Systemic administration of antisense p75NTR oligodeoxynucleotides rescues axotomised spinal motor neurons

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Abstract
The 75 kD low‐affinity neurotrophin receptor (p75NTR) is expressed in developing and axotomised spinal motor neurons. There is now convincing evidence that p75NTR can, under some circumstances, become cytotoxic and promote neuronal cell death. We report here that a single application of antisense p75NTR oligodeoxynucleotides to the proximal nerve stumps of neonatal rats significantly reduces the loss of axotomised motor neurons compared to controls treated with nonsense oligodeoxynucleotides or phosphate‐buffered saline. Our investigations also show that daily systemic intraperitoneal injections of antisense p75NTR oligodeoxynucleotides for 14 days significantly reduce the loss of axotomised motor neurons compared to controls. Furthermore, we found that systemic delivery over a similar period continues to be effective following axotomy when intraperitoneal injections were 1) administered after a delay of 24 hr, 2) limited to the first 7 days, or 3) administered every third day. In addition, p75NTR protein levels were reduced in spinal motor neurons following treatment with antisense p75NTR oligodeoxynucleotides. There were also no obvious side effects associated with antisense p75NTR oligodeoxynucleotide treatments as determined by behavioural observations and postnatal weight gain. Our findings indicate that antisense‐based strategies could be a novel approach for the prevention of motor neuron degeneration associated with injuries or disease. J. Neurosci. Res. 64:11–17, 2001.

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