Dexpramipexole alleviates chronic allodynia from sciatic neuropathy and reduces spinal interferon-g (IFN-g) and other proinflammatory cytokines in spinal cord and DRG in mice.
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Abstract
Dexpramipexole is a small molecule compound with properties previously shown to block the voltage-gated sodium channel, Nav1.8 on nociceptors. It additionally has anti-inflammatory properties in immune cells. In addition to clinical trials investigating the therapeutic efficacy of dexpramipexole to control eosinophilic asthma, dexpramipexole is effective in alleviating peripheral neuropathies in preclinical mouse models such as sciatic nerve chronic constriction injury, which reverses pathological sensitivity to light touch (i.e. allodynia). Pain signals are further processed in limbic areas of the brain that serve to regulate stress. Such overlapping regulation elicits increases in hypothalamic efferent sympathetic activity, which engages the spleen and adrenal glands in response to stress; organs critical in regulating immune responses and producing catecholaminergic norepinephrine, respectively. Thus, the current study evaluated the action of dexpramipexole (1) on the full timecourse of peripheral (intravenous) dexpramipexole and the acute timecourse of spinal (intrathecal) dexpramipexole on established allodynia from chronic constriction injury, and (2) characterized spinal and limbic proinflammatory cytokine protein expression following the spinal intrathecal dexpramipexole application in female mice. Splenic cytokine mRNA expression and adrenal norepinephrine levels were measured, as chronic constriction injury-induced neuropathy elicits elevated sympathetic nervous activity. Hindpaw sensitivity was assessed using the von Frey method. After intrathecal dexpramipexole and hindpaw reassessment at 1hr, the anterior cingulate cortex, amygdala, hypothalamus, dorsal lumbar spinal cord, lumbar dorsal root ganglia, spleen and adrenal glands were collected. Intravenous dexpramipexole, resulted in profound allodynic reversal within 1hr through 24hr, that returned by 48hr occurred. Intrathecal dexpramipexole, resulted in full reversal of allodynia by 1hr occurred. Chronic constriction injury-induced elevations in spinal interferon-gamma protein was significantly suppressed from intrathecal dexpramipexole-treated mice that also demonstrated allodynia reversal, whereas trends for reduced spinal interleukin-1 β and tumor necrosis factor-α were observed. Lumbar dorsal root ganglia from allodynic reversed mice given intrathecal dexpramipexole revealed reduced interleukin-1β and tumor necrosis factor-α, as was observed in the hypothalamus. Intrathecal dexpramipexole did not reliably alter splenic cytokine mRNA expression nor adrenal norepinephrine. These data suggest dexpramipexole may control allodynia by decreasing spinal interferon-gamma and sensory ganglia interleukin-1 β and tumor necrosis factor-α, which may serve as a potential pain therapeutic in addition to its action at Nav1.8.
Article Details
How to Cite
D MILLIGAN, Erin et al.
Dexpramipexole alleviates chronic allodynia from sciatic neuropathy and reduces spinal interferon-g (IFN-g) and other proinflammatory cytokines in spinal cord and DRG in mice..
Medical Research Archives, [S.l.], v. 14, n. 5, june 2026.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/7499>. Date accessed: 23 june 2026.
doi: https://doi.org/10.18103/mra.v14i5.7499.
