Effects of vaccination with altered peptide ligand on chronic pain in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis

Neuropathic pain is a chronic symptom of multiple sclerosis (MS) and affects nearly half of all MS sufferers. A key instigator of this pain is the pro-inflammatory response in MS. We investigated the behavioural effects of immunisation with a mutant peptide of myelin basic protein (MBP), termed altered peptide ligand (APL), known to initiate immune deviation from a pro-inflammatory state to an anti-inflammatory response in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Male and female Lewis rats were injected with vehicle control or with varying doses of 50 or 100 µg guinea pig MBP in combination with or without APL. APL-treated animals established significantly lower disease severity compared to encephalitogenic MBP-treated animals. Animals with EAE developed mechanical, but not thermal pain hypersensitivity. Mechanical pain sensitivities were either improved or normalised during periods of clinical disease in male and female APL-treated animals as compared to the encephalitogenic group. No significant changes to thermal latency were observed upon co-immunisation with APL. Together these data indicate that APL ameliorates disease states and selectively mediates an analgesic effect on EAE animals

Gap junction proteins and their role in spinal cord injury

© 2015 Tonkin, Mao, O'Carroll, Nicholson, Green, Gorrie and Moalem-Taylor. Gap junctions are specialized intercellular communication channels that are formed by two hexameric connexin hemichannels, one provided by each of the two adjacent cells. Gap junctions and hemichannels play an important role in regulating cellular metabolism, signaling, and functions in both normal and pathological conditions. Following spinal cord injury (SCI), there is damage and disturbance to the neuronal elements of the spinal cord including severing of axon tracts and rapid cell death. The initial mechanical disruption is followed by multiple secondary cascades that cause further tissue loss and dysfunction. Recent studies have implicated connexin proteins as playing a critical role in the secondary phase of SCI by propagating death signals through extensive glial networks. In this review, we bring together past and current studies to outline the distribution, changes and roles of various connexins found in neurons and glial cells, before and in response to SCI. We discuss the contribution of pathologically activated connexin proteins, in particular connexin 43, to functional recovery and neuropathic pain, as well as providing an update on potential connexin specific pharmacological agents to treat SCI

Active immunization with myelin-derived altered peptide ligand reduces mechanical pain hypersensitivity following peripheral nerve injury

BACKGROUND: T cells have been implicated in neuropathic pain that is caused by peripheral nerve injury. Immunogenic myelin basic protein (MBP) peptides have been shown to initiate mechanical allodynia in a T cell-dependent manner. Antagonistic altered peptide ligands (APLs) are peptides with substitutions in amino acid residues at T cell receptor contact sites and can inhibit T cell function and modulate inflammatory responses. In the present study, we studied the effects of immunization with MBP-derived APL on pain behavior and neuroinflammation in an animal model of peripheral nerve injury. METHODS: Lewis rats were immunized subcutaneously at the base of the tail with either a weakly encephalitogenic peptide of MBP (cyclo-MBP(87-99)) or APL (cyclo-(87-99)[A(91),A(96)]MBP(87-99)) in complete Freund’s adjuvant (CFA) or CFA only (control), following chronic constriction injury (CCI) of the left sciatic nerve. Pain hypersensitivity was tested by measurements of paw withdrawal threshold to mechanical stimuli, regulatory T cells in spleen and lymph nodes were analyzed by flow cytometry, and immune cell infiltration into the nervous system was assessed by immunohistochemistry (days 10 and 30 post-CCI). Cytokines were measured in serum and nervous tissue of nerve-injured rats (day 10 post-CCI). RESULTS: Rats immunized with the APL cyclo-(87-99)[A(91),A(96)]MBP(87-99) had significantly reduced mechanical pain hypersensitivity in the ipsilateral hindpaw compared to cyclo-MBP(87-99)-treated and control rats. This was associated with significantly decreased infiltration of T cells and ED1+ macrophages in the injured nerve of APL-treated animals. The percentage of anti-inflammatory (M2) macrophages was significantly upregulated in the APL-treated rats on day 30 post-CCI. Compared to the control rats, microglial activation in the ipsilateral lumbar spinal cord was significantly increased in the MBP-treated rats, but was not altered in the rats immunized with the MBP-derived APL. In addition, immunization with the APL significantly increased splenic regulatory T cells. Several cytokines were significantly altered after CCI, but no significant difference was observed between the APL-treated and control rats. CONCLUSIONS: These results suggest that immune deviation by active immunization with a non-encephalitogenic MBP-derived APL mediates an analgesic effect in animals with peripheral nerve injury. Thus, T cell immunomodulation warrants further investigation as a possible therapeutic strategy for the treatment of peripheral neuropathic pain

