Lack of correlation between spinal microgliosis and long-term development of tactile hypersensitivity in two different sciatic nerve crush injury

Kim, Hyoung Woo; Won, Chan Hee; Oh, Seog Bae

doi:10.1177/17448069211011326

Cited by 4 publications

(4 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Astrogliosis, marked by increased cell volume and numbers, was prominent during chronic pain development, with microgliosis primarily implicated in pain initiation rather than maintenance. This was consistent with other studies showed the microglia activation generally precedes and subsides prior to astrocytes activation [ 22 , 29 , 30 ]. Indicating that microglia and astrocytes have separate roles in the induction, maintenance and resolution of chronic pain, with the initiation involves microgliosis while later phase involves astrogliosis.…”

Section: Discussionsupporting

confidence: 93%

BDNF/TrkB Signaling Inhibition Suppresses Astrogliosis and Alleviates Mechanical Allodynia in a Partial Crush Injury Model

Phan,

Jayathilake,

Lee

et al. 2023

Exp Neurobiol

View full text Add to dashboard Cite

Neuropathic pain presents a formidable clinical challenge due to its persistent nature and limited responsiveness to conventional analgesic treatments. While significant progress has been made in understanding the role of spinal astrocytes in neuropathic pain, their contribution and functional changes following a partial crush injury (PCI) remain unexplored. In this study, we investigated structural and functional changes in spinal astrocytes during chronic neuropathic pain, employing a partial crush injury model. This model allowes us to replicate the transition from initial nociceptive responses to persistent pain, highlighting the relevance of astrocytes in pain maintenance and sensitization. Through the examination of mechanical allodynia, a painful sensation in response to innocuous stimuli, and the correlation with increased levels of brain-derived neurotrophic factor (BDNF) along with reactive astrocytes, we identified a potential mechanistic link between astrocytic activity and BDNF signaling. Ultimately, our research provides evidence that inhibiting astrocyte activation through a BDNF/TrkB inhibitor alleviates mechanical allodynia, underscoring the therapeutic potential of targeting glial BDNF-related pathways for pain management. These findings offer critical insights into the cellular and molecular dynamics of neuropathic pain, paving the way for innovative and targeted treatment strategies for this challenging condition.

show abstract

Section: Discussionsupporting

confidence: 93%

BDNF/TrkB Signaling Inhibition Suppresses Astrogliosis and Alleviates Mechanical Allodynia in a Partial Crush Injury Model

Phan,

Jayathilake,

Lee

et al. 2023

Exp Neurobiol

View full text Add to dashboard Cite

show abstract

“…On day 1, when IL-1β expression already reached its maximum, we observed only a low level of microgliosis. This became evident on post-operative day 3 and—in line with observations from other laboratories [ 51 , 52 ]—fully developed on day 7. At this time point, NLRP3 was already upregulated in microglia as well; however, it did not colocalize with ASC, while IL-1β expression decreased to almost control levels, suggesting absence of inflammasome assembly in these cells.…”

Section: Discussionsupporting

confidence: 89%

Motoneuronal inflammasome activation triggers excessive neuroinflammation and impedes regeneration after sciatic nerve injury

Molnár

Nógrádi

Kristóf

et al. 2022

J Neuroinflammation

View full text Add to dashboard Cite

Background Peripheral nerve injuries are accompanied by inflammatory reactions, over-activation of which may hinder recovery. Among pro-inflammatory pathways, inflammasomes are one of the most potent, leading to release of active IL-1β. Our aim was to understand how inflammasomes participate in central inflammatory reactions accompanying peripheral nerve injury. Methods After axotomy of the sciatic nerve, priming and activation of the NLRP3 inflammasome was examined in cells of the spinal cord. Regeneration of the nerve was evaluated after coaptation using sciatic functional index measurements and retrograde tracing. Results In the first 3 days after the injury, elements of the NLRP3 inflammasome were markedly upregulated in the L4–L5 segments of the spinal cord, followed by assembly of the inflammasome and secretion of active IL-1β. Although glial cells are traditionally viewed as initiators of neuroinflammation, in this acute phase of inflammation, inflammasome activation was found exclusively in affected motoneurons of the ventral horn in our model. This process was significantly inhibited by 5-BDBD, a P2X4 receptor inhibitor and MCC950, a potent NLRP3 inhibitor. Although at later time points the NLRP3 protein was upregulated in microglia too, no signs of inflammasome activation were detected in these cells. Inhibition of inflammasome activation in motoneurons in the first days after nerve injury hindered development of microgliosis in the spinal cord. Moreover, P2X4 or inflammasome inhibition in the acute phase significantly enhanced nerve regeneration on both the morphological and the functional levels. Conclusions Our results indicate that the central reaction initiated by sciatic nerve injury starts with inflammasome activation in motoneurons of the ventral horn, which triggers a complex inflammatory reaction and activation of microglia. Inhibition of neuronal inflammasome activation not only leads to a significant reduction of microgliosis, but has a beneficial effect on the recovery as well.

