umu.sePublications
Change search
Link to record
Permanent link

Direct link
BETA
Novikova, Liudmila N
Alternative names
Publications (10 of 38) Show all publications
Wiberg, R., Novikova, L. N. & Kingham, P. J. (2018). Evaluation of apoptotic pathways in dorsal root ganglion neurons following peripheral nerve injury. NeuroReport, 779-785
Open this publication in new window or tab >>Evaluation of apoptotic pathways in dorsal root ganglion neurons following peripheral nerve injury
2018 (English)In: NeuroReport, ISSN 0959-4965, E-ISSN 1473-558X, p. 779-785Article in journal (Refereed) Published
Abstract [en]

Peripheral nerve injuries induce significant sensory neuronal cell death in the dorsal root ganglia (DRG); however, the role of specific apoptotic pathways is still unclear. In this study, we performed peripheral nerve transection on adult rats, after which the corresponding DRGs were harvested at 7, 14, and 28 days after injury for subsequent molecular analyses with quantitative reverse transcription-PCR, western blotting, and immunohistochemistry. Nerve injury led to increased levels of caspase-3 mRNA and active caspase-3 protein in the DRG. Increased expression of caspase-8, caspase-12, caspase-7, and calpain suggested that both the extrinsic and the endoplasmic reticulum (ER) stress-mediated apoptotic pathways were activated. Phosphorylation of protein kinase R-like ER kinase further implied the involvement of ER-stress in the DRG. Phosphorylated protein kinase R-like ER kinase was most commonly associated with isolectin B4 (IB4)-positive neurons in the DRG and this may provide an explanation for the increased susceptibility of these neurons to die following nerve injury, likely in part because of an activation of the ER-stress response.

Place, publisher, year, edition, pages
Lippincott Williams & Wilkins, 2018
National Category
Cell and Molecular Biology Neurosciences
Identifiers
urn:nbn:se:umu:diva-127356 (URN)10.1097/WNR.0000000000001031 (DOI)000433096700013 ()29659443 (PubMedID)
Note

Originally included in thesis in manuscript form.

Available from: 2016-11-09 Created: 2016-11-09 Last updated: 2018-06-25Bibliographically approved
McGrath, A. M., Brohlin, M., Wiberg, R., Kingham, P. J., Novikov, L. N., Wiberg, M. & Novikova, L. N. (2018). Long-Term Effects of Fibrin Conduit with Human Mesenchymal Stem Cells and Immunosuppression after Peripheral Nerve Repair in a Xenogenic Model. Cell Medicine, 10, 1-13
Open this publication in new window or tab >>Long-Term Effects of Fibrin Conduit with Human Mesenchymal Stem Cells and Immunosuppression after Peripheral Nerve Repair in a Xenogenic Model
Show others...
2018 (English)In: Cell Medicine, ISSN 2155-1790, Vol. 10, p. 1-13Article in journal (Refereed) Published
Abstract [en]

Introduction: Previously we showed that a fibrin glue conduit with human mesenchymal stem cells (hMSCs) and cyclosporine A (CsA) enhanced early nerve regeneration. In this study long term effects of this conduit are investigated. Methods: In a rat model, the sciatic nerve was repaired with fibrin conduit containing fibrin matrix, fibrin conduit containing fibrin matrix with CsA treatment and fibrin conduit containing fibrin matrix with hMSCs and CsA treatment, and also with nerve graft as control. Results: At 12 weeks 34% of motoneurons of the control group regenerated axons through the fibrin conduit. CsA treatment alone or with hMSCs resulted in axon regeneration of 67% and 64% motoneurons respectively. The gastrocnemius muscle weight was reduced in the conduit with fibrin matrix. The treatment with CsA or CsA with hMSCs induced recovery of the muscle weight and size of fast type fibers towards the levels of the nerve graft group. Discussion: The transplantation of hMSCs for peripheral nerve injury should be optimized to demonstrate their beneficial effects. The CsA may have its own effect on nerve regeneration.

