Spatial and temporal correlation in progressive degeneration of neurons and astrocytes in contusion-induced spinal cord injury

Min, Kyoung‐jin; Jeong, Hey-Kyeong; Kim, Beomsue; Hwang, Dae Hyun; Shin, Hae Young; Nguyen, An Tran; Kim, Jong-hyeon; Jou, Ilo; Kim, Byung Gon; Joe, Eun‐Hye

doi:10.1186/1742-2094-9-100

Cited by 43 publications

(71 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Surprisingly, only a small extension of PhMN loss was observed over time, despite the progressive increase in lesion volume beyond 1 DPI. Consistent with our observations and other work, 2,15 Andrade and colleagues showed that secondary neurodegeneration is pronounced following moderate SCI, unlike following more severe injury. 18 In our current study, the secondary degenerative process may have been minimized because of the severity of the initial 395 kD impact.…”

Section: Discussionsupporting

confidence: 82%

“…10 Our study demonstrates that following unilateral C4 contusion SCI, PhMN loss in the ipsilateral phrenic nucleus primarily occurs within the first 24 h post-injury. Very early loss of motor neurons (i.e., between 12 and 24 h post-injury) has already been shown in thoracic contusion models, [15][16][17] further suggesting that therapeutic interventions targeting motor neuron sparing should be delivered within 1 DPI. Surprisingly, only a small extension of PhMN loss was observed over time, despite the progressive increase in lesion volume beyond 1 DPI.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Early Phrenic Motor Neuron Loss and Transient Respiratory Abnormalities after Unilateral Cervical Spinal Cord Contusion

Nicaise

Frank

Hala

et al. 2013

Journal of Neurotrauma

View full text Add to dashboard Cite

Contusion-type cervical spinal cord injury (SCI) is one of the most common forms of SCI observed in patients. In particular, injuries targeting the C3-C5 region affect the pool of phrenic motor neurons (PhMNs) that innervates the diaphragm, resulting in significant and often chronic respiratory dysfunction. Using a previously described rat model of unilateral midcervical C4 contusion with the Infinite Horizon Impactor, we have characterized the early time course of PhMN degeneration and consequent respiratory deficits following injury, as this knowledge is important for designing relevant treatment strategies targeting protection and plasticity of PhMN circuitry. PhMN loss (48% of the ipsilateral pool) occurred almost entirely during the first 24 h post-injury, resulting in persistent phrenic nerve axonal degeneration and denervation at the diaphragm neuromuscular junction (NMJ). Reduced diaphragm compound muscle action potential amplitudes following phrenic nerve stimulation were observed as early as the first day post-injury (30% of pre-injury maximum amplitude), with slow functional improvement over time that was associated with partial reinnervation at the diaphragm NMJ. Consistent with ipsilateral diaphragmatic compromise, the injury resulted in rapid, yet only transient, changes in overall ventilatory parameters measured via whole-body plethysmography, including increased respiratory rate, decreased tidal volume, and decreased peak inspiratory flow. Despite significant ipsilateral PhMN loss, the respiratory system has the capacity to quickly compensate for partially impaired hemidiaphragm function, suggesting that C4 hemicontusion in rats is a model of SCI that manifests subacute respiratory abnormalities. Collectively, these findings demonstrate significant and persistent diaphragm compromise in a clinically relevant model of midcervical contusion SCI; however, the therapeutic window for PhMN protection is restricted to early time points post-injury. On the contrary, preventing loss of innervation by PhMNs and/or inducing plasticity in spared PhMN axons at the diaphragm NMJ are relevant long-term targets.

show abstract

Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Early Phrenic Motor Neuron Loss and Transient Respiratory Abnormalities after Unilateral Cervical Spinal Cord Contusion

Nicaise

Frank

Hala

et al. 2013

Journal of Neurotrauma

View full text Add to dashboard Cite

show abstract

“…However, we and others have reported that brain inflammation is not neurotoxic but is instead neuroprotective and functions to repair the injured brain (Batchelor et al, 1999; Elkabes et al, 1996; Howe and Barres, 2012; Jeong et al, 2010; 2013a; 2013b; Kim et al, 2010; Koch and Szecsey, 2000; Lehrmann et al, 1998; Min et al, 2012; Reines et al, 2004; Scharf et al, 1999; van Gool et al, 2003; Vinet et al, 2012; Yang et al, 2007). In this study, we demonstrated that inflammatory responses were similar in both KA-and NMDA-injected cortexes.…”

