Granulocyte colony-stimulating factor attenuates spinal cord injury-induced mechanical allodynia in adult rats

Kato, Kei; Koda, Masao; Takahashi, Hiroshi; Sakuma, Takashi; Inada, Taigo; Kamiya, Koshiro; M, Ota; Maki, Satoshi; Okawa, Akihiko; Takahashi, Kazuhisa; Yamazaki, Masashi; Aramomi, Masaaki; Hashimoto, Masayuki; Ikeda, Osamu; Mannoji, Chikato; Furuya, Takeo

doi:10.1016/j.jns.2015.05.024

Cited by 15 publications

(16 citation statements)

References 23 publications

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“…That is, while GCSF is upregulated in tSCI, it is downregulated in cSCI with time-to-time changes also in contrary motion with the exception of day 56. As purified GCSF administration alone and in combination with adipose- and bone-marrow-derived stem and neural stem cells has been shown to be highly beneficial in rodent and human tSCI—including increased tissue preservation, reduced apoptosis and scarring, and improved BBB, BMS and A [46,47,48,49,50,51,52,53,54,55,56]—such a paradigm may prove to be even more effective in the all stages of cSCI where a deficiency in GCSF is seen.…”

Section: Discussionmentioning

confidence: 99%

Level-Specific Differences in Systemic Expression of Pro- and Anti-Inflammatory Cytokines and Chemokines after Spinal Cord Injury

Hong

Chang

Zavvarian

et al. 2018

IJMS

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While over half of all spinal cord injuries (SCIs) occur in the cervical region, the majority of preclinical studies have focused on models of thoracic injury. However, these two levels are anatomically distinct—with the cervical region possessing a greater vascular supply, grey-white matter ratio and sympathetic outflow relative to the thoracic region. As such, there exists a significant knowledge gap in the secondary pathology at these levels following SCI. In this study, we characterized the systemic plasma markers of inflammation over time (1, 3, 7, 14, 56 days post-SCI) after moderate-severe, clip-compression cervical and thoracic SCI in a rat model. Using high-throughput ELISA panels, we observed a clear level-specific difference in plasma levels of VEGF, leptin, IP10, IL18, GCSF, and fractalkine. Overall, cervical SCI had reduced expression of both pro- and anti-inflammatory proteins relative to thoracic SCI, likely due to sympathetic dysregulation associated with higher level SCIs. However, contrary to the literature, we did not observe level-dependent splenic atrophy with our incomplete SCI model. This is the first study to compare the systemic plasma-level changes following cervical and thoracic SCI using level-matched and time-matched controls. The results of this study provide the first evidence in support of level-targeted intervention and also challenge the phenomenon of high SCI-induced splenic atrophy in incomplete SCI models.

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Section: Discussionmentioning

confidence: 99%

Level-Specific Differences in Systemic Expression of Pro- and Anti-Inflammatory Cytokines and Chemokines after Spinal Cord Injury

Hong

Chang

Zavvarian

et al. 2018

IJMS

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“…Our previous studies have shown that early systemic GCSF treatment after peripheral nerve injury can recruit more opioid-containing polymorphonuclear (PMN) cells to the injured site, which can thereafter decrease pro-inflammatory cytokines (IL-1β and TNF-α) in the dorsal root ganglion (DRG) and suppress microglia activation in the dorsal horn 6 . Recently, similar animal studies showed that delayed multiple GCSF treatments can attenuate neuropathic pain after chronic constriction injury (CCI) and spinal cord injury 7 8 . Furthermore, human phase I and IIa clinical trials have demonstrated that systemic GCSF treatment can significantly alleviate neuropathic pain in patients with compression myelopathy 9 .…”

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confidence: 99%

“…Furthermore, human phase I and IIa clinical trials have demonstrated that systemic GCSF treatment can significantly alleviate neuropathic pain in patients with compression myelopathy 9 . Although CGSF has been shown in both human and animal studies to have an analgesic effect on neuropathic pain after nerve injury and compression myelopathy 6 7 8 9 , the underlying mechanisms of the analgesic effects of GCSF on neuropathic pain remain unclear.…”

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confidence: 99%

“…In animal studies, systemic GCSF treatment may suppress the expression of the pro-inflammatory cytokines IL-1β and TNF-α at both the mRNA and protein levels after spinal cord injury 24 25 . Delayed systemic GCSF treatments in rats that had received CCI surgery and rats with spinal cord injury can also decrease p-p38 and IL-1β levels in the dorsal horn and suppress neuropathic pain 7 8 .…”

