Toll-like receptor 2 and 4 antagonism for the treatment of experimental autoimmune encephalomyelitis (EAE)-related pain

Kwilasz, Andrew J.; Fulgham, Suzanne M. Green; Duran-Malle, Julissa Chante; Schrama, Anouk E.W.; Mitten, Eric H.; Todd, Laurel S.; Patel, Hardik; Larson, Tracey A; Clements, Madison A.; Harris, Kevin M.; Litwiler, Scott T.; Harvey, Lewis O.; Maier, Steven F.; Chavez, Raymond A.; Rice, Kenner C.; Dam, Anne Marie Van; Watkins, Linda R.

doi:10.1016/j.bbi.2020.12.016

Cited by 13 publications

(22 citation statements)

References 128 publications

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“…Moreover, previous studies showed that inhibiting the TLR4 pathway alleviated motor impairment and dopaminergic neuron death in the Parkinson's disease mouse model [37]. And Kwilasz et al showed that TLR4 antagonists prevented the production of proinflammatory factors and motor dysfunction in the experimental autoimmune encephalomyelitis mouse model [38]. All these studies have shown that TLR4 might be a promising target in neuroinflammation treatment.…”

Section: Discussionmentioning

confidence: 98%

Trilobatin Alleviates Cognitive Deficits and Pathologies in an Alzheimer’s Disease Mouse Model

Ding

Huang

Dai

et al. 2021

Oxidative Medicine and Cellular Longevity

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Alzheimer’s disease (AD) is the most common neurodegenerative disease nowadays that causes memory impairments. It is characterized by extracellular aggregates of amyloid-beta (Aβ), intracellular aggregates of hyperphosphorylated Tau (p-Tau), and other pathological features. Trilobatin (TLB), a natural flavonoid compound isolated from Lithocarpuspolystachyus Rehd., has emerged as a neuroprotective agent. However, the effects and mechanisms of TLB on Alzheimer’s disease (AD) remain unclear. In this research, different doses of TLB were orally introduced to 3×FAD AD model mice. The pathology, memory performance, and Toll-like receptor 4- (TLR4-) dependent inflammatory pathway protein level were assessed. Here, we show that TLB oral treatment protected 3×FAD AD model mice against the Aβ burden, neuroinflammation, Tau hyperphosphorylation, synaptic degeneration, hippocampal neuronal loss, and memory impairment. The TLR4, a pattern recognition immune receptor, has been implicated in neurodegenerative disease-related neuroinflammation. We found that TLB suppressed glial activation by inhibiting the TLR4-MYD88-NFκB pathway, which leads to the inflammatory factor TNF-α, IL-1β, and IL-6 reduction. Our study shows that TLR4 might be a key target of TLB in AD treatment and suggests a multifaceted target of TLB in halting AD. Taken together, our findings suggest a potential therapeutic effect of TLB in AD treatment.

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Section: Discussionmentioning

confidence: 98%

Trilobatin Alleviates Cognitive Deficits and Pathologies in an Alzheimer’s Disease Mouse Model

Ding

Huang

Dai

et al. 2021

Oxidative Medicine and Cellular Longevity

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“…Previous proof-of-concept studies have demonstrated that TLR4 small-molecule antagonists would provide a nonconventional avenue to improve the clinical efficacy of opioids and possibly improve safety ( 7 , 53 ). Consequently, numerous TLR4 antagonists have been developed ( 54 , 55 ). However, few of them could cross BBB ( 16 ).…”

Section: Discussionmentioning

confidence: 99%

Cannabidivarin alleviates neuroinflammation by targeting TLR4 co-receptor MD2 and improves morphine-mediated analgesia

Wang

Lin

et al. 2022

Front. Immunol.

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Toll-like receptor 4 (TLR4) is a pattern-recognition receptor (PRR) that regulates the activation of immune cells, which is a target for treating inflammation. In this study, Cannabidivarin (CBDV), an active component of Cannabis, was identified as an antagonist of TLR4. In vitro, intrinsic protein fluorescence titrations revealed that CBDV directly bound to TLR4 co-receptor myeloid differentiation protein 2 (MD2). Cellular thermal shift assay (CETSA) showed that CBDV binding decreased MD2 stability, which is consistent with in silico simulations that CBDV binding increased the flexibility of the internal loop of MD2. Moreover, CBDV was found to restrain LPS-induced activation of TLR4 signaling axes of NF-κB and MAPKs, therefore blocking LPS-induced pro-inflammatory factors NO, IL-1β, IL-6 and TNF-α. Hot plate test showed that CBDV potentiated morphine-induced antinociception. Furthermore, CBDV attenuated morphine analgesic tolerance as measured by the formalin test by specifically inhibiting chronic morphine-induced glial activation and pro-inflammatory factors expression in the nucleus accumbent. This study confirms that MD2 is a direct binding target of CBDV for the anti-neuroinflammatory effect and implies that CBDV has great translational potential in pain management.

