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Spinal delivery of p38 and TNF-alpha inhibitors

Posted by plosmedicine on 30 Mar 2009 at 23:59 GMT

Author: Edward Tobinick
Position: Assistant Clinical Professor of Medicine
Institution: UCLA School of Medicine
Submitted Date: September 08, 2006
Published Date: September 12, 2006
This comment was originally posted as a “Reader Response” on the publication date indicated above. All Reader Responses are now available as comments.

The new study by Boyle and colleagues provides important data on basic science mechanisms involved in pain and inflammation[1]. Their data, along with that from previous studies, provides further basic science evidence documenting p38/TNF-alpha interactions, and suggests that spinal p38 or spinal TNF-alpha blockade may have clinical relevance[1-2]. The present study documents that p38 activation may be occuring predominantly in microglia. The present study, therefore, joins other recent work which suggests the importance of p38-glial-TNF-alpha interactions in neuroinflammation and synaptic signaling[3-6]. This increasing evidence may have clinical relevance not only to arthritis pain, but also to the pathogenesis of various forms of neuropathic pain and Alzheimer's disease[1-8].

Because the present study suggests that spinal delivery may be more effective than systemic delivery when attempting to intervene in spinally-mediated inflammatory mechanisms, the authors note the potential importance of developing compounds that may bypass the blood-brain barrier. The present author speculates that the rapid and significant clinical effects noted following perispinal administration of etanercept in small pilot studies suggest that perispinal administration of p38 inhibitors may also allow these compounds to reach the spinal cord and dorsal root ganglia in therapeutically effective amounts[7-8]. It is hypothesized that this may be possible via passage through the vertebral portion of the cerebrospinal venous system, and this may explain the efficacy of perispinal etanercept in the above cited studies[7-9]. Previous studies have documented that epidural administration of large molecules may result in delivery to the endoneurial space[10]. This evidence, along with the basic science evidence provided by the present study of the potential clinical importance of spinal delivery, supports consideration of investigation of this novel route of administration.

1. Boyle, D.L., et al., Regulation of Peripheral Inflammation by Spinal p38 MAP Kinase in Rats. PLoS Med, 2006. 3(9).
2. Schafers, M., et al., Tumor necrosis factor-alpha induces mechanical allodynia after spinal nerve ligation by activation of p38 MAPK in primary sensory neurons. J Neurosci, 2003. 23(7): p. 2517-21.
3. Culbert, A.A., et al., MAPK-activated Protein Kinase 2 Deficiency in Microglia Inhibits Pro-inflammatory Mediator Release and Resultant Neurotoxicity: RELEVANCE TO NEUROINFLAMMATION IN A TRANSGENIC MOUSE MODEL OF ALZHEIMER DISEASE. J Biol Chem, 2006. 281(33): p. 23658-67.
4. Takeuchi, H., et al., Tumor necrosis factor-alpha induces neurotoxicity via glutamate release from hemichannels of activated microglia in an autocrine manner. J Biol Chem, 2006.
5. Stellwagen, D. and R.C. Malenka, Synaptic scaling mediated by glial TNF-alpha. Nature, 2006. 440(7087): p. 1054-9.
6. Sommer, C., et al., Etanercept reduces hyperalgesia in experimental painful neuropathy. J Peripher Nerv Syst, 2001. 6(2): p. 67-72.
7. Tobinick, E., et al., TNF-alpha Modulation for Treatment of Alzheimer's Disease: A 6-Month Pilot Study. MedGenMed, 2006. 8(2): p. 25.
8. Tobinick, E.L. and S. Britschgi-Davoodifar, Perispinal TNF-alpha inhibition for discogenic pain. Swiss Med Wkly, 2003. 133(11-12): p. 170-7.
9. Tobinick, E., The cerebrospinal venous system: anatomy, physiology, and clinical implications. MedGenMed, 2006. 8(1): p. 53.
10. Byrod, G., et al., Transport of epidurally applied horseradish peroxidase to the endoneurial space of dorsal root ganglia: a light and electron microscopic study. J Peripher Nerv Syst, 2000. 5(4): p. 218-26.

Competing interests declared: The author has pending and issued U.S. and international patents, including US patents 6,015,557; 6,982,089, and others, which describe methods of perispinal administration of etanercept, and owns stock in Amgen.