Thymulin treatment attenuates inflammatory pain by modulating spinal cellular and molecular signaling pathways

Nasseri, Behzad; Zaringhalam, Jalal; Daniali, Seyede Shahrbanoo; Manaheji, Homa; Abbasnejad, Zahra; Nazemian, Vida

doi:10.1016/j.intimp.2019.02.042

Cited by 15 publications

(10 citation statements)

References 34 publications

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“…This effect correlated with the ultimately less-severe disease state, and may be explained by a weakened primary response to adjuvants. These results are consistent with a very recent study that showed that thymulin reduced thermal hyperalgesia and paw edema induced by CFA, as well as CFA-induced activation of microglia cells, phosphorylation of p38 MAPK, and the production of spinal pro-inflammatory cytokines (TNF-α, IL-6) [6].…”

Section: Discussionsupporting

confidence: 93%

“…One potential therapy that shows little or no adverse effects is the thymic peptide thymulin, a metallopeptide consisting of a nonapeptide (Glu-Ala-Lys-Ser-Gln-Gly-Gly-Ser-Asp) in complex with a zinc ion, which has been reported not only to regulate maturation of lymphocytes in the thymus, but also to modulate the immune and neuroendocrine systems’ activities [3]. Numerous data showed that thymulin exerts mostly inhibitory effects on the inflammatory immune response both in vitro and in vivo [4,5,6]. Thymulin also affects the neuroendocrine stress response system including its major pathway, the hypothalamic–pituitary–adrenal axis [3], and produces analgesic effects in inflammatory conditions [7].…”

Section: Introductionmentioning

confidence: 99%

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Protective Effect of PBCA Nanoparticles Loaded with Thymulin Against the Relapsing-Remitting Form of Experimental Autoimmune Encephalomyelitis in Mice

Лунин

Хренов

Глушкова

et al. 2019

IJMS

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Relapsing–remitting experimental autoimmune encephalomyelitis (rEAE) in mice is a model that closely resembles relapsing–remitting multiple sclerosis in humans. This study aims to investigate a new approach to modulation of the inflammatory response in rEAE mice using a thymic peptide thymulin bound to polybutylcyanoacrylate (PBCA) nanoparticles. PBCA nanoparticles were used to prolong the presence of thymulin in the blood. Cytokine levels in blood were measured by ELISA; NF-κB and SAPK/JNK cascade activation, as well as Hsp72 and p53 protein expression, were measured by Western blotting. Animal health statuses were estimated using severity scores. Results showed that the cytokine response in rEAE was multi-staged: an early phase was accompanied by an increase in plasma interferon-γ, while the interleukin (IL)-17 response was markedly increased at a later stage. The stages were attributed to rEAE induction and maintenance phases. Thymulin significantly alleviated symptoms of rEAE and lowered plasma cytokine levels both in early and later stages of rEAE, and decreased NF-κB and SAPK/JNK cascade activation. Thymulin modulated NF-kappaB pathway activity via site-specific phosphorylation of RelA/p65 protein (at Ser276 and Ser536). The effect of nanoparticle-bound thymulin was more pronounced than the effect of free thymulin. Therefore, PBCA–thymulin can be considered a prospective treatment for this pathology.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Protective Effect of PBCA Nanoparticles Loaded with Thymulin Against the Relapsing-Remitting Form of Experimental Autoimmune Encephalomyelitis in Mice

Лунин

Хренов

Глушкова

et al. 2019

IJMS

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show abstract

“…CFA-induced inflammatory pain was caused by a single subcutaneous injection of (100μL) heat-killed Mycobacterium tuberculosis suspended in sterile mineral oil (10 mg/ml; CFA; Sigma, St Louis, MO, USA) into the rats’ hind paw on day zero under light anesthesia with methoxyisoflurane. The first week after CFA injection was considered the inflammatory phase and the third week was the arthritic phase [ 36 , 37 ].…”

Section: Methodsmentioning

confidence: 99%

RETRACTED: Noopept; a nootropic dipeptide, modulates persistent inflammation by effecting spinal microglia dependent Brain Derived Neurotropic Factor (BDNF) and pro-BDNF expression throughout apoptotic process

