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 ∼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. © 1999 John Wiley & Sons, Inc. J Neurobiol 40: 185–201, 1999

Spinal Motor Neuronal Degeneration After Knee Joint Immobilization in the Guinea Pig

“…25 As a consequence of such lesions, the spinal motor neurons showed chromatolysis, loss of Nissl bodies, and dramatic perikarayal shrinkage, leading to apoptosis. 26 In the current study, however, no nerve lesions were involved; yet, the data revealed a series of progressive motor neuronal and axonal degenerative changes over periods of knee joint immobilization. These changes consisted of axonal demyelination, up-regulated neuronal NOS-LI, folding of nuclear envelope, and increases in nuclear chromatic density.…”

“…For example, nitric oxide-mediated oxidative stress after nerve lesions would cause subcellular degenerative changes before neuronal death, including interruption of the integrity of mitochondria, redistribution of rough endoplasmic reticulum, shrunken nuclear envelop, and small compact clumps of chromatin. 26 Although these findings are not identical, they are similar to the findings of this study.…”

DNA base-excision repair enzyme apurinic/apyrimidinic endonuclease/redox factor-1 is increased and competent in the brain and spinal cord of individuals with amyotrophic lateral sclerosis

“…It is possible that APE/Ref-1 is induced in response to oxidative stress occurring during the chromatolytic stage of motor neuron degeneration. Recent studies have shown that neurons undergoing apoptosis in animal models pass through three major structural stages of degeneration: chromatolysis, somatodendritic atrophy, and apoptosis (Al-Abdulla and Martin, 1998;Martin et al, 1999;Martin and Liu, 2002). Motor neurons in ALS appear to follow this staging scheme of degeneration (Martin, 1999).…”

Nitric oxide has dual opposite roles during early and late phases of apoptosis in cerebellar granule neurons

“…Formation of nitrotyrosine residues has been correlated with neurodegenerative events and has been detected in the spinal cord after ventral root avulsion [62], in transgenic mice expressing amyotrophic lateral sclerosis (ALS)-mutant SOD [63], both in upper and lower motor neurons of ASL-patients [15], and in motor neuron apoptosis [50]. The results in Fig.…”