Lentiviral-mediated transfer of CDNF promotes nerve regeneration and functional recovery after sciatic nerve injury in adult rats

Cheng, Lei; Liu, Yi; Zhao, Hua; Zhang, Wen; Guo, Yingjun; Lin, Na

doi:10.1016/j.bbrc.2013.09.084

Cited by 18 publications

(10 citation statements)

References 26 publications

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“…Both NGF and MCS can induce morphological changes NF200, which plays a critical role in preventing axonal neuron degeneration after brain [33], or spinal cord injury [34] and used to efficacy of neurological therapies [35, 36]. NGF signaling by a mimetic is likely to induce cellular reorganization/elongation of cytoskeletal microtubules (formation of neuritic shafts) and development of filopodia/lamellipodia with flexible growth cones that extend along a biological matrix (e.g.…”

Section: Discussionmentioning

confidence: 99%

Neurotrophic Effects of Mu Bie Zi (Momordica cochinchinensis) Seed Elucidated by High-Throughput Screening of Natural Products for NGF Mimetic Effects in PC-12 Cells

et al. 2015

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Post-mitotic central nervous system (CNS) neurons have limited capacity for regeneration, creating a challenge in the development of effective therapeutics for spinal cord injury or neurodegenerative diseases. Furthermore, therapeutic use of human neurotrophic agents such as nerve growth factor (NGF) are limited due to hampered transport across the blood brain barrier (BBB) and a large number of peripheral side effects (e.g. neuro-inflammatory pain/tissue degeneration etc.). Therefore, there is a continued need for discovery of small molecule NGF mimetics that can penetrate the BBB and initiate CNS neuronal outgrowth/regeneration. In the current study, we conduct an exploratory high-through-put (HTP) screening of 1144 predominantly natural/herb products (947 natural herbs/plants/spices, 29 polyphenolics and 168 synthetic drugs) for ability to induce neurite outgrowth in PC12 dopaminergic cells grown on rat tail collagen, over 7 days. The data indicate a remarkably rare event-low hit ratio with only 1/1144 tested substances (<111.25 µg/mL) being capable of inducing neurite outgrowth in a dose dependent manner, identified as; Mu Bie Zi, Momordica cochinchinensis seed extract (MCS). To quantify the neurotrophic effects of MCS, 36 images (n = 6) (average of 340 cells per image), were numerically assessed for neurite length, neurite count/cell and min/max neurite length in microns (µm) using Image J software. The data show neurite elongation from 0.07 ± 0.02 µm (controls) to 5.5 ± 0.62 µm (NGF 0.5 μg/mL) and 3.39 ± 0.45 µm (138 μg/mL) in MCS, where the average maximum length per group extended from 3.58 ± 0.42 µm (controls) to 41.93 ± 3.14 µm (NGF) and 40.20 ± 2.72 µm (MCS). Imaging analysis using immunocytochemistry (ICC) confirmed that NGF and MCS had similar influence on 3-D orientation/expression of 160/200 kD neurofilament, tubulin and F-actin. These latent changes were associated with early rise in phosphorylated extracellular signal-regulated kinase (ERK) p-Erk1 (T202/Y204)/p-Erk2 (T185/Y187) at 60 min with mild changes in pAKT peaking at 5 min, and no indication of pMEK involvement. These findings demonstrate a remarkable infrequency of natural products or polyphenolic constituents to exert neurotrophic effects at low concentrations, and elucidate a unique property of MCS extract to do so. Future research will be required to delineate in depth mechanism of action of MCS, constituents responsible and potential for therapeutic application in CNS degenerative disease or injury.

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Section: Discussionmentioning

confidence: 99%

Neurotrophic Effects of Mu Bie Zi (Momordica cochinchinensis) Seed Elucidated by High-Throughput Screening of Natural Products for NGF Mimetic Effects in PC-12 Cells

et al. 2015

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“…In 6-hydroxydopamine (6-OHDA)-induced parkinsonian rat models, intrastriatal CDNF gene therapy mediated by viral vectors [ 11 , 12 ] and intrastriatal injection of CDNF protein as a single dose [ 2 ] or chronic infusion [ 13 ] also showed protective effects. CDNF gene therapy has shown a regenerative effect in the rat sciatic nerve injury model [ 14 ]. In addition to the neurotrophic effects, recent studies on primary glial cell cultures suggest that CDNF has an anti-inflammatory effect [ 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

