Citation: Tobinick E (2006) Spinal Delivery of p38: TNF-alpha Inhibitors. PLoS Med 3(11): e511. doi:10.1371/journal.pmed.0030511
Published: November 28, 2006
Copyright: © 2006 Edward Tobinick. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The author received no specific funding for this article.
Competing interests: The author has pending and issued US and international patents, including US patents 6,015,557; 6,982,089; and others, which describe methods of perispinal administration of etanercept. The author also owns stock in Amgen.
The new study by Boyle and colleagues provides important data on basic science mechanisms involved in pain and inflammation . Their data, along with that from previous studies, provides further basic scientific 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 occurring 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 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 . This evidence, along with the basic scientific 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 DL, Jones TL, Hammaker D, Svensson CI, Rosengren S, et al. (2006) Regulation of peripheral inflammation by spinal p38 MAP kinase in rats. PLoS Med 3: e338. doi:10.1371/journal.pmed.0030338.
- 2. Schafers M, Svensson CI, Sommer C, Sorkin LS (2003) Tumor necrosis factor-alpha induces mechanical allodynia after spinal nerve ligation by activation of p38 MAPK in primary sensory neurons. J Neurosci 23: 2517–2521.
- 3. Culbert AA, Skaper SD, Howlett DR, Evans NA, Facci L, et al. (2006) 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 281: 23658–23667.
- 4. Takeuchi H, Jin S, Wang J, Zhang G, Kawanokuchi J, et al. (2006) Tumor necrosis factor-alpha induces neurotoxicity via glutamate release from hemichannels of activated microglia in an autocrine manner. J Biol Chem 281: 21362–21368.
- 5. Stellwagen D, Malenka RC (2006) Synaptic scaling mediated by glial TNF-alpha. Nature 440: 1054–1059.
- 6. Sommer C, Schafers M, Marziniak M, Toyka KV (2001) Etanercept reduces hyperalgesia in experimental painful neuropathy. J Peripher Nerv Syst 6: 67–72.
- 7. Tobinick E, Gross H, Weinberger A, Cohen H (2006) TNF-alpha modulation for treatment of Alzheimer's disease: A 6-month pilot study. MedGenMed 8: 25.
- 8. Tobinick EL, Britschgi-Davoodifar S (2003) Perispinal TNF-alpha inhibition for discogenic pain. Swiss Med Wkly 133: 170–177.
- 9. Tobinick E (2006) The cerebrospinal venous system: Anatomy, physiology, and clinical implications. MedGenMed 8: 53.
- 10. Byrod G, Rydevik B, Johansson BR, Olmarker K (2000) Transport of epidurally applied horseradish peroxidase to the endoneurial space of dorsal root ganglia: A light and electron microscopic study. J Peripher Nerv Syst 5: 218–226.