Effects of active immunisation with myelin basic protein and myelin-derived altered peptide ligand on pain hypersensitivity and neuroinflammation

Perera, Chamini J.; Lees, Justin G.; Duffy, Samuel S.; Makker, Preet G S; Fivelman, Brett; Apostolopoulos, Vasso; Moalem‐Taylor, Gila

doi:10.1016/j.jneuroim.2015.07.004

Cited by 13 publications

(9 citation statements)

References 84 publications

(108 reference statements)

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“…However, previous studies using EAE models to investigate the neuropathic pain mechanism in MS revealed the involvement of both neurological and immunological factors in the PNS, including satellite glia-cell activation 44 and elevated levels of tumor necrosis factor α 45 and brain-derived neurotrophic factor 46 , in DRG of EAE animals. Moreover, our EAEnp mouse model is supported by evidence of mild symptoms accompanied by hyperalgesia in the rat EAE model, which also does not contain PTX 13 47 . To our knowledge, we are the first to use the EAEnp mouse model to investigate pain mechanisms in EAE and show that it is feasible in behavioral or pathological experiments.…”

Section: Discussionmentioning

confidence: 63%

“…Comparing a previous study 49 with our results of EAEnp mice, peripheral nerve injury in EAE might only partially result from PTX injection. Of note, previous studies used a rat EAE model, which did not include PTX injection, to study pain 13 47 . In addition to rats, human studies have also illustrated peripheral nerve injury in MS patients 23 .…”

Section: Discussionmentioning

confidence: 99%

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Peripheral sensory neuron injury contributes to neuropathic pain in experimental autoimmune encephalomyelitis

Wang

Chung

Liao

et al. 2017

Sci Rep

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Multiple sclerosis (MS)-induced neuropathic pain deteriorates quality of life in patients but is often refractory to treatment. In experimental autoimmune encephalomyelitis (EAE), a rodent model of MS, animals develop neuropathy and inflammation-induced tissue acidosis, which suggests the involvement of acid-sensing ion channels (ASICs). Also, peripheral neuropathy is reported in MS patients. However, the involvement of the peripheral nervous system (PNS) in MS neuropathic pain remains elusive. This study investigated the contribution of ASICs and peripheral neuropathy in MS-induced neuropathic pain. Elicited pain levels were as high in Asic1a−/−, Asic2−/− and Asic3−/− mice as wild-type mice even though only Asic1a−/− mice showed reduced EAE disease severity, which indicates that pain in EAE was independent of disease severity. We thus adopted an EAE model without pertussis toxin (EAEnp) to restrain activated immunity in the periphery and evaluate the PNS contribution to pain. Both EAE and EAEnp mice showed similar pain behaviors and peripheral neuropathy in nerve fibers and DRG neurons. Moreover, pregabalin significantly reduced neuropathic pain in both EAE and EAEnp mice. Our findings highlight the essential role of the PNS in neuropathic pain in EAE and pave the way for future development of analgesics without side effects in the CNS.

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Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Peripheral sensory neuron injury contributes to neuropathic pain in experimental autoimmune encephalomyelitis

Wang

Chung

Liao

et al. 2017

Sci Rep

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“…Autoantigenic MBP peptides, as well as molecular mimics thereof, have been discovered and characterised 60 . These could be disease-triggering or even preventive factors when modified correctly 61, 62 , the underlying mechanisms currently being unclear. Picturing the above molecular steps of MDL formation should allow to better understand the myelination process as well as demyelinating disorders.…”

Section: Discussionmentioning

confidence: 99%

Membrane Association Landscape of Myelin Basic Protein Portrays Formation of the Myelin Major Dense Line

Raasakka

Ruskamo

Kowal

et al. 2017

Sci Rep

152

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Compact myelin comprises most of the dry weight of myelin, and its insulative nature is the basis for saltatory conduction of nerve impulses. The major dense line (MDL) is a 3-nm compartment between two cytoplasmic leaflets of stacked myelin membranes, mostly occupied by a myelin basic protein (MBP) phase. MBP is an abundant myelin protein involved in demyelinating diseases, such as multiple sclerosis. The association of MBP with lipid membranes has been studied for decades, but the MBP-driven formation of the MDL remains elusive at the biomolecular level. We employed complementary biophysical methods, including atomic force microscopy, cryo-electron microscopy, and neutron scattering, to investigate the formation of membrane stacks all the way from MBP binding onto a single membrane leaflet to the organisation of a stable MDL. Our results support the formation of an amorphous protein phase of MBP between two membrane bilayers and provide a molecular model for MDL formation during myelination, which is of importance when understanding myelin assembly and demyelinating conditions.

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“…The observation that it is the centrally located, but not the N-terminal, MBP peptide sequences initiate allodynia [10] suggests a potential drug target. Thus, therapy using the central MBP-derived mutant/altered peptide ligand (APL) analogues, impair T cell function and alleviate mechanical allodynia associated with EAE [51] and CCI [52, 53]. Since our studies employ female rats, the MBP-induced T cell activation in nerve and spinal cord [10] is a plausible mechanism underlying the differential female versus male processing of mechanical pain hypersensitivity after PNS injury [7].…”

Section: Discussionmentioning

confidence: 99%

Spinal activity of interleukin 6 mediates myelin basic protein-induced allodynia

Eddinger

Angert

et al. 2016

Brain, Behavior, and Immunity

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Mechanosensory fibers are enveloped by myelin, a unique multilamellar membrane permitting salutatory neuronal conduction. Damage to myelin is thought to contribute to severe pain evoked by innocuous tactile stimulation (i.e. mechanical allodynia). Our earlier (Liu et al, J. Neuroinflammation, 9 (1): 119, 2012) and present data demonstrate that a single injection of a myelin basic protein-derived peptide (MBP84–104) into an intact sciatic nerve produces a robust and long-lasting (>30 days) mechanical allodynia in female rats. The MBP84-104 peptide represents the immunodominant epitope and requires T cells to maintain allodynia. Surprisingly, only systemic gabapentin (a ligand of voltage-gated calcium channel α2δ1), but not ketorolac (COX inhibitor), lidocaine (sodium channel blocker) or MK801 (NMDA antagonist) reverse allodynia induced by the intrasciatic MBP84-104. The genome-wide transcriptional profiling of the sciatic nerve followed by the bioinformatics analyses of the expression changes identified interleukin (IL)-6 as the major cytokine induced by MBP84-104 in both the control and athymic T cell-deficient nude rats. The intrasciatic MBP84-104 injection resulted in both unilateral allodynia and unilateral IL-6 increase the segmental spinal cord (neurons and astrocytes). An intrathecal delivery of a function-blocking IL-6 antibody reduced the allodynia in part by the transcriptional effects in large-diameter primary afferents in DRG. Our data suggest that MBP regulates IL-6 expression in the nervous system and that the spinal IL-6 activity mediates nociceptive processing stimulated by the MBP epitopes released after damage or disease of the somatosensory nervous system.

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Effects of active immunisation with myelin basic protein and myelin-derived altered peptide ligand on pain hypersensitivity and neuroinflammation

Cited by 13 publications

References 84 publications

Peripheral sensory neuron injury contributes to neuropathic pain in experimental autoimmune encephalomyelitis

Peripheral sensory neuron injury contributes to neuropathic pain in experimental autoimmune encephalomyelitis

Membrane Association Landscape of Myelin Basic Protein Portrays Formation of the Myelin Major Dense Line

Spinal activity of interleukin 6 mediates myelin basic protein-induced allodynia

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