National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-60908 (URN)10.1177/2155179018760327 (DOI)000433910200001 ()
Available from: 2012-11-02 Created: 2012-11-01 Last updated: 2018-09-10Bibliographically approved
Jones, I., Novikova, L. N., Novikov, L. N., Renardy, M., Ullrich, A., Wiberg, M., . . . Kingham, P. J. (2018). Regenerative effects of human embryonic stem cell-derived neural crest cells for treatment of peripheral nerve injury. Journal of Tissue Engineering and Regenerative Medicine, 12(4), E2099-E2109
Open this publication in new window or tab >>Regenerative effects of human embryonic stem cell-derived neural crest cells for treatment of peripheral nerve injury
Show others...
2018 (English)In: Journal of Tissue Engineering and Regenerative Medicine, ISSN 1932-6254, E-ISSN 1932-7005, Vol. 12, no 4, p. E2099-E2109Article in journal (Refereed) Published
Abstract [en]

Surgical intervention is the current gold standard treatment following peripheral nerve injury. However, this approach has limitations, and full recovery of both motor and sensory modalities often remains incomplete. The development of artificial nerve grafts that either complement or replace current surgical procedures is therefore of paramount importance. An essential component of artificial grafts is biodegradable conduits and transplanted cells that provide trophic support during the regenerative process. Neural crest cells are promising support cell candidates because they are the parent population to many peripheral nervous system lineages. In this study, neural crest cells were differentiated from human embryonic stem cells. The differentiated cells exhibited typical stellate morphology and protein expression signatures that were comparable with native neural crest. Conditioned media harvested from the differentiated cells contained a range of biologically active trophic factors and was able to stimulate in vitro neurite outgrowth. Differentiated neural crest cells were seeded into a biodegradable nerve conduit, and their regeneration potential was assessed in a rat sciatic nerve injury model. A robust regeneration front was observed across the entire width of the conduit seeded with the differentiated neural crest cells. Moreover, the up-regulation of several regeneration-related genes was observed within the dorsal root ganglion and spinal cord segments harvested from transplanted animals. Our results demonstrate that the differentiated neural crest cells are biologically active and provide trophic support to stimulate peripheral nerve regeneration. Differentiated neural crest cells are therefore promising supporting cell candidates to aid in peripheral nerve repair.

Keywords
artificial nerve graft, human embryonic stem cells, neural crest cells, peripheral nerve injuries, ripheral nervous system, VELOPMENTAL EVOLUTION, V314B, P95 e Gabsang, 2007, NATURE BIOTECHNOLOGY, V25, P1468
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-147466 (URN)10.1002/term.2642 (DOI)000430395400024 ()29327452 (PubMedID)
Funder
Swedish Research Council, 2014-2306
Available from: 2018-05-28 Created: 2018-05-28 Last updated: 2018-06-09Bibliographically approved
Novikova, L. N., Kolar, M. K., Kingham, P. J., Ullrich, A., Oberhoffner, S., Renardy, M., . . . Novikov, L. N. (2018). Trimethylene carbonate-caprolactone conduit with poly-p-dioxanone microfilaments to promote regeneration after spinal cord injury. Acta Biomaterialia, 66, 177-191
Open this publication in new window or tab >>Trimethylene carbonate-caprolactone conduit with poly-p-dioxanone microfilaments to promote regeneration after spinal cord injury
Show others...
2018 (English)In: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 66, p. 177-191Article in journal (Refereed) Published
Abstract [en]