Section: Discussionmentioning

confidence: 78%

“…Thus, astrocyte support is required for neuronal survival (Jeong et al, 2013c; Min et al, 2012). A loss of EAAT2/GLT-1 and decreased glutamate transport have been identified in human ALS patients (Rothstein et al, 1992; 1995).…”

Section: Discussionmentioning

confidence: 99%

Astrogliosis Is a Possible Player in Preventing Delayed Neuronal Death

Jeong¹,

Ji²,

Min³

et al. 2014

Molecules and Cells

Self Cite

View full text Add to dashboard Cite

Mitigating secondary delayed neuronal injury has been a therapeutic strategy for minimizing neurological symptoms after several types of brain injury. Interestingly, secondary neuronal loss appeared to be closely related to functional loss and/or death of astrocytes. In the brain damage induced by agonists of two glutamate receptors, N-ethyl-D-aspartic acid (NMDA) and kainic acid (KA), NMDA induced neuronal death within 3 h, but did not increase further thereafter. However, in the KA-injected brain, neuronal death was not obviously detectable even at injection sites at 3 h, but extensively increased to encompass the entire hemisphere at 7 days. Brain inflammation, a possible cause of secondary neuronal damage, showed little differences between the two models. Importantly, however, astrocyte behavior was completely different. In the NMDA-injected cortex, the loss of glial fibrillary acidic protein-expressing (GFAP+) astrocytes was confined to the injection site until 7 days after the injection, and astrocytes around the damage sites showed extensive gliosis and appeared to isolate the damage sites. In contrast, in the KA-injected brain, GFAP+ astrocytes, like neurons, slowly, but progressively, disappeared across the entire hemisphere. Other markers of astrocytes, including S100β, glutamate transporter EAAT2, the potassium channel Kir4.1 and glutamine synthase, showed patterns similar to that of GFAP in both NMDA- and KA-injected cortexes. More importantly, astrocyte disappearance and/or functional loss preceded neuronal death in the KA-injected brain. Taken together, these results suggest that loss of astrocyte support to neurons may be a critical cause of delayed neuronal death in the injured brain.

show abstract

“…More importantly, the microglia died prior to the neurons in the penumbra region, where the delayed neuronal death occurs [2, 35]. We previously reported that LPS did not induce neuronal death in the cortex but induced it slowly in the SN, where astrocytes density was high and low, respectively [35].…”

Section: Discussionmentioning

confidence: 99%

Absence of Delayed Neuronal Death in ATP-Injected Brain: Possible Roles of Astrogliosis

2013

Self Cite

View full text Add to dashboard Cite

Although secondary delayed neuronal death has been considered as a therapeutic target to minimize brain damage induced by several injuries, delayed neuronal death does not occur always. In this study, we investigated possible mechanisms that prevent delayed neuronal death in the ATP-injected substantia nigra (SN) and cortex, where delayed neuronal death does not occur. In both the SN and cortex, ATP rapidly induced death of the neurons and astrocytes in the injection core area within 3 h, and the astrocytes in the penumbra region became hypertropic and rapidly surrounded the damaged areas. It was observed that the neurons survived for up to 1-3 months in the area where the astrocytes became hypertropic. The damaged areas of astrocytes gradually reduced at 3 days, 7 days, and 1-3 months. Astrocyte proliferation was detectable at 3-7 days, and vimentin was expressed in astrocytes that surrounded and/or protruded into the damaged sites. The NeuN-positive cells also reappeared in the injury sites where astrocytes reappeared. Taken together, these results suggest that astroycte survival and/or gliosis in the injured brain may be critical for neuronal survival and may prevent delayed neuronal death in the injured brain.

show abstract

Spatial and temporal correlation in progressive degeneration of neurons and astrocytes in contusion-induced spinal cord injury

Cited by 43 publications

References 69 publications

Early Phrenic Motor Neuron Loss and Transient Respiratory Abnormalities after Unilateral Cervical Spinal Cord Contusion

Early Phrenic Motor Neuron Loss and Transient Respiratory Abnormalities after Unilateral Cervical Spinal Cord Contusion

Astrogliosis Is a Possible Player in Preventing Delayed Neuronal Death

Absence of Delayed Neuronal Death in ATP-Injected Brain: Possible Roles of Astrogliosis

Contact Info

Product

Resources

About