Taghizadeh

Maghsoudi

Manaheji

et al. 2021

Heliyon

Self Cite

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There are largely unknown associations between changes in pain behavior responses during persistent peripheral inflammation and spinal cell alteration such as apoptosis. Some evidence suggests that microglia and microglia related mediators play notable roles in induction and maintenance of central nervous system pathologies and inflammatory pain. By considering those relationships and microglia related nootrophic factors, such as the Brain Derived Neurotrophic Factor (BDNF) in CNS, we attempted to assess the relationship between microglia dependent BDNF and its precursor with pain behavior through spinal cell apoptosis as well as the effect of Noopept on this relationship. Persistent peripheral inflammation was induced by a single subcutaneous injection of Complete Freund's Adjuvant (CFA) on day 0. Thermal hyperalgesia, paw edema, microglial activity, microglia dependent BDNF, pro-BDNF expression, and apoptosis were assessed in different experimental groups by confirmed behavioral and molecular methods on days 0, 7, and 21 of the study. Our findings revealed hyperalgesia and spinal cell apoptosis significantly increased during the acute phase of CFA-induced inflammation but was then followed by a decrement in the chronic phase of the study. Aligned with these variations in spinal microglial activity, microglia dependent BDNF significantly increased during the acute phase of CFA-induced inflammation. Our results also indicated that daily administration of Noopept (during 21 days of the study) not only caused a significant decrease in hyperalgesia and microglia dependent BDNF expression but also changed the apoptosis process in relation to microglia activity alteration. It appears that the administration of Noopept can decrease spinal cell apoptosis and hyperalgesia during CFA-induced inflammation due to its direct effects on microglial activity and microglia dependent BDNF and pro-BDNF expression.

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“…CFA-induced inflammatory pain was caused by a single subcutaneous injection of (100µL) heat-killed Mycobacterium tuberculosis suspended in sterile mineral oil (10 mg/ml; CFA; Sigma, St Louis, MO, USA) into the rats' hind paw on day zero under light anesthesia with methoxyisoflurane. The first week after CFA injection was considered the inflammatory phase and the third week was the arthritic phase [30,31].…”

Section: Inflammatory Pain Inductionmentioning

confidence: 99%

Nootropic dipeptide, Noopept can modulate hyperalgesia by effecting on spinal microglia dependent Brain Derived Neurotropic Factor (BDNF) and pro-BDNF expression and apoptosis during persistent inflammation

Taghizadeh

Maghsoudi

Manaheji

et al. 2020

Preprint

Self Cite

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Background: There are largely unknown associations between changes in pain behavior responses during persistent peripheral inflammation and spinal cell alteration such as apoptosis. Some evidence suggests that microglia and microglia related mediators play notable roles in induction and maintenance of central nervous system pathologies and inflammatory pain. By considering those relationships and microglia related nootrophic factors, such as the Brain Derived Neurotrophic Factor (BDNF) in CNS, we attempted to assess the relationship between microglia dependent BDNF and its precursor with pain behavior through spinal cell apoptosis as well as the effect of Noopept on this relationship. Methods: Persistent peripheral inflammation was induced by a single subcutaneous injection of Complete Freund’s Adjuvant (CFA) on day 0. Thermal hyperalgesia, paw edema, microglial activity, microglia dependent BDNF, pro-BDNF expression, and apoptosis were assessed in different experimental groups by confirmed behavioral and molecular methods on days 0, 7, and 21 of the study. Results: Our findings revealed hyperalgesia and spinal cell apoptosis significantly increased during the acute phase of CFA-induced inflammation but was then followed by a decrement in the chronic phase of the study. Aligned with these variations in spinal microglial activity, microglia dependent BDNF significantly increased during the acute phase of CFA-induced inflammation. Our results also indicated that daily administration of Noopept (during 21 days of the study) not only caused a significant decrease in hyperalgesia and microglia dependent BDNF expression but also changed the apoptosis process in relation to microglia activity alteration. Conclusions: It appears that the administration of Noopept can decrease spinal cell apoptosis and hyperalgesia during CFA-induced inflammation due to its direct effects on microglial activity and microglia dependent BDNF and pro-BDNF expression.

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Thymulin treatment attenuates inflammatory pain by modulating spinal cellular and molecular signaling pathways

Cited by 15 publications

References 34 publications

Protective Effect of PBCA Nanoparticles Loaded with Thymulin Against the Relapsing-Remitting Form of Experimental Autoimmune Encephalomyelitis in Mice

Protective Effect of PBCA Nanoparticles Loaded with Thymulin Against the Relapsing-Remitting Form of Experimental Autoimmune Encephalomyelitis in Mice

RETRACTED: Noopept; a nootropic dipeptide, modulates persistent inflammation by effecting spinal microglia dependent Brain Derived Neurotropic Factor (BDNF) and pro-BDNF expression throughout apoptotic process

Nootropic dipeptide, Noopept can modulate hyperalgesia by effecting on spinal microglia dependent Brain Derived Neurotropic Factor (BDNF) and pro-BDNF expression and apoptosis during persistent inflammation

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