Spinal cord injury (SCI) is often associated with scarring and cavity formation and therefore bridging strategies are essential to provide a physical substrate for axonal regeneration. In this study we investigated the effects of a biodegradable conduit made from trimethylene carbonate and c-caprolactone (TC) containing poly-p-dioxanone microfilaments (PDO) with longitudinal grooves on regeneration after SCI in adult rats. In vitro studies demonstrated that different cell types including astrocytes, meningeal fibroblasts, Schwann cells and adult sensory dorsal root ganglia neurons can grow on the TC and PDO material. For in vivo experiments, the TC/PDO conduit was implanted into a small 2-3 mm long cavity in the C3-C4 cervical segments immediately after injury (acute SCI) or at 2-5 months after initial surgery (chronic SCI). At 8 weeks after implantation into acute SCI, numerous 5HT-positive descending raphaespinal axons and sensory CGRP-positive axons regenerated across the conduit and were often associated with PDO microfilaments and migrated host cells. Implantation into chronically injured SCI induced regeneration mainly of the sensory CGRP-positive axons. Although the conduit had no effect on the density of OX42-positive microglial cells when compared with SCI control, the activity of GFAP-positive astrocytes was reduced. The results suggest that a TC/PDO conduit can support axonal regeneration after acute and chronic SCI even without addition of exogenous glial or stem cells.

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
Synthetic conduit, Tissue engineering, Biomaterials, Spinal cord injury, Regeneration
National Category
Biomaterials Science
Identifiers
urn:nbn:se:umu:diva-145385 (URN)10.1016/j.actbio.2017.11.028 (DOI)000424309200013 ()29174588 (PubMedID)
Available from: 2018-03-01 Created: 2018-03-01 Last updated: 2018-06-09Bibliographically approved
Wiberg, R., Kingham, P. J. & Novikova, L. (2017). A Morphological and Molecular Characterization of the Spinal Cord after Ventral Root Avulsion or Distal Peripheral Nerve Axotomy Injuries in Adult Rats. Journal of Neurotrauma, 34(3), 652-660
Open this publication in new window or tab >>A Morphological and Molecular Characterization of the Spinal Cord after Ventral Root Avulsion or Distal Peripheral Nerve Axotomy Injuries in Adult Rats
2017 (English)In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 34, no 3, p. 652-660Article in journal (Refereed) Published
Abstract [en]

Retrograde cell death in sensory dorsal root ganglion cells following peripheral nerve injury is well established. However, available data regarding the underlying mechanism behind injury induced motoneuron death are conflicting. By comparing morphological and molecular changes in spinal motoneurons after L4-L5 ventral root avulsion (VRA) and distal peripheral nerve axotomy (PNA) 7 and 14 days postoperatively, we aimed to gain more insight about the mechanism behind injury-induced motoneuron degeneration. Morphological changes in spinal cord were assessed by using quantitative immunohistochemistry. Neuronal degeneration was revealed by decreased immunostaining for microtubuleassociated protein-2 in dendrites and synaptophysin in presynaptic boutons after both VRA and PNA. Significant motoneuron atrophy was already observed at 7 days post-injury, independently of injury type. Immunostaining for ED1 reactive microglia was significantly elevated in all experimental groups, as well as the astroglial marker glial fibrillary acidic protein (GFAP). Quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis of the ventral horn from L4-L5 spinal cord segments revealed a significant upregulation of genes involved in programmed cell death including caspase-3, caspase-8, and related death receptors TRAIL-R, tumor necrosis factor (TNF)-R, and Fas following VRA. In contrast, following PNA, caspase-3 and the death receptor gene expression levels did not differ from the control, and there was only a modest increased expression of caspase-8. Moreover, the altered gene expression correlated with protein changes. These results show that the spinal motoneurons reacted in a similar fashion with respect to morphological changes after both proximal and distal injury. However, the increased expression of caspase-3, caspase-8, and related death receptors after VRA suggest that injury- induced motoneuron degeneration is mediated through an apoptotic mechanism, which might involve both the intrinsic and the extrinsic pathways.

