Abstract
Peripheral nerve injuries (PNI) are continuing to be an ever-growing socio-economic burden affecting mainly the young working population and the current clinical treatments to PNI provide a poor clinical outcome involving significant loss of sensation. Thus, our understanding of the underlying factors responsible for the extensive loss of the sensory cutaneous subpopulation in the dorsal root ganglia (DRG) that occurs following injury needs to be improved. The current investigations focus in identifying visual cues of mitochondria-related apoptotic events in the various subpopulations of sensory cutaneous neurons. Sensory neuronal subpopulations were identified using FastBlue retrograde labelling following axotomy. Specialised fluorogenic probes, MitoTracker Red and MitoTracker Orange, were employed to visualise the dynamic changes of the mitochondrial population of neurons. The results reveal a fragmented mitochondrial network in sural neurons following apoptosis, whereas a fused elongated mitochondrial population is present in sensory proprioceptive muscle neurons following tibial axotomy. We also demonstrate the neuroprotective properties of NAC and ALCAR therapy in vitro. The dynamic mitochondrial network breaks down following oxidative exposure to hydrogen peroxide (H2O2), but reinitiates fusion after NAC and ALCAR therapy. In conclusion, this study provides both qualitative and quantitative evidence of the susceptibility of sensory cutaneous sub-population in apoptosis and of the neuroprotective effects of NAC and ALCAR treatment on H2O2-challenged neurons.
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Barsoum MJ, Yuan H, Gerencser AA et al (2006) Nitric oxide-induced mitochondrial fission is regulated by dynamin-related GTPases in neurons. EMBO J 25:3900–3911. doi:10.1038/sj.emboj.7601253
Benn SC, Woolf CJ (2004) Adult neuron survival strategies–slamming on the brakes. Nat Rev Neurosci 5:686–700. doi:10.1038/nrn1477
Bremer J (1990) The role of carnitine in intracellular metabolism. J Clin Chem Clin Biochem 28:297–301
Buckman JF, Hernández H, Kress GJ, Votyakova TV, Pal S, Reynolds IJ (2001) MitoTracker labeling in primary neuronal and astrocytic cultures: influence of mitochondrial membrane potential and oxidants. J Neurosci Methods 104:165–176
Chen L, Liu L, Yin J, Luo Y, Huang S (2009) Hydrogen peroxide-induced neuronal apoptosis is associated with inhibition of protein phosphatase 2A and 5, leading to activation of MAPK pathway. Int J Biochem Cell Biol 41:1284–1295. doi:10.1016/j.biocel.2008.10.029
Cheung EC, McBride HM, Slack RS (2007) Mitochondrial dynamics in the regulation of neuronal cell death. Apoptosis 12:979–992. doi:10.1007/s10495-007-0745-5
Di Cesare Mannelli L, Ghelardini C, Calvani M et al (2007) Protective effect of acetyl-L-carnitine on the apoptotic pathway of peripheral neuropathy. Eur J Neurosci 26:820–827. doi:10.1111/j.1460-9568.2007.05722.x
Esposti MD, Hatzinisiriou I, McLennan H, Ralph S (1999) Bcl-2 and mitochondrial oxygen radicals. New approaches with reactive oxygen species-sensitive probes. J Biol Chem 274:29831–29837
Ferrari G, Yan C, Greene L (1995) N-acetylcysteine (D- and L-stereoisomers) prevents apoptotic death of neuronal cells. J Neurosci 15:2857–2866
Frank S, Gaume B, Bergmann-Leitner ES et al (2001) The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis. Dev Cell 1:515–525
Gaudet AD, Popovich PG, Ramer MS (2011) Wallerian degeneration: gaining perspective on inflammatory events after peripheral nerve injury. J Neuroinflamm 8:110. doi:10.1186/1742-2094-8-110
Glater EE, Schwarz TL (2009) Encyclopedia of Neuroscience: mitochondrial organization and transport in neurons. Elsevier Ltd, Boston, MA
Groves M, Christopherson T, Giometto B, Scaravilli F (1997) Axotomy-induced apoptosis in adult rat primary sensory neurons. J Neurocytol 26:615–624