Comparison of eta and eta' production in the pp -> pp eta(eta') reactions near threshold

The total cross section of the pp -> pp eta' reaction has been measured at two energies near threshold by detecting the final protons in a magnetic spectrometer. The values obtained are about a factor of 70 less than for the corresponding eta production, in good agreement with the predictions of a one-pion-exchange model.Comment: 10 pages, Latex with 3 eps figure

S-wave eta'-proton FSI; phenomenological analysis of near-threshold production of pi0, eta, and eta' mesons in proton-proton collisions

We describe a novel technique for comparing total cross sections for the reactions pp --> pp pi(0), pp --> pp eta, and pp --> pp eta' close to threshold. The initial and final state proton-proton interactions are factored out of the total cross section, and the dependence of this reduced cross section on the volume of phase space is discussed. Different models of the proton-proton interaction are compared. We argue that the scattering length of the S-wave eta'-proton interaction is of the order of 0.1 fm.Comment: 10 pages, 5 figure

Characterisation of Peptide5 systemic administration for treating traumatic spinal cord injured rats

© 2017, Springer-Verlag GmbH Germany. Systemic administration of a Connexin43 mimetic peptide, Peptide5, has been shown to reduce secondary tissue damage and improve functional recovery after spinal cord injury (SCI). This study investigated safety measures and potential off-target effects of Peptide5 systemic administration. Rats were subjected to a mild contusion SCI using the New York University impactor. One cohort was injected intraperitoneally with a single dose of fluorescently labelled Peptide5 and euthanised at 2 or 4 h post-injury for peptide distribution analysis. A second cohort received intraperitoneal injections of Peptide5 or a scrambled peptide and was culled at 8 or 24 h post-injury for the analysis of connexin proteins and systemic cytokine profile. We found that Peptide5 did not cross the blood-spinal cord barrier in control animals, but reached the lesion area in the spinal cord-injured animals without entering non-injured tissue. There was no evidence that the systemic administration of Peptide5 modulates Connexin43 protein expression or hemichannel closure in the heart and lung tissue of SCI animals. The expression levels of other major connexin proteins including Connexin30 in astrocytes, Connexin36 in neurons and Connexin47 in oligodendrocytes were also unaltered by systemic delivery of Peptide5 in either the injured or non-injured spinal cords. In addition, systemic delivery of Peptide5 had no significant effect on the plasma levels of cytokines, chemokines or growth factors. These data indicate that the systemic delivery of Peptide5 is unlikely to cause any off-target or adverse effects and may thus be a safe treatment option for traumatic SCI

Energy Dependence of the Near-Threshold Total Cross-Section for the pp --> pp eta' Reaction

Total cross sections for the pp --> pp eta' reaction have been measured in the excess energy range from Q = 1.53 MeV to Q = 23.64 MeV. The experiment has been performed at the internal installation COSY-11 using a stochastically cooled proton beam of the COoler SYnchrotron COSY and a hydrogen cluster target. The determined energy dependence of the total cross section weakens the hypothesis of the S-wave repulsive interaction between the eta' meson and the proton. New data agree well with predictions based on the phase-space distribution modified by the proton-proton final-state-interaction (FSI) only.Comment: 12 pages, 1 table, 4 figure

SEARCH FOR NARROW ISOVECTOR DIBARYONS CLOSE TO LOW MASSES THRESHOLD

For masses larger than 2 MN + Mπ, narrow peaks in two proton invariant (missing) masses spectra : Mpp (Mx) are now well established. The existence of such narrow peaks is not so unquestionable below 2 MN + Mπ. Tensor analyzing power T20 of the invariant mass Mpp has been studied using the p ([MATH], pp) reaction. Depending on the assumption done for background substraction -a hole or an oscillation may appear at Mpp = 1941 MeV. Additional data are under analysis and will improve the statistics