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Sensory neuroprotection, mitochondrial preservation, and therapeutic potential of N-acetyl-cysteine after nerve injury.
Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Hand Surgery.
Umeå University, Faculty of Medicine, Integrative Medical Biology, Anatomy.
Umeå University, Faculty of Medicine, Integrative Medical Biology, Anatomy. Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Hand Surgery.
2004 (English)In: Neuroscience, ISSN 0306-4522, Vol. 125, no 1, 91-101 p.Article in journal (Refereed) Published
Abstract [en]

Neuronal death is a major factor in many neuropathologies, particularly traumatic, and yet no neuroprotective therapies are currently available clinically, although antioxidants and mitochondrial protection appear to be fruitful avenues of research. The simplest system involving neuronal death is that of the dorsal root ganglion after peripheral nerve trauma, where the loss of approximately 40% of primary sensory neurons is a major factor in the overwhelmingly poor clinical outcome of the several million nerve injuries that occur each year worldwide. N-acetyl-cysteine (NAC) is a glutathione substrate which is neuroprotective in a variety of in vitro models of neuronal death, and which may enhance mitochondrial protection. Using TdT uptake nick-end labelling (TUNEL), optical disection, and morphological studies, the effect of systemic NAC treatment upon L4 and 5 primary sensory neuronal death after sciatic nerve transection was investigated. NAC (150 mg/kg/day) almost totally eliminated the extensive neuronal loss found in controls both 2 weeks (no treatment 21% loss, NAC 3%, P=0.03) and 2 months after axotomy (no treatment 35% loss, NAC 3%, P=0.002). Glial cell death was reduced (mean number TUNEL positive cells 2 months after axotomy: no treatment 51/ganglion pair, NAC 16/ganglion pair), and mitochondrial architecture was preserved. The effects were less profound when a lower dose was examined (30 mg/kg/day), although significant neuroprotection still occurred. This provides evidence of the importance of mitochondrial dysregulation in axotomy-induced neuronal death in the peripheral nervous system, and suggests that NAC merits investigation in CNS trauma. NAC is already in widespread clinical use for applications outside the nervous system; it therefore has immediate clinical potential in the prevention of primary sensory neuronal death, and has therapeutic potential in other neuropathological systems.

Place, publisher, year, edition, pages
2004. Vol. 125, no 1, 91-101 p.
Keyword [en]
Acetylcysteine/*therapeutic use, Animals, Axotomy, Dose-Response Relationship; Drug, Ganglia; Spinal/drug effects/pathology, In Situ Nick-End Labeling, Lumbosacral Region, Male, Microscopy; Electron, Mitochondria/*drug effects/ultrastructure, Nerve Degeneration/*drug therapy, Neurons; Afferent/drug effects/*pathology, Neuroprotective Agents/*therapeutic use, Rats, Sciatic Nerve/pathology/surgery
URN: urn:nbn:se:umu:diva-12710DOI: doi:10.1016/j.neuroscience.2003.12.040PubMedID: 15051148OAI: diva2:152381
Available from: 2007-12-11 Created: 2007-12-11 Last updated: 2009-10-13Bibliographically approved
In thesis
1. Sensory neuronal protection & improving regeneration after peripheral nerve injury
Open this publication in new window or tab >>Sensory neuronal protection & improving regeneration after peripheral nerve injury
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Peripheral nerve trauma is a common cause of considerable functional morbidity, and healthcare expenditure. Particularly in the ~15% of injuries unsuitable for primary repair, standard clinical management results in inadequate sensory restitution in the majority of cases, despite the rigorous application of complex microsurgical techniques. This can largely be explained by the failure of surgical management to adequately address the neurobiological hurdles to optimal regeneration. Most significant of these is the extensive sensory neuronal death that follows injury, and which is accompanied by a reduction in the regenerative potential of axotomised neurons, and in the supportive capacity of the Schwann cell population if nerve repair is delayed.

The present study aimed to accurately delineate the timecourse of neuronal death, in order to identify a therapeutic window during which clinically applicable neuroprotective strategies might be adopted. It then proceeded to investigate means to increase the regenerative capacity of chronically axotomised neurons, and to augment the Schwann cells’ ability to promote that regenerative effort.

Unilateral sciatic nerve transection in the rat was the model used, initially assessing neuronal death within the L4&5 dorsal root ganglia by a combination of morphology, TdT uptake nick-end labelling (TUNEL), and statistically unbiased estimation of neuronal loss using the stereological optical disector technique. Having identified 2 weeks, and 2 months post-axotomy as the most biologically relevant timepoints to study, the effect upon neuronal death of systemic treatment with acetyl-L-carnitine (ALCAR 10, or 50mg/kg/day) or N-acetyl-cysteine (NAC 30, or 150mg/kg/day) was determined. A model of secondary nerve repair was then adopted; either 2 or 4 months after unilateral sciatic nerve division, 1cm gap repairs were performed using either reversed isografts, or poly-3-hydroxybutyrate (PHB) conduits containing an alginate-fibronectin hydrogel. Six weeks later nerve regeneration and the Schwann cell population were quantified by digital image analysis of frozen section immunohistochemistry.

Sensory neuronal death begins within 24 hours of injury, but takes 1 week to translate into significant neuronal loss. The rate of neuronal death peaks 2 weeks after injury, and neuronal loss is essentially complete by 2 months post-axotomy. Nerve repair is incompletely neuroprotective, but the earlier it is performed the greater the benefit. Two clinically safe pharmaceutical agents, ALCAR & NAC, were found to virtually eliminate sensory neuronal death after peripheral nerve transection. ALCAR also enhanced nerve regeneration independently of its neuroprotective role. Plain PHB conduits were found to be technically simple to use, and supported some regeneration, but were not adequate in themselves. Leukaemia inhibitory factor enhanced nerve regeneration, though cultured autologous Schwann cells (SC’s) were somewhat more effective. Both were relatively more efficacious after a 4 month delay in nerve repair. The most profuse regeneration was found with recombinant glial growth factor (rhGGF-2) in repairs performed 2 months after axotomy, with results that were arguably better than were obtained with nerve grafts. A similar conclusion can be drawn from the result found using both rhGGF-2 and SC’s in PHB conduits 4 months after axotomy.

In summary, these findings reinforce the significance of sensory neuronal death in peripheral nerve trauma, and the possibility of its` limitation by early nerve repair. Two agents for the adjuvant therapy of such injuries were identified, that can virtually eliminate neuronal death, and enhance regeneration. Elements in the creation of a bioartificial nerve conduit to replace, or surpass autologous nerve graft for secondary nerve repair are presented.

Place, publisher, year, edition, pages
Umeå: Kirurgisk och perioperativ vetenskap, 2003. 61 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 679
Neurosciences, cell death, TUNEL, optical disection, dorsal root ganglion, peripheral nerve, nerve conduit, Schwann cell, glial growth factor, leukaemia inhibitory factor, acetyl-L-carnitine, N-acetyl-cysteine, Neurovetenskap
National Category
Research subject
urn:nbn:se:umu:diva-52 (URN)91-7305-370-8 (ISBN)
Public defence
2003-05-28, Stora föreläsningssalen, Biologihuset, Umeå, 09:00 (English)
Available from: 2003-06-19 Created: 2003-06-19 Last updated: 2009-10-13Bibliographically approved

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