissue with no obvious gaps. Moreover, there were fewer astrocytes (GFAP positive) and macrophages (ED1 positive) around the lesion site in the SAPNS-treated animals than were found in the controls. Thus, SAPNS may help to reconstruct the acutely injured brain and reduce the glial reaction and inflammation in the surrounding brain tissue. FROM THE CLINICAL EDITOR: Self-assembling peptide nanofiber scaffold (SAPNS) was reported earlier to bridge the injured spinal cord, elicit axon regeneration, and promote locomotor recovery. In this study the effect of SAPNS for the reconstruction of acutely injured brain was investigated. In SAPNS-treated animals the graft integrated well with the host tissue with no obvious gaps. SAPNS may help to reconstruct the acutely injured brain and reduced the glial reaction and inflammation in the surrounding brain tissue.
Nanomedicine: nanotechnology, biology, and medicine 04/2009; 5(3):345-51. · 5.44 Impact Factor
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ABSTRACT: Spinal root avulsion injury causes motoneuron death and immediate loss of sensory and motor functions. Surgical intervention such as reimplantation of avulsed root is proven useful to restore neural circuitry of spinal cord and targeted muscles. Yet, additional strategies are required for faster and better functional recovery which is overall unsatisfactory. Accumulating evidences in animal studies, particularly in peripheral nerve injuries, demonstrated the effectiveness of neurotrophic factors in rescuing injured motoneurons and promoting axon regeneration. It is, however, important to recognize the differences between peripheral nerve and avulsion injury. In this review, we will briefly describe the changes in motoneurons after avulsion and provides a comprehensive list of neurotrophic factors which are known to exert neuroprotective effects on motoneurons. We will include recent studies on trophic factors for motoneuron survival and regeneration in peripheral nerve and avulsion injuries. We will also discuss the potential use of trophic factors in the context of avulsion injuries.
Central Nervous System Agents in Medicinal Chemistry(Formerly Current Medicinal Chemistry - Central Nervous System Agents) 03/2009; 9(1):40-55.
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ABSTRACT: We previously showed that motor nerves are superior to sensory nerves in promoting axon regeneration after spinal root avulsion. It is, however, impractical to use motor nerves as grafts. One potential approach to enhancing axonal regeneration using sensory nerves is to deliver trophic factors to the graft. Here, we examined the regulation of receptors for brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor, ciliary neurotrophic factor, and pleiotrophin after root avulsion in adult rats. We then tested their survival-promoting and neuroregenerative effects on spinal motoneurons. The results showed that receptors for brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor were upregulated and that these trophic factors promoted survival and axonal regeneration of motoneurons when they were injected into the sensory nerve graft before implantation. In contrast, receptors for ciliary neurotrophic factor and pleiotrophin were downregulated after avulsion. Ciliary neurotrophic factor did not promote survival and axonal regeneration, whereas pleiotrophin promoted axonal regeneration but not survival of injured spinal motoneurons. Our results suggest that infusion of trophic factors into sensory nerve grafts promote motoneuron survival and axonal regeneration. The technique is technically easy and is, therefore, potentially clinically applicable.
Journal of Neuropathology and Experimental Neurology 01/2009; 68(1):94-101. · 4.26 Impact Factor
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ABSTRACT: Motoneurons undergo retrograde degeneration following axonal injuries. The degree of degeneration varies with types of injuries,
proximity of injury site to the cell body, species, and age of the animal. Unlike other injuries, spinal root avulsion induces
a rapid and massive cell loss of the motoneurons. It not only provides a mean to study the degenerative changes of spinal
motoneurons but also resembles the brachial plexus injury in human. Despite being situated in the central nervous system,
motoneurons have a strong ability to regenerate under a suitable environment. We herein present step-by-step procedures for
performing extravertebral and intravertebral avulsion at seventh cervical segment in rat spinal cord and peripheral nerve
implantation to allow regeneration of the motoneurons.