Hagen TM, Liu J, Lykkesfeldt J et al (2002) Feeding acetyl-L-carnitine and lipoic acid to old rats significantly improves metabolic function while decreasing oxidative stress. Proc Natl Acad Sci USA 99:1870–1875. doi:10.1073/pnas.261708898
Hart A, Terenghi G, Kellerth J, Wiberg M (2004) Sensory neuroprotection, mitochondrial preservation, and therapeutic potential of N-acetyl-cysteine after nerve injury. Neuroscience 125:91–101. doi:10.1016/j.neuroscience.2003.12.040
Heales SJ, Bolanos JP, Stewart VC, Brookes PS, Land JM, Clark JB (1999) Nitric oxide, mitochondria and neurological disease. Biochim Biophys Acta 1410:215–228
Hu P, McLachlan E (2003) Selective reactions of cutaneous and muscle afferent neurons to peripheral nerve transection in rats. J Neurosci 23:10559–10567
Ishii T, Shimpo Y, Matsuoka Y, Kinoshita K (2000) Anti-apoptotic effect of acetyl-l-carnitine and I-carnitine in primary cultured neurons. Jpn J Pharmacol 83:119–124
Lawen A (2003) Apoptosis-an introduction. BioEssays 25:888–896. doi:10.1002/bies.10329
Lundborg G (2000) A 25-year perspective of peripheral nerve surgery: evolving neuroscientific concepts and clinical significance. J Hand Surg Am 25:391–414. doi:10.1053/jhsu.2000.4165
McKay Hart A, Brannstrom T, Wiberg M, Terenghi G (2002) Primary sensory neurons and satellite cells after peripheral axotomy in the adult rat: timecourse of cell death and elimination. Exp Brain Res 142:308–318. doi:10.1007/s00221-001-0929-0
Parcellier A, Tintignac LA, Zhuravleva E et al (2009) The carboxy-terminal modulator protein (CTMP) regulates mitochondrial dynamics. PLoS One 4:e5471. doi:10.1371/journal.pone.0005471
Pettegrew JW, Levine J, McClure RJ (2000) Acetyl-L-carnitine physical-chemical, metabolic, and therapeutic properties: relevance for its mode of action in Alzheimer’s disease and geriatric depression. Mol Psychiatry 5:616–632
Reid AJ, Shawcross SG, Hamilton AE, Wiberg M, Terenghi G (2009) N-acetylcysteine alters apoptotic gene expression in axotomised primary sensory afferent subpopulations. Neurosci Res 65:148–155. doi:10.1016/j.neures.2009.06.008
Reid AJ, Welin D, Wiberg M, Terenghi G, Novikov LN (2010) Peripherin and ATF3 genes are differentially regulated in regenerating and non-regenerating primary sensory neurons. Brain Res 1310:1–7. doi:10.1016/j.brainres.2009.11.011
Rotshenker S (2011) Wallerian degeneration: the innate-immune response to traumatic nerve injury. J Neuroinflamm 8:109. doi:10.1186/1742-2094-8-109
Senoglu M, Nacitarhan V, Kurutas EB, Senoglu N, Altun I, Atli Y, Ozbag D (2009) Intraperitoneal Alpha-Lipoic Acid to prevent neural damage after crush injury to the rat sciatic nerve. J Brachial Plex Peripher Nerve Inj 4:22. doi:10.1186/1749-7221-4-22
Tandrup T, Woolf CJ, Coggeshall RE (2000) Delayed loss of small dorsal root ganglion cells after transection of the rat sciatic nerve. J Comp Neurol 422:172–180. doi:10.1002/(SICI)1096-9861(20000626)422:2<172::AID-CNE2>3.0.CO;2-H
Welin D, Novikova LN, Wiberg M, Kellerth JO, Novikov LN (2008) Survival and regeneration of cutaneous and muscular afferent neurons after peripheral nerve injury in adult rats. Exp Brain Res 186:315–323. doi:10.1007/s00221-007-1232-5
Whittemore ER, Loo DT, Watt JA, Cotman CW (1995) A detailed analysis of hydrogen peroxide-induced cell death in primary neuronal culture. Neuroscience 67:921–932
Wilson AD, Hart A, Brannstrom T, Wiberg M, Terenghi G (2003) Primary sensory neuronal rescue with systemic acetyl-L-carnitine following peripheral axotomy. A dose-response analysis. Br J Plast Surg 56:732–739
Youle RJ, Karbowski M (2005) Mitochondrial fission in apoptosis. Nat Rev Mol Cell Biol 6:657–663. doi:10.1038/nrm1697
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Englezou, P.C., Esposti, M.D., Wiberg, M. et al. Mitochondrial involvement in sensory neuronal cell death and survival. Exp Brain Res 221, 357–367 (2012). https://doi.org/10.1007/s00221-012-3179-4
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DOI: https://doi.org/10.1007/s00221-012-3179-4