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confidence: 99%

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An early granulocyte colony-stimulating factor treatment attenuates neuropathic pain through activation of mu opioid receptors on the injured nerve

Liao

Yeh

et al. 2016

Sci Rep

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Several studies have shown that the mu opioid receptor (MOR) located in the peripheral nerves can be activated after nerve injury and that it attenuates peripheral nociceptive signals to the spinal dorsal horn. Various cytokines and phosphorylated-p38 (p-p38) activation in the dorsal horn also play an important role in neuropathic pain development. Granulocyte-colony stimulating factor (GCSF) is a growth factor that can stimulate granulocyte formation and has been shown to exert an analgesic effect on neuropathic pain through recruiting opioid-containing leukocytes to the injured nerve. However, the underlying mechanisms are not well understood. Herein, the results of behavior tests in addition to MOR levels in the injured sciatic nerve and the levels of p-p38 and various cytokines in the spinal dorsal horn were studied in vehicle-treated or GCSF-treated chronic constriction injured (CCI) rats at different time points (i.e., 1, 3, and 7 days, respectively) after nerve injury. The results showed that a single early systemic GCSF treatment after nerve injury can up-regulate MORs in the injured nerve, which can decrease peripheral nociceptive signals. Thereafter, those changes suppress the pro-inflammatory cytokine IL-6 but enhance the anti-inflammatory cytokine IL-4, followed by decreases in p-p38 in the dorsal horn, and thus further attenuate neuropathic pain.

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“…Evidence for the latter in mediating neuropathic pain comes from behavioral recovery after connexin‐43 inhibition (Lee‐Kubli et al, ). Microgliosis, which has been strongly linked to neuropathic pain after peripheral nerve injury (Coull et al, ; Aldskogius, ; Aldskogius and Kozlova, ; Mika et al, ; Tsuda et al, ; Guan et al, ), also occurs both within the spinal cord remote from the lesion (Detloff et al, ; Gwak and Hulsebosch, ; Gwak et al, ; Kato et al, ) and in supraspinal structures such as thalamus, hippocampus, and cortex (Wu et al, ). Indeed a great deal of emphasis has been placed on the role of microglia in pain following peripheral nerve injury because of their role in spinal disinhibition; activated microglia upregulate brain‐derived neurotrophic factor, which is thought to downregulate the potassium/chloride cotransporter KCC2 in spinal nociceptive neurons.…”

Section: Etiology Of Neuropathic Pain Following Traumatic Sci: Evidenmentioning

confidence: 99%

Neuropathic pain following traumatic spinal cord injury: Models, measurement, and mechanisms

Kramer

Minhas

Jutzeler

et al. 2016

J of Neuroscience Research

107

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Neuropathic pain following spinal cord injury (SCI) is notoriously difficult to treat and is a high priority for many in the SCI population. Resolving this issue requires animal models fidelic to the clinical situation in terms of injury mechanism and pain phenotype. This Review discusses the means by which neuropathic pain has been induced and measured in experimental SCI and compares these with human outcomes, showing that there is a substantial disconnection between experimental investigations and clinical findings in a number of features. Clinical injury level is predominantly cervical, whereas injury in the laboratory is modeled mainly at the thoracic cord. Neuropathic pain is primarily spontaneous or tonic in people with SCI (with a relatively smaller incidence of allodynia), but measures of evoked responses (to thermal and mechanical stimuli) are almost exclusively used in animals. There is even the question of whether pain per se has been under investigation in most experimental SCI studies rather than simply enhanced reflex activity with no affective component. This Review also summarizes some of the problems related to clinical assessment of neuropathic pain and how advanced imaging techniques may circumvent a lack of patient/clinician objectivity and discusses possible etiologies of neuropathic pain following SCI based on evidence from both clinical studies and animal models, with examples of cellular and molecular changes drawn from the entire neuraxis from primary afferent terminals to cortical sensory and affective centers. © 2016 Wiley Periodicals, Inc.

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Granulocyte colony-stimulating factor attenuates spinal cord injury-induced mechanical allodynia in adult rats

Cited by 15 publications

References 23 publications

Level-Specific Differences in Systemic Expression of Pro- and Anti-Inflammatory Cytokines and Chemokines after Spinal Cord Injury

Level-Specific Differences in Systemic Expression of Pro- and Anti-Inflammatory Cytokines and Chemokines after Spinal Cord Injury

An early granulocyte colony-stimulating factor treatment attenuates neuropathic pain through activation of mu opioid receptors on the injured nerve

Neuropathic pain following traumatic spinal cord injury: Models, measurement, and mechanisms

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