Place, publisher, year, edition, pages
Mary Ann Liebert, 2017
Keywords
apoptosis, motoneurons, PNA, VRA
National Category
Surgery Neurosciences Neurology
Identifiers
urn:nbn:se:umu:diva-127355 (URN)10.1089/neu.2015.4378 (DOI)000392815600013 ()27297543 (PubMedID)
Note

Online Ahead of Print: July 8, 2016

Available from: 2016-11-09 Created: 2016-11-09 Last updated: 2018-06-09Bibliographically approved
Louw, A. M., Kolar, M. K., Novikova, L. N., Kingham, P. J., Wiberg, M., Kjems, J. & Novikov, L. N. (2016). Chitosan polyplex mediated delivery of miRNA-124 reduces activation of microglial cells in vitro and in rat models of spinal cord injury. Nanomedicine: Nanotechnology, Biology and Medicine, 12(3), 643-653
Open this publication in new window or tab >>Chitosan polyplex mediated delivery of miRNA-124 reduces activation of microglial cells in vitro and in rat models of spinal cord injury
Show others...
2016 (English)In: Nanomedicine: Nanotechnology, Biology and Medicine, ISSN 1549-9634, E-ISSN 1549-9642, Vol. 12, no 3, p. 643-653Article in journal (Refereed) Published
Abstract [en]

Traumatic injury to the central nervous system (CNS) is further complicated by an increase in secondary neuronal damage imposed by activated microglia/macrophages. MicroRNA-124 (miR-124) is responsible for mouse monocyte quiescence and reduction of their inflammatory cytokine production. We describe the formulation and ex vivo transfection of chitosan/miR-124 polyplex particles into rat microglia and the resulting reduction of reactive oxygen species (ROS) and TNF-α and lower expression of MHC-II. Upon microinjection into uninjured rat spinal cords, particles formed with Cy3-labeled control sequence RNA, were specifically internalized by OX42 positive macrophages and microglia cells. Alternatively particles injected in the peritoneum were transported by macrophages to the site of spinal cord injury 72h post injection. Microinjections of chitosan/miR-124 particles significantly reduced the number of ED-1 positive macrophages in the injured spinal cord. Taken together, these data present a potential treatment technique to reduce inflammation for a multitude of CNS neurodegenerative conditions.

National Category
Basic Medicine Nano Technology
Research subject
Human Anatomy
Identifiers
urn:nbn:se:umu:diva-117111 (URN)10.1016/j.nano.2015.10.011 (DOI)000373924000007 ()26582736 (PubMedID)
Note

2016-05-16: Originally published in manuscript form.

Available from: 2016-02-22 Created: 2016-02-22 Last updated: 2018-06-07Bibliographically approved
Karalija, A., Novikova, L. N., Orädd, G., Wiberg, M. & Novikov, L. N. (2016). Differentiation of pre- and postganglionic nerve injury using MRI of the spinal cord. PLoS ONE, 11(12), Article ID e0168807.
Open this publication in new window or tab >>Differentiation of pre- and postganglionic nerve injury using MRI of the spinal cord
Show others...
2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 12, article id e0168807Article in journal (Refereed) Published
Abstract [en]

Brachial plexus injury (BPI) is a devastating type of nerve injury, potentially causing loss of motor and sensory function. Principally, BPI is either categorized as preganglionic or post- ganglionic, with the early establishment of injury level being crucial for choosing the correct treatment strategy. Despite diagnostic advances, the need for a reliable, non-invasive method for establishing the injury level remains. We studied the usefulness of in vivo mag- netic resonance imaging (MRI) of the spinal cord for determination of injury level. The find- ings were related to neuronal and glial changes. Rats underwent unilateral L4 & L5 ventral roots avulsion or sciatic nerve axotomy. The injuries served as models for pre- and postgan- glionic BPI, respectively. MRI of the L4/L5 spinal cord segments 4 weeks after avulsion showed ventral horn (VH) shrinkage on the injured side compared to the uninjured side. Axotomy induced no change in the VH size on MRI. Following avulsion, histological sections of L4/L5 revealed shrinkage in the VH grey matter area occupied by NeuN-positive neurons, loss of microtubular-associated protein-2 positive dendritic branches (MAP2), pan-neurofila- ment positive axons (PanNF), synaptophysin-positive synapses (SYN) and increase in immunoreactivity for the microglial OX42 and astroglial GFAP markers. Axotomy induced no changes in NeuN-reactivity, modest decrease of MAP2 immunoreactivity, no changes in SYN and PanNF labelling, and a modest increase in OX42 and SYN labeling. Histological and radiological findings were congruent when assessing changes after axotomy, while MRI somewhat underestimated the shrinkage. This study indicates a potential diagnostic value of structural spinal cord MRI following BPI. 

