Calpain-2 contributes to neuropathic pain following motor nerve injury via up-regulating interleukin-6 in DRG neurons

Zang, Ying; Chen, Shao-Xia; Liao, Guang-Jie; Zhu, He-Quan; Wei, Xu-Hong; Chen, Yu; Na, Xiaodong; Pang, Rui‐Ping; Xin, Wenjun; Zhou, Lijun; Liu, Xianguo

doi:10.1016/j.bbi.2014.08.003

Cited by 35 publications

(49 citation statements)

References 76 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A recent report suggested calpain II as one of the earliest mediators for cytokine regulation and its activation is closely linked with up-regulation of IL-6 expression in DRG neurons and induction of mechanical allodynia in the model of neuropathic pain. MDL 28170 have elicited antiallodynic effects with prevention of IL-6 upregulation in neuropathic rats (Zang et al, 2015). Our previous reports suggested significantly increased activities of COX-2, NF-kB, TNF-a and IL-6 in the STZinduced rat model of diabetic neuropathy indicating a severe inflammatory state in diabetes (Kumar and Sharma, 2010;Negi and Sharma, 2015).…”

Section: Discussionmentioning

confidence: 98%

Calpain inhibitor, MDL 28170 confer electrophysiological, nociceptive and biochemical improvement in diabetic neuropathy

2015

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 98%

Calpain inhibitor, MDL 28170 confer electrophysiological, nociceptive and biochemical improvement in diabetic neuropathy

2015

View full text Add to dashboard Cite

“…Although calpains 1 and 2 share several common substrates 31 , recent studies show that they have different functional profiles under physiological 32–34 and pathological conditions 35–38 . Also, there is evidence for isoform-specific roles for calpains 1 and 2 in induction and consolidation phase of LTP, respectively 34 .…”

Section: Discussionmentioning

confidence: 99%

Isoform-specific hyperactivation of calpain-2 occurs presymptomatically at the synapse in Alzheimer’s disease mice and correlates with memory deficits in human subjects

Ahmad

Das

Kommaddi

et al. 2018

Sci Rep

View full text Add to dashboard Cite

Calpain hyperactivation is implicated in late-stages of neurodegenerative diseases including Alzheimer’s disease (AD). However, calpains are also critical for synaptic function and plasticity, and hence memory formation and learning. Since synaptic deficits appear early in AD pathogenesis prior to appearance of overt disease symptoms, we examined if localized dysregulation of calpain-1 and/or 2 contributes to early synaptic dysfunction in AD. Increased activity of synaptosomal calpain-2, but not calpain-1 was observed in presymptomatic 1 month old APPswe/PS1ΔE9 mice (a mouse model of AD) which have no evident pathological or behavioural hallmarks of AD and persisted up to 10 months of age. However, total cellular levels of calpain-2 remained unaffected. Moreover, synaptosomal calpain-2 was hyperactivated in frontal neocortical tissue samples of post-mortem brains of AD-dementia subjects and correlated significantly with decline in tests for cognitive and memory functions, and increase in levels of β-amyloid deposits in brain. We conclude that isoform-specific hyperactivation of calpain-2, but not calpain-1 occurs at the synapse early in the pathogenesis of AD potentially contributing to the deregulation of synaptic signaling in AD. Our findings would be important in paving the way for potential therapeutic strategies for amelioration of cognitive deficits observed in ageing-related dementia disorders like AD.

show abstract

“…; Zang et al . ) mimics clinical pain symptoms associated with post‐poliomyelitis (Stoelb et al . ; Rekand et al .…”

mentioning

confidence: 96%

“…We showed that L5‐VRT transiently activates CALP2 in both distal‐ and proximal‐stumps of nerve root between 10 and 180 min following nerve injury (Zang et al . ), suggesting that the neurodegenerative process in the transected motor fiber is triggered at an early stage. Degeneration in myelinated efferent fibers is sufficient to induce spontaneous activity in unmyelinated C‐fiber afferents (Wu et al .…”

mentioning

confidence: 99%

See 1 more Smart Citation

Early CALP2 expression and microglial activation are potential inducers of spinal IL‐6 up‐regulation and bilateral pain following motor nerve injury

Chen

Wang

Yao

et al. 2018

Journal of Neurochemistry

Self Cite

View full text Add to dashboard Cite

Previous work from our laboratory showed that motor nerve injury by lumbar 5 ventral root transection (L5-VRT) led to interleukin-6 (IL-6) over-expression in bilateral spinal cord, and that intrathecal administration of IL-6 neutralizing antibody delayed the induction of mechanical allodynia in bilateral hind paws. However, early events and upstream mechanisms underlying spinal IL-6 expression following L5-VRT require elucidation. The model of L5-VRT was used to induce neuropathic pain, which was assessed with von Frey hairs and the plantar tester in adult male Sprague-Dawley rats. Calpain-2 (CALP2, a calcium-dependent protease) knockdown or over-expression and microglia depletion were conducted intrathecally. Western blots and immunohistochemistry were performed to explore the possible mechanisms. Here, we provide the first evidence that both IL-6 and CALP2 levels are increased in lumbar spinal cord within 30 min following L5-VRT. IL-6 and CALP2 co-localized in both spinal dorsal horn (SDH) and spinal ventral horn. Post-operative (PO) increase in CALP2 in ipsilateral SDH was evident at 10 min PO, preceding increased IL-6 at 20 min PO. Knockdown of spinal CALP2 by intrathecal CALP2-shRNA administration prevented VRT-induced IL-6 overproduction in ipsilateral spinal cord and alleviated bilateral mechanical allodynia. Spinal microglia activation also played a role in early IL-6 up-regulation. Macrophage/microglia markers ED1/Iba1 were increased at 30 min PO, while glial fibrillary acidic protein (astrocyte) and CNPase (oligodendrocyte) markers were not. Increased Iba1 was detected as early as 20 min PO and peaked at 3 days. Morphology changed from a small soma with fine processes in resting cells to an activated ameboid shape. Depletion of microglia using Mac-1-saporin partially prevented IL-6 up-regulation and attenuated VRT-induced bilateral mechanical allodynia. Taken together, our findings provide evidence that increased spinal cord CALP2 and microglia cell activation may have early causative roles in IL-6 over-expression following motor nerve injury. Agents that inhibit CALP2 and/or microglia activation may therefore prove valuable for treating neuropathic pain.

show abstract

Calpain-2 contributes to neuropathic pain following motor nerve injury via up-regulating interleukin-6 in DRG neurons

Cited by 35 publications

References 76 publications

Calpain inhibitor, MDL 28170 confer electrophysiological, nociceptive and biochemical improvement in diabetic neuropathy

Calpain inhibitor, MDL 28170 confer electrophysiological, nociceptive and biochemical improvement in diabetic neuropathy

Isoform-specific hyperactivation of calpain-2 occurs presymptomatically at the synapse in Alzheimer’s disease mice and correlates with memory deficits in human subjects

Early CALP2 expression and microglial activation are potential inducers of spinal IL‐6 up‐regulation and bilateral pain following motor nerve injury

Contact Info

Product

Resources

About