Glia Activation Inhibitors in neuropathic pain

Glia activation inhibitors have become hot, once the neurological community understood that neurons are not solely responsible for neuropathic pain. Meanwhile, it has been widely recognized that glia and asterocytes play an important role in the up regulation of neuropathic pain (winding up).

16519526-Spectraldesign-Dreamstime-INP Glia Acitivation Inhibitors in neuropathic painThese non neural cells release neuro excitatory, pain-enhancing substances such as pro-inflammatory cytokines. And these cytokines deregulate the actions of our own endogenous opioids.

Thus, new molecules are under development to inhibit the activation of the glia cells. Gliopathic pain is a new term coined for neuropathic pain. And activated glia and asterocytes are increasingly recognized as key players in chronic pain.[1][2]

Ibudilast and others 

The NCE AV411 (ibudilast), suppresses the production of pro-inflammatory cytokines — (interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, and IL-6). And enhance the production of the anti-inflammatory cytokine IL-10.

This compound also up regulates releases of neurotrophic factors plying a role in neuropathic pain, such as glial-derived neurotrophic factor and nerve growth factor.

AV411, ATL313 and XT101 in for neuropathic pain 

AV411 is currently developed by Avigen, Inc., and is in phase II. In the  preclinical phase still is the glial attenuator ATL313, an intrathecal drug being developed by Adenosine Therapeutics, LLC.

This NCE influences the maturaion of glia cells and could shif glial cells from producing pro-inflammatory cytokines to glia cells producing anti-inflammatory cytokines. The drug is developed to administer intrathecally via a non-viral, microparticle-delivered plasmid.

More on ibudilast, XT101

The glial blocker XT101 demonstrated in the preclinical phase to be able to upregulates IL-10. It is developed by Xalud Therapeutics, Inc.

Data on AV411 (ibudilast) has been presented by Paul Rolan, M.D., FRACP, Professor of Pharmacology, University of Adelaide, Australia, at the 10th International Conference on the Mechanisms and Treatment of Neuropathic Pain held in Salt Lake City, Utah, in 2007.

Summary data were presented at the meeting demonstrating AV411 to be safe and well tolerated in a phase IIa study at doses up to 80 mg/day. The press release of the company stated:

  • The data also indicated a favorable dose to blood plasma level relationship. Although in this preliminary efficacy trial, there appears to be no difference in overall mean visual analog scale (VAS) scores between active and placebo arms. A pharmacokinetic assessment indicates an encouraging correlation between AV411 plasma levels and the number of patients that reported a decrease in pain scores, as assessed by VAS. Additionally, there was a trend towards decreased opioid use that correlated with increased AV411 dose.

These were the results from a two-week, placebo-controlled, double-blinded study, primarily in patients suffering from diabetic neuropathy. The dose-escalating trial evaluated doses up to 80 mg/day. The trial was also designed to generate data to support larger clinical trials that Avigen started in 2008.  

October 2010, Jan M. Keppel Hesselink, MD, PhD
‘Glia Acitivation Inhibitors in neuropathic pain’

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[1] Obata H, Sakurazawa S, Kimura M, Saito S. | Activation of astrocytes in the spinal cord contributes to the development of bilateral allodynia after peripheral nerve injury in rats. | Brain Res. | 2010 Dec 2;1363:72-80. Epub 2010 Oct 25.

[2] Ohara PT, Vit JP, Bhargava A, Romero M, Sundberg C, Charles AC, Jasmin L. | Gliopathic pain: when satellite glial cells go bad. | Neuroscientist. | 2009 Oct;15(5):450-63.

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