Keywords
Neural injury, Surgery, MRI, Rat, Axonal injury, Brachial plexus injury
National Category
Neurosciences
Research subject
Human Anatomy
Identifiers
urn:nbn:se:umu:diva-127437 (URN)10.1371/journal.pone.0168807 (DOI)000391229300032 ()
Available from: 2016-11-11 Created: 2016-11-11 Last updated: 2018-06-09Bibliographically approved
Wiberg, R., Jonsson, S., Novikova, L. N. & Kingham, P. J. (2015). Investigation of the Expression of Myogenic Transcription Factors, microRNAs and Muscle-Specific E3 Ubiquitin Ligases in the Medial Gastrocnemius and Soleus Muscles following Peripheral Nerve Injury. PLoS ONE, 10(12), Article ID e0142699.
Open this publication in new window or tab >>Investigation of the Expression of Myogenic Transcription Factors, microRNAs and Muscle-Specific E3 Ubiquitin Ligases in the Medial Gastrocnemius and Soleus Muscles following Peripheral Nerve Injury
2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 12, article id e0142699Article in journal (Refereed) Published
Abstract [en]

Despite surgical innovation, the sensory and motor outcome after a peripheral nerve injury remains incomplete. One contributing factor to the poor outcome is prolonged denervation of the target organ, leading to apoptosis of both mature myofibres and satellite cells with subsequent replacement of the muscle tissue with fibrotic scar and adipose tissue. In this study, we investigated the expression of myogenic transcription factors, muscle specific microRNAs and muscle-specific E3 ubiquitin ligases at several time points following denervation in two different muscles, the gastrocnemius (containing predominantly fast type fibres) and soleus (slow type) muscles, since these molecules may influence the degree of atrophy following denervation. Both muscles exhibited significant atrophy (compared with the contra-lateral sides) at 7 days following either a nerve transection or crush injury. In the crush model, the soleus muscle showed significantly increased muscle weights at days 14 and 28 which was not the case for the gastrocnemius muscle which continued to atrophy. There was a significantly more pronounced up-regulation of MyoD expression in the denervated soleus muscle compared with the gastrocnemius muscle. Conversely, myogenin was more markedly elevated in the gastrocnemius versus soleus muscles. The muscles also showed significantly contrasting transcriptional regulation of the microRNAs miR-1 and miR-206. MuRF1 and Atrogin-1 showed the highest levels of expression in the denervated gastrocnemius muscle. This study provides further insights regarding the intracellular regulatory molecules that generate and maintain distinct patterns of gene expression in different fibre types following peripheral nerve injury.

Place, publisher, year, edition, pages
San Francisco: Public Library Science, 2015
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-114579 (URN)10.1371/journal.pone.0142699 (DOI)000367092300002 ()26691660 (PubMedID)
Available from: 2016-02-16 Created: 2016-01-25 Last updated: 2018-06-07Bibliographically approved
Kingham, P. J., Kolar, M. K., Novikova, L. N., Novikov, L. N. & Wiberg, M. (2014). Stimulating the neurotrophic and angiogenic properties of human adipose-derived stem cells enhances nerve repair. Stem Cells and Development, 23(7), 741-754
Open this publication in new window or tab >>Stimulating the neurotrophic and angiogenic properties of human adipose-derived stem cells enhances nerve repair
Show others...
2014 (English)In: Stem Cells and Development, ISSN 1547-3287, E-ISSN 1557-8534, Vol. 23, no 7, p. 741-754Article in journal (Refereed) Published
Abstract [en]