Keywords
Allodynia, Peripheral Neuropathy, Mice, Dexpramipexole, Interferon-gamma, Spinal cord, von Frey fiber test, hypothalamus
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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5. Schäfers M, Sorkin LS, Sommer C. Intramuscular injection of tumor necrosis factor-alpha induces muscle hyperalgesia in rats. Pain. 2003/08/01;104(3)doi:10.1016/S0304-3959(03)00115-5
6. Leo M, Schulte M, Schmitt L-I, Schäfers M, Kleinschnitz C, Hagenacker T. Intrathecal Resiniferatoxin Modulates TRPV1 in DRG Neurons and Reduces TNF‐Induced Pain‐Related Behavior. Mediators of Inflammation. 2017/01/01;2017(1)doi:10.1155/2017/2786427
7. Dogrul A, Gul H, Yesilyurt O, Ulas UH, Yildiz O. Systemic and spinal administration of etanercept, a tumor necrosis factor alpha inhibitor, blocks tactile allodynia in diabetic mice. Acta Diabetol. Jun 2011;48(2):135–42. doi:10.1007/s00592-010-0237-x
8. Reeve AJ, Patel S, Fox A, Walker K, Urban L. Intrathecally administered endotoxin or cytokines produce allodynia, hyperalgesia and changes in spinal cord neuronal responses to nociceptive stimuli in the rat. European Journal of Pain. 2000/09/01;4(3)
doi:10.1053/eujp.2000.0177
9. Kleibeuker W, Gabay E, Kavelaars A, et al. IL-1 beta signaling is required for mechanical allodynia induced by nerve injury and for the ensuing reduction in spinal cord neuronal GRK2. Brain Behav Immun. Feb 2008;22(2):200–8. doi:10.1016/j.bbi.2007.07.009
10. Pu S, Li S, Xu Y, Wu J, Lv Y, Du D. Role of receptor-interacting protein 1/receptor-interacting protein 3 in inflammation and necrosis following chronic constriction injury of the sciatic nerve. NeuroReport. November 7, 2018;29(16)doi:10.1097/WNR.0000000000001120
11. Chen X-M, Xu J, Song J-G, Zheng B-J, Wang X-R, Galley HF. Electroacupuncture inhibits excessive interferon-γ evoked up-regulation of P2X4 receptor in spinal microglia in a CCI rat model for neuropathic pain. BJA: British Journal of Anaesthesia. 2015/01/01;114(1)doi:10.1093/bja/aeu199
12. Zhou Y-L, Zhou S-Z, Li H-L, et al. Bidirectional modulation between infiltrating CD3+ T-lymphocytes and astrocytes in the spinal cord drives the development of allodynia in monoarthritic rats. Scientific Reports 2017 8:1. 2018–01–08;8(1)doi:10.1038/s41598-017-18357-z
13. Ito R, Shin-Ya M, Kishida T, et al. Interferon-gamma is causatively involved in experimental inflammatory bowel disease in mice. Clinical and Experimental Immunology. 2006/09/27;146(2)
doi:10.1111/j.1365-2249.2006.03214.x
14. Moen G-H, Moen A, Schistad EI, Gjerstad J. Local up-regulation of interferon-γ (IFN-γ) following disc herniation is involved in the inflammatory response underlying acute lumbar radicular pain. Cytokine. 2017/09/01;97doi:10.1016/j.cyto.2017.06.005
15. Costigan M, Moss A, Latremoliere A, et al. T-Cell Infiltration and Signaling in the Adult Dorsal Spinal Cord Is a Major Contributor to Neuropathic Pain-Like Hypersensitivity. Journal of Neuroscience. 2009–11–18;29(46)doi:10.1523/JNEUROSCI.4569-09.2009
16. Xu J, Wang Y, Li Y, Wang H, Liu W. Clinical characteristics and risk factors of depression in prodromal Parkinson’s disease. Frontiers in Neuroscience. 2026 Jan 12;19doi:10.3389/fnins.2025.1708805
17. Ghilardi JR, Freeman KT, Jimenez-Andrade JM, et al. Neuroplasticity of sensory and sympathetic nerve fibers in a mouse model of a painful arthritic joint. Arthritis Rheum. Jul 2012;64(7):2223–32. doi:10.1002/art.34385
18. Holt MK. The ins and outs of the caudal nucleus of the solitary tract: An overview of cellular populations and anatomical connections. J Neuroendocrinol. Jun 2022;34(6):e13132. doi:10.1111/jne.13132
19. Mantyh PW. Connections of midbrain periaqueductal gray in the monkey. II. Descending efferent projections. J Neurophysiol. Mar 1983;49(3):582–94. doi:10.1152/jn.1983.49.3.582
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