Transient transfection of human CDNF gene reduces the 6-hydroxydopamine-induced neuroinflammation in the rat substantia nigra

Nadella

Voutilainen

Saarma

et al. 2014

J Neuroinflammation

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BackgroundThe anti-inflammatory effect of the cerebral dopamine neurotrophic factor (CDNF) was shown recently in primary glial cell cultures, yet such effect remains unknown both in vivo and in 6-hydroxydopamine (6-OHDA) models of Parkinson’s disease (PD). We addressed this issue by performing an intranigral transfection of the human CDNF (hCDNF) gene in the critical period of inflammation after a single intrastriatal 6-OHDA injection in the rat.MethodsAt day 15 after lesion, the plasmids p3xNBRE-hCDNF or p3xNBRE-EGFP, coding for enhanced green florescent protein (EGFP), were transfected into the rat substantia nigra (SN) using neurotensin (NTS)-polyplex. At day 15 post-transfection, we measured nitrite and lipoperoxide levels in the SN. We used ELISA to quantify the levels of TNF-α, IL-1β, IL-6, endogenous rat CDNF (rCDNF) and hCDNF. We also used qRT-PCR to measure rCDNF and hCDNF transcripts, and immunofluorescence assays to evaluate iNOS, CDNF and glial cells (microglia, astrocytes and Neuron/Glial type 2 (NG2) cells). Intact SNs were additional controls.ResultsIn the SN, 6-OHDA triggered nitrosative stress, increased inflammatory cytokines levels, and activated the multipotent progenitor NG2 cells, which convert into astrocytes to produce rCDNF. In comparison with the hemiparkinsonian rats that were transfected with the EGFP gene or without transfection, 6-OHDA treatment and p3xNBRE-hCDNF transfection increased the conversion of NG2 cells into astrocytes resulting in 4-fold increase in the rCDNF protein levels. The overexpressed CDNF reduced nitrosative stress, glial markers and IL-6 levels in the SN, but not TNF-α and IL-1β levels.ConclusionOur results show the anti-inflammatory effect of CDNF in a 6-OHDA rat of Parkinson’s disease. Our results also suggest the possible participation of TNF-α, IL-1β and IL-6 in rCDNF production by astrocytes, supporting their anti-inflammatory role.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-014-0209-0) contains supplementary material, which is available to authorized users.

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“…Cheng and colleague found that virus-mediated overexpression of the conserved dopamine neurotrophic factor (CDNF) in the transected distal sciatic nerve of rat significantly improved the regeneration of axonal and Schwann cells compared with the control groups at 4 and 8 weeks after injury. 41 Further study indicated that the limb muscle weight and functional recovery are closely related with muscle innervation. In a long-term (up to 12 months) denervation study using a rat hind limb model with the transected tibial nerve, Kobayashi and colleague observed a precipitous and profound decrease in the recovery of both muscle mass and integrated motor function in the experimental rats.…”

Section: Rat Model For Limb Regenerationmentioning

confidence: 97%

A concise review of common animal models for the study of limb regeneration

et al. 2016

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Correct selection of an appropriate animal mode to closely mimic human extremity diseases or to exhibit desirable phenotypes of limb regeneration is the first critical step for all scientists in biomedical and regenerative researches. The commonly-used animals in limb regeneration and repairing studies, such as axolotl, mice, and rats, are discussed in the review and other models including cockroaches, dogs, and horses are also mentioned. The review weighs the general advantages, disadvantages, and precedent uses of each model in the context of limb and peripheral injury and subsequent regeneration. We hope that this review can provide the reader an overview of each model, from which to select one for their specific purpose.

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Lentiviral-mediated transfer of CDNF promotes nerve regeneration and functional recovery after sciatic nerve injury in adult rats

Cited by 18 publications

References 26 publications

Neurotrophic Effects of Mu Bie Zi (Momordica cochinchinensis) Seed Elucidated by High-Throughput Screening of Natural Products for NGF Mimetic Effects in PC-12 Cells

Neurotrophic Effects of Mu Bie Zi (Momordica cochinchinensis) Seed Elucidated by High-Throughput Screening of Natural Products for NGF Mimetic Effects in PC-12 Cells

Transient transfection of human CDNF gene reduces the 6-hydroxydopamine-induced neuroinflammation in the rat substantia nigra

A concise review of common animal models for the study of limb regeneration

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