show abstract

“…We have previously shown the development of a slow-onset mechanical hypersensitivity in a mouse model of "partial" sciatic nerve crush that does not appear after a more severe "full" crush injury. 23,50 This suggests the presence of an inflection point in the relationship between injury severity and the outcome of positive and negative sensory symptoms that challenges previous assumptions of clinical nerve injuries. 18 Here, we report a comprehensive behavioral and anatomical exploration of the partial and full sciatic nerve crush models at acute (2-7 days) and chronic (.30 days) time points in adult mice of both sexes using a simple and reproducible tool.…”

Section: Introductionmentioning

confidence: 94%

“…We have previously shown the development of a slow-onset mechanical hypersensitivity in a mouse model of “partial” sciatic nerve crush that does not appear after a more severe “full” crush injury. 23,50 This suggests the presence of an inflection point in the relationship between injury severity and the outcome of positive and negative sensory symptoms that challenges previous assumptions of clinical nerve injuries. 18…”

Section: Introductionmentioning

confidence: 96%

Long-term tactile hypersensitivity after nerve crush injury in mice is characterized by the persistence of intact sensory axons

Kim

Shim

Zhao

et al. 2023

Pain

Self Cite

View full text Add to dashboard Cite

Traumatic peripheral nerve injuries are at high risk of neuropathic pain for which novel effective therapies are urgently needed. Preclinical models of neuropathic pain typically involve irreversible ligation and/or nerve transection (neurotmesis). However, translation of findings to the clinic has so far been unsuccessful, raising questions on injury model validity and clinically relevance. Traumatic nerve injuries seen in the clinic commonly result in axonotmesis (ie, crush), yet the neuropathic phenotype of “painful” nerve crush injuries remains poorly understood. We report the neuropathology and sensory symptoms of a focal nerve crush injury using custom-modified hemostats resulting in either complete (“full”) or incomplete (“partial”) axonotmesis in adult mice. Assays of thermal and mechanically evoked pain-like behavior were paralleled by transmission electron microscopy, immunohistochemistry, and anatomical tracing of the peripheral nerve. In both crush models, motor function was equally affected early after injury; by contrast, partial crush of the nerve resulted in the early return of pinprick sensitivity, followed by a transient thermal and chronic tactile hypersensitivity of the affected hind paw, which was not observed after a full crush injury. The partially crushed nerve was characterized by the sparing of small-diameter myelinated axons and intraepidermal nerve fibers, fewer dorsal root ganglia expressing the injury marker activating transcription factor 3, and lower serum levels of neurofilament light chain. By day 30, axons showed signs of reduced myelin thickness. In summary, the escape of small-diameter axons from Wallerian degeneration is likely a determinant of chronic pain pathophysiology distinct from the general response to complete nerve injury.

show abstract

Lack of correlation between spinal microgliosis and long-term development of tactile hypersensitivity in two different sciatic nerve crush injury

Cited by 4 publications

References 49 publications

BDNF/TrkB Signaling Inhibition Suppresses Astrogliosis and Alleviates Mechanical Allodynia in a Partial Crush Injury Model

BDNF/TrkB Signaling Inhibition Suppresses Astrogliosis and Alleviates Mechanical Allodynia in a Partial Crush Injury Model

Motoneuronal inflammasome activation triggers excessive neuroinflammation and impedes regeneration after sciatic nerve injury

Long-term tactile hypersensitivity after nerve crush injury in mice is characterized by the persistence of intact sensory axons

Contact Info

Product

Resources

About