In future, adipose-derived stem cells (ASC) might be used to treat neurological disorders. In this study, the neurotrophic and angiogenic properties of human ASC were evaluated, and their effects in a peripheral nerve injury model were determined. In vitro growth factor stimulation of the cells resulted in increased secretion of brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF), vascular endothelial growth factor-A (VEGF-A), and angiopoietin-1 proteins. Conditioned medium from stimulated cells increased neurite outgrowth of dorsal root ganglia (DRG) neurons. Similarly, stimulated cells showed an enhanced ability to induce capillary-like tube formation in an in vitro angiogenesis assay. ASC were seeded into a fibrin conduit that was used to bridge a 10 mm rat nerve gap. After 2 weeks, the animals treated with control or stimulated ASC showed an enhanced axon regeneration distance. Stimulated cells evoked more total axon growth. Analysis of regeneration and apoptosis-related gene expression showed that both ASC and stimulated ASC enhanced GAP-43 and activating transcription factor 3 (ATF-3) expression in the spinal cord and reduced c-jun expression in the DRG. Caspase-3 expression in the DRG was reduced by stimulated ASC. Both ASC and stimulated ASC also increased the vascularity of the fibrin nerve conduits. Thus, ASC produce functional neurotrophic and angiogenic factors, creating a more desirable microenvironment for nerve regeneration.

National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-83708 (URN)10.1089/scd.2013.0396 (DOI)000333613700007 ()24124760 (PubMedID)
Available from: 2013-12-05 Created: 2013-12-05 Last updated: 2018-06-08Bibliographically approved
Karalija, A., Novikova, L. N., Kingham, P. J., Wiberg, M. & Novikov, L. N. (2014). The effects of N-acetyl-cysteine and acetyl-l-carnitine on neural survival, neuroinflammation and regeneration following spinal cord injury. Neuroscience, 269, 143-151
Open this publication in new window or tab >>The effects of N-acetyl-cysteine and acetyl-l-carnitine on neural survival, neuroinflammation and regeneration following spinal cord injury
Show others...
2014 (English)In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 269, p. 143-151Article in journal (Refereed) Published
Abstract [en]

Traumatic spinal cord injury induces a long-standing inflammatory response in the spinal cord tissue, leading to a progressive apoptotic death of spinal cord neurons and glial cells. We have recently demonstrated that immediate treatment with the antioxidants N-acetyl-cysteine (NAC) and acetyl-l-carnitine (ALC) attenuates neuroinflammation, induces axonal sprouting, and reduces the death of motoneurons in the vicinity of the trauma zone 4weeks after initial trauma. The objective of the current study was to investigate the effects of long-term antioxidant treatment on the survival of descending rubrospinal neurons after spinal cord injury in rats. It also examines the short- and long-term effects of treatment on apoptosis, inflammation, and regeneration in the spinal cord trauma zone. Spinal cord hemisection performed at the level C3 induced a significant loss of rubrospinal neurons 8weeks after injury. At 2weeks, an increase in the expression of the apoptosis-associated markers BCL-2-associated X protein (BAX) and caspase 3, as well as the microglial cell markers OX42 and ectodermal dysplasia 1 (ED1), was seen in the trauma zone. After 8weeks, an increase in immunostaining for OX42 and the serotonin marker 5HT was detected in the same area. Antioxidant therapy reduced the loss of rubrospinal neurons by approximately 50%. Treatment also decreased the expression of BAX, caspase 3, OX42 and ED1 after 2weeks. After 8weeks, treatment decreased immunoreactivity for OX42, whereas it was increased for 5HT. In conclusion, this study provides further insight in the effects of treatment with NAC and ALC on descending pathways, as well as short- and long-term effects on the spinal cord trauma zone.

Keywords
adult rats, spinal cord, motoneurons, antioxidants, apoptosis
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-88071 (URN)10.1016/j.neuroscience.2014.03.042 (DOI)000335903900014 ()24680856 (PubMedID)
Available from: 2014-04-23 Created: 2014-04-23 Last updated: 2018-06-08Bibliographically approved
Organisations

Search in DiVA

Show all publications