Motor neuron degeneration after sciatic nerve avulsion in adult rat evolves with oxidative stress and is apoptosis

Abstract

The mechanisms for motor neuron degeneration and regeneration in adult spinal cord following axotomy and target deprivation are not fully understood. We used a unilateral sciatic nerve avulsion model in adult rats to test the hypothesis that retrograde degeneration of motor neurons resembles apoptosis. By 21 days postlesion, the number of large motor neurons in lumbar spinal cord was reduced by approximately 30%. The death of motor neurons was confirmed using the terminal transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling method for detecting fragmentation of nuclear DNA. Motor neuron degeneration was characterized by aberrant accumulation of perikaryal phosphorylated neurofilaments. Structurally, motor neuron death was apoptosis. Apoptotic motor neurons undergo chromatolysis followed by progressive cytoplasmic and nuclear condensation with chromatin compaction into uniformly large round clumps. Prior to apoptosis, functionally active mitochondria accumulate within chromatolytic motor neurons, as determined by cytochrome c oxidase activity. These dying motor neurons sustain oxidative damage to proteins and nucleic acids within the first 7 days after injury during the progression of apoptosis, as identified by immunodetection of nitrotyrosine and hydroxyl-modified deoxyguanosine and guanosine. We conclude that the retrograde death of motor neurons in the adult spinal cord after sciatic nerve avulsion is apoptosis. Accumulation of active mitochondria within the perikaryon and oxidative damage to nucleic acids and proteins may contribute to the mechanisms for apoptosis of motor neurons in the adult spinal cord.

Autophagy, and BiP level decrease are early key events in retrograde degeneration of motoneurons

“…It may also lead to therapeutical pespectives in spinal cord trauma and MN diseases, as the root avulsion model has been proposed as non-genetic model for some neurodegenerative diseases. 4 In this regard, gene therapy promoting overexpression of BiP seems a promising strategy.…”

“…Thus, after distal axotomy a nonsignificant loss of motoneurons has been found, 3 whereas lesions at the spinal root, due to traction or avulsion, in the adult lead to progressive and marked loss of the axotomized MNs. 4,5 There exist controversial studies about the processes that lead to this MN degeneration; some authors claimed that it is mainly an apoptotic process, 4 whereas others pointed to a rather necrotic death. 6,7 Axotomy produces an initial rupture of the plasma membrane that leads to calcium influx 8 and disassembly of the cytoskeleton, triggering long-lasting electrophysiological disturbances involving the entire neuron.…”

On the use of fast blue, fluoro-gold and diamidino yellow for retrograde tracing after peripheral nerve injury: uptake, fading, dye interactions, and toxicity

“…By analogy to findings in the DRGs (Ygge and Aldskogius, 1984;Arvidsson et al, 1986;Groves et al, 1997), an increased amount of neuronal disappearence in the motor columns could take place if very long survival times were studied. Furthermore, the degree of motoneuronal (Martin et al, 1999) and DRG neuronal (Ygge, 1989) death after axonal injury in adult mammals was found to be mainly dependent on the severity of the injury and on the distance from the axonal injury to the neuronal body.…”

Critical interval of somal calcium transient after neurite transection determines B104 cell survival

“…Apoptosis is induced after in vivo axotomy of retinal ganglion, spinal cord, and cortical neurons (Kermer et al, 1998;AlAbdulla et al, 1998;Chaudary et al, 1999;Martin, et al, 1999) or percussive trauma to the cortex or spinal cord (Yakovlev et al, 1997). Neurons also die via apoptosis following growth factor withdrawal (Cardone et al, 1998), glutamate excitotoxicity (Portera-Cailliau et al, 1997), cell exposure to reactive oxygen species (Volbracht et al, 2001;Leist et al, 1997), ischemia (Namura et al, 1998;Velier et al, 1999), and normal development (O'Connor et al, 1974).…”