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“…Pain in EAE is mediated by ongoing demyelination as well as various proinflammatory cell types and mediators including cytokines released from both glia and T cells. For example, we have shown that spinal interleukin-1β (IL-1β) is necessary for EAE-induced pain in Dark Agouti (DA) rats ( 16 ), and others have demonstrated that IL-1β is necessary for EAE-induced pain in mice ( 20 ). Ligation of Toll-like receptors 2 and 4 (TLR2–TLR4) by Danger-associated molecular patterns (DAMPs) induces NF-kB activation, which primes the nod-like receptor protein 3 (NLRP3) inflammasome which can then lead to the production of the proinflammatory cytokine IL-1β ( 29 , 30 ).…”

Section: Introductionmentioning

confidence: 99%

“…Toll-like receptors 2 and 4 antagonists are one promising strategy to treat pain from MS ( 16 ), as well as neuropathic pain from both peripheral and central origin ( 34 – 37 ). Toll-like receptors 2 and 4 are commonly expressed on glial cells ( 29 , 38 ) as well as less commonly on neurons ( 38 , 39 ) and T cells ( 40 , 41 ).…”

Section: Introductionmentioning

confidence: 99%

“…In contrast, we have previously shown that daily systemic administration of the non-opioid low-affinity TLR2–TLR4 antagonist, (+)-naltrexone [(+)-NTX] ( 49 – 51 ), reverses pain induced by low-dose EAE in a DA rat model of pain ( 16 ) and have furthermore demonstrated that this same treatment returns dorsal lumbar spinal cord glial activation and NLRP3, IL-1β, and IL-17 mRNAs to control levels ( 16 ). Here, we study the role of TLR2–TLR4, NLRP3, and IL-17 in pain and associated spinal cord alterations induced by this novel SD rat model of MOG-induced EAE, optimized to avoid confounding hindpaw-associated motor impairments/disabilities.…”

Section: Introductionmentioning

confidence: 99%

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Involvement of TLR2–TLR4, NLRP3, and IL-17 in pain induced by a novel Sprague-Dawley rat model of experimental autoimmune encephalomyelitis

Kwilasz¹,

Clements²,

Larson³

et al. 2022

Front. Pain Res.

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Up to 92% of patients suffering from multiple sclerosis (MS) experience pain, most without adequate treatment, and many report pain long before motor symptoms associated with MS diagnosis. In the most commonly studied rodent model of MS, experimental autoimmune encephalomyelitis (EAE), motor impairments/disabilities caused by EAE can interfere with pain testing. In this study, we characterize a novel low-dose myelin-oligodendrocyte-glycoprotein (MOG)-induced Sprague-Dawley (SD) model of EAE-related pain in male rats, optimized to minimize motor impairments/disabilities. Adult male SD rats were treated with increasing doses of intradermal myelin-oligodendrocyte-glycoprotein (MOG1−125) (0, 4, 8, and 16 μg) in incomplete Freund's adjuvant (IFA) vehicle to induce mild EAE. Von Frey testing and motor assessments were conducted prior to EAE induction and then weekly thereafter to assess EAE-induced pain and motor impairment. Results from these studies demonstrated that doses of 8 and 16 μg MOG1−125 were sufficient to produce stable mechanical allodynia for up to 1 month in the absence of hindpaw motor impairments/disabilities. In the follow-up studies, these doses of MOG1−125, were administered to create allodynia in the absence of confounded motor impairments. Then, 2 weeks later, rats began daily subcutaneous injections of the Toll-like receptor 2 and 4 (TLR2–TLR4) antagonist (+)-naltrexone [(+)-NTX] or saline for an additional 13 days. We found that (+)-NTX also reverses EAE-induced mechanical allodynia in the MOG-induced SD rat model of EAE, supporting parallels between models, but now allowing a protracted timecourse to be examined completely free of motor confounds. Exploring further mechanisms, we demonstrated that both spinal NOD-like receptor protein 3 (NLRP3) and interleukin-17 (IL-17) are necessary for EAE-induced pain, as intrathecal injections of NLRP3 antagonist MCC950 and IL-17 neutralizing antibody both acutely reversed EAE-induced pain. Finally, we show that spinal glial immunoreactivity induced by EAE is reversed by (+)-NTX, and that spinal demyelination correlates with the severity of motor impairments/disabilities. These findings characterize an optimized MOG-induced SD rat model of EAE for the study of pain with minimal motor impairments/disabilities. Finally, these studies support the role of TLR2–TLR4 antagonists as a potential treatment for MS-related pain and other pain and inflammatory-related disorders.

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Toll-like receptor 2 and 4 antagonism for the treatment of experimental autoimmune encephalomyelitis (EAE)-related pain

Cited by 13 publications

References 128 publications

Trilobatin Alleviates Cognitive Deficits and Pathologies in an Alzheimer’s Disease Mouse Model

Trilobatin Alleviates Cognitive Deficits and Pathologies in an Alzheimer’s Disease Mouse Model

Cannabidivarin alleviates neuroinflammation by targeting TLR4 co-receptor MD2 and improves morphine-mediated analgesia

Involvement of TLR2–TLR4, NLRP3, and IL-17 in pain induced by a novel Sprague-Dawley rat model of experimental autoimmune encephalomyelitis

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