12/2008: pages 487-496;
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ABSTRACT: In the present study, we compared the effects of implanting peripheral sensory nerve and motor nerve on motoneuron survival and regeneration after spinal root avulsion in adult rats. Our results showed that 116% more motoneurons regenerated axons into the motor than the sensory nerve graft and 59% of motoneurons survived in the motor nerve-implanted group compared to 48% in the sensory nerve-implanted group. We demonstrated by real time PCR that levels of BDNF and GDNF mRNA were significantly higher in the motor than the sensory nerve five days after implantation into the spinal cord. This may account for the superiority of motor over sensory nerve in promoting motor axon regeneration and motoneuron survival. Lastly, we also showed that implanting two sensory nerves enhances motoneuron regeneration over implanting a single nerve.
Experimental Neurology 06/2008; 212(2):562-5. · 4.70 Impact Factor
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Sha Mi,
Bing Hu,
Kyungmin Hahm,
Yi Luo,
Edward Sai Kam Hui,
Qiuju Yuan,
Wai Man Wong,
Li Wang,
Huanxing Su, Tak-Ho Chu,
Jiasong Guo,
Wenming Zhang,
Kwok-Fai So,
Blake Pepinsky,
Zhaohui Shao,
Christilyn Graff,
Ellen Garber,
Vincent Jung,
Ed Xuekui Wu,
Wutian Wu
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ABSTRACT: Demyelinating diseases, such as multiple sclerosis, are characterized by the loss of the myelin sheath around neurons, owing to inflammation and gliosis in the central nervous system (CNS). Current treatments therefore target anti-inflammatory mechanisms to impede or slow disease progression. The identification of a means to enhance axon myelination would present new therapeutic approaches to inhibit and possibly reverse disease progression. Previously, LRR and Ig domain-containing, Nogo receptor-interacting protein (LINGO-1) has been identified as an in vitro and in vivo negative regulator of oligodendrocyte differentiation and myelination. Here we show that loss of LINGO-1 function by Lingo1 gene knockout or by treatment with an antibody antagonist of LINGO-1 function leads to functional recovery from experimental autoimmune encephalomyelitis. This is reflected biologically by improved axonal integrity, as confirmed by magnetic resonance diffusion tensor imaging, and by newly formed myelin sheaths, as determined by electron microscopy. Antagonism of LINGO-1 or its pathway is therefore a promising approach for the treatment of demyelinating diseases of the CNS.
Nature Medicine 11/2007; 13(10):1228-33. · 22.46 Impact Factor
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ABSTRACT: Transplantation of neural progenitor cells (NPCs) holds great potential for the treatment of spinal cord injuries. The survival and differential fates of transplanted NPCs in the cord are key factors contributing to the success of the therapy. In this study, we investigate the effects of lithium, a widely used antidepressant drug, on the survival, proliferation and differentiation of spinal cord-derived NPCs in cultures and after transplantation into the spinal cord. Our results show that clinically relevant doses of lithium increase the proliferation of grafted NPCs at 2 weeks post-grafting and neuronal generation by grafted NPCs at 2 weeks and 4 weeks post-grafting. However, lithium does not cause preferential differentiation of NPCs into astrocytes or oligodendrocytes both in vitro and after transplantation. Our results also show that chronic treatment with lithium (up to 4 weeks) reduces microglia and macrophage activation, indicating that lithium treatment can affect the host immune response. The results of the present study provide evidence that lithium may have therapeutic potential in cell replacement strategies for CNS injury due to its ability to promote proliferation and neuronal generation of grafted NPCs and reduce the host immune reaction.
Experimental Neurology 09/2007; 206(2):296-307. · 4.70 Impact Factor
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ABSTRACT: Neuronal survival and death-related effects of nitric oxide synthase are widely studied, yet its potential involvement in regeneration remains largely unexplored. In the present study, the regenerative role of nitric oxide synthase in injured motoneurons was investigated. A ventral root was avulsed and a piece of peripheral nerve was implanted into the spinal cord. Results showed that nitric oxide synthase inhibitor reduced the number of regenerating motoneurons to half compared with sham-operated control at 2 weeks and 4 weeks after injury, but the rate of axonal regeneration was not affected. Our study adds a new line of evidence that expression of nitric oxide synthase is beneficial to the axonal regeneration of the injured spinal motoneurons.
Neuroreport 08/2006; 17(10):969-73. · 1.66 Impact Factor
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http://sunzi.lib.hku.hk/hkuto/record/B41633751.
