N-acetylcysteine alters apoptotic gene expression in axotomised primary sensory afferent subpopulations.
Novel approaches are required in peripheral nerve injury management because current surgical techniques, which do not address axotomy-induced neuronal death, lead to deficient sensory recovery. Sensory neuronal death has functional preference with cutaneous neurons dying in great numbers whilst muscle afferents survive axotomy. This offers the potential of comparing similar cell types that suffer distinct fates upon nerve injury. Here, a novel approach, combining in vivo rat nerve injury model with laser microdissection and quantitative real-time polymerase chain reaction, identifies crucial disparities in apoptotic gene expression attributable to subpopulations of differing sensory modalities and examines the response to N-acetylcysteine (NAC) therapy. We show that axotomised muscle afferent neurons survive injury due to a neuroprotective response which markedly downregulates Bax and caspase-3 mRNA. In contrast, axotomised cutaneous sensory neurons significantly upregulate caspase-3 and alter both Bcl-2 and Bax expression such that pro-apoptotic Bax predominates. N-Acetylcysteine (NAC) intervention promotes neuroprotection of cutaneous sensory neurons through considerable upregulation of Bcl-2 and downregulation of both Bax and caspase-3 mRNA. The data presented identifies differential activation of apoptotic genes in axotomised neuronal subpopulations. Furthermore, NAC therapy instigates apoptotic gene expression changes in axotomised neurons, thereby offering pharmacotherapeutic potential in the clinical treatment of nerve injury.
Reid
Adam J
AJ
Blond McIndoe Research Laboratories, Tissue Injury & Repair Group, University of Manchester, UK. adam.reid@manchester.ac.uk
Shawcross
Susan G
SG
Hamilton
Alex E
AE
Wiberg
Mikael
M
Terenghi
Giorgio
G
D000111:Acetylcysteine / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D019771:Axotomy; D053148:Caspase 3 / Q000235:genetics; D002470:Cell Survival / Q000502:physiology; D019610:Cytoprotection / Q000502:physiology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D016166:Free Radical Scavengers / Q000494:pharmacology / Q000627:therapeutic use; D005727:Ganglia, Spinal / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D008297:Male; D018482:Muscle, Skeletal / Q000294:innervation; D059348:Peripheral Nerve Injuries; D010525:Peripheral Nerves / Q000378:metabolism / Q000503:physiopathology; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011984:Sensory Receptor Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D012867:Skin / Q000294:innervation; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000235:genetics
D016166:Free Radical Scavengers; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D051028:bcl-2-Associated X Protein; D053148:Caspase 3; D000111:Acetylcysteine