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Diagnostic and therapeutic strategies following spinal cord and brachial plexus injuries
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.ORCID iD: 0000-0002-2023-247X
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Traumatic injuries to the spinal cord and brachial plexus induce a significant inflammatory response in the nervous tissue with progressive degeneration of neurons and glial cells, and cause considerable physical and mental suffering in affected patients. This thesis investigates the effects of the antioxidants N-acetyl-cysteine (NAC) and acetyl-L- carnitine (ALC) on the survival of motoneurons in the brainstem and spinal cord, the expression of pro-apoptotic and pro-inflammatory cell markers, axonal sprouting and glial cell reactions after spinal hemisection in adult rats. In addition, a novel MRI protocol has been developed to analyse the extent of neuronal degeneration in the spinal cord. Rubrospinal neurons and tibial motoneurons were pre-labelled with the fluorescent tracer Fast Blue one week before cervical C3 or lumbar L5 spinal cord hemisection. The intrathecal treatment with the antioxidants NAC (2.4mg/day) or ALC (0.9 mg/day) was initiated immediately after injury using Alzet2002 osmotic mini pumps. Spinal cord injury increased the expression of apoptotic cell markers BAX and caspase 3, induced significant degeneration of rubrospinal neurons and spinal motoneurons with associated decrease in immunoreactivity for microtubule-associated protein-2 (MAP2) in dendritic branches, synaptophysin in presynaptic boutons and neurofilaments in nerve fibers. Immunostaining for the astroglial marker glial fibrillary acidic protein and microglial markers OX42 and ED1 was markedly increased. Treatment with NAC and ALC attenuated levels of BAX, caspase 3, OX42 and ED1 expression after 2 weeks postoperatively. After 4-8 weeks of continuous intratheca ltreatment, NAC and ALC rescued approximately half of the rubrospinal neurons and spinal motoneurons destined to die, promoted axonal sprouting, restored the density of MAP2 and synaptophysin immunoreactivity and reduced the microglial reaction. However, antioxidant therapy did not affect the reactive astrocytes in the trauma zone. The inflammation modulating properties of ALC were also studied using cultures of human microglial cells. ALC increased the microglial production of interleukin IL-6 and BDNF, thereby possibly mediating the anti-inflammatory and pro-regenerative effects shown in vivo. To study degeneration in the spinal cord following pre-ganglionic and post-ganglionic brachial plexus injuries, adult rat models of ventral root avulsion and peripheral nerve injury were used. A novel MRI protocol was employed and the images were compared to morphological changes found in histological preparations. Ventral root avulsion caused degeneration of dendritic branches and axonal terminals in the spinal cord, followed by significant shrinkage of the ventral horn. Extensive astroglial and microglial reactions were detected in the histological preparations. Peripheral nerve injury reduced the density of dendritic branches but did not cause shrinkage of the ventral horn. Quantitative analysis of MRI images demonstrated changes in the ventral horn following ventral root avulsion only, thus validating the developed MRI technique as a possible tool for the differentiation of pre-ganglionic and post-ganglionic nerve injuries.

Place, publisher, year, edition, pages
Umeå: Umeå University , 2016. , 87 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1848
Keyword [en]
Spinal cord injury, brachial plexus injury, acetyl-L-carnitine, N-acetyl-cysteine, MRI, motoneurons
National Category
Neurosciences
Research subject
Human Anatomy
Identifiers
URN: urn:nbn:se:umu:diva-127519ISBN: 978-91-7601-585-8OAI: oai:DiVA.org:umu-127519DiVA: diva2:1046688
Public defence
2016-12-09, Sal N320, Naturvetarhuset, Umeå universitet, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2016-11-18 Created: 2016-11-14 Last updated: 2016-11-16Bibliographically approved
List of papers
1. Neuroprotective Effects of N-Acetyl-Cysteine and Acetyl-L-Carnitine after Spinal Cord Injury in Adult Rats
Open this publication in new window or tab >>Neuroprotective Effects of N-Acetyl-Cysteine and Acetyl-L-Carnitine after Spinal Cord Injury in Adult Rats
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2012 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 7, no 7, e41086- p.Article in journal (Refereed) Published
Abstract [en]

Following the initial acute stage of spinal cord injury, a cascade of cellular and inflammatory responses will lead to progressive secondary damage of the nerve tissue surrounding the primary injury site. The degeneration is manifested by loss of neurons and glial cells, demyelination and cyst formation. Injury to the mammalian spinal cord results in nearly complete failure of the severed axons to regenerate. We have previously demonstrated that the antioxidants N-acetyl-cysteine (NAC) and acetyl-L-carnitine (ALC) can attenuate retrograde neuronal degeneration after peripheral nerve and ventral root injury. The present study evaluates the effects of NAC and ALC on neuronal survival, axonal sprouting and glial cell reactions after spinal cord injury in adult rats. Tibial motoneurons in the spinal cord were pre-labeled with fluorescent tracer Fast Blue one week before lumbar L5 hemisection. Continuous intrathecal infusion of NAC (2.4 mg/day) or ALC (0.9 mg/day) was initiated immediately after spinal injury using Alzet 2002 osmotic minipumps. Neuroprotective effects of treatment were assessed by counting surviving motoneurons and by using quantitative immunohistochemistry and Western blotting for neuronal and glial cell markers 4 weeks after hemisection. Spinal cord injury induced significant loss of tibial motoneurons in L4-L6 segments. Neuronal degeneration was associated with decreased immunostaining for microtubular-associated protein-2 (MAP2) in dendritic branches, synaptophysin in presynaptic boutons and neurofilaments in nerve fibers. Immunostaining for the astroglial marker GFAP and microglial marker OX42 was increased. Treatment with NAC and ALC rescued approximately half of the motoneurons destined to die. In addition, antioxidants restored MAP2 and synaptophysin immunoreactivity. However, the perineuronal synaptophysin labeling was not recovered. Although both treatments promoted axonal sprouting, there was no effect on reactive astrocytes. In contrast, the microglial reaction was significantly attenuated. The results indicate a therapeutic potential for NAC and ALC in the early treatment of traumatic spinal cord injury.

Place, publisher, year, edition, pages
San Fransisco: Public library of Science, 2012
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-57817 (URN)10.1371/journal.pone.0041086 (DOI)000306507000063 ()
Available from: 2012-08-17 Created: 2012-08-16 Last updated: 2016-11-14Bibliographically approved
2. The effects of N-acetyl-cysteine and acetyl-l-carnitine on neural survival, neuroinflammation and regeneration following spinal cord injury
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
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2014 (English)In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 269, 143-151 p.Article 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.

Keyword
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: 2016-11-14Bibliographically approved
3. The effects of acetyl-­L-­carnitine treatment on neuroinflammation: An in vitro study
Open this publication in new window or tab >>The effects of acetyl-­L-­carnitine treatment on neuroinflammation: An in vitro study
(English)Manuscript (preprint) (Other academic)
Keyword
Microglia, HMC3, Neuroinflammation, Acetyl‐L-­carnitine, Antioxidants
National Category
Neurosciences
Research subject
Human Anatomy
Identifiers
urn:nbn:se:umu:diva-127453 (URN)
Available from: 2016-11-14 Created: 2016-11-14 Last updated: 2016-11-16Bibliographically approved
4. Differentiation of pre- and postganglionic nerve injury using MRI of the spinal cord
Open this publication in new window or tab >>Differentiation of pre- and postganglionic nerve injury using MRI of the spinal cord
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(English)Manuscript (preprint) (Other academic)
Keyword
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)
Available from: 2016-11-11 Created: 2016-11-11 Last updated: 2016-11-16

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