ERK1/2 and p38 mitogen-activated protein kinase mediate iNOS-induced spinal neuron degeneration after acute traumatic spinal cord injury

Xu, Zhen; Wang, Bai-Ren; Wang, Xi; Kuang, Fang; Duan, Xingwu; Jiao, Xi-Ying; Ju, Gong

doi:10.1016/j.lfs.2006.06.023

Cited by 105 publications

(95 citation statements)

References 38 publications

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“…Previous studies have reported increased levels of p38 MAPK after spinal cord injury (Horiuchi et al, 2003;Yune et al, 2003;Z. Xu et al, 2006).…”

Section: Discussionmentioning

confidence: 86%

“…However, p38 MAPK also mediates a variety of cellular functions involved in development, cell survival and proliferation (Roux and Blenis, 2004;Krens et al, 2006). Studies inhibiting p38 MAPK after SCI have shown differing results, from slightly improved outcome (i.e., increased standing frequency) and reduced apoptosis (Horiuchi et al, 2003;Z. Xu et al, 2006) to no improvements in locomotor recovery .…”

Section: Introductionmentioning

confidence: 99%

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Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MK2) Contributes to Secondary Damage after Spinal Cord Injury

Ghasemlou¹,

López-Vales²,

Lachance³

et al. 2010

J. Neurosci.

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The inflammatory response contributes importantly to secondary tissue damage and functional deficits after spinal cord injury (SCI). In this work, we identified mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MAPKAPK2 or MK2), a downstream substrate of p38 MAPK, as a potential target using microarray analysis of contused spinal cord tissue taken at the peak of the inflammatory response. There was increased expression and phosphorylation of MK2 after SCI, with phospho-MK2 expressed in microglia/ macrophages, neurons and astrocytes. We examined the role of MK2 in spinal cord contusion injury using MK2 Ϫ/Ϫ mice. These results show that locomotor recovery was significantly improved in MK2 Ϫ/Ϫ mice, compared with wild-type controls. MK2 Ϫ/Ϫ mice showed reduced neuron and myelin loss, and increased sparing of serotonergic fibers in the ventral horn caudal to the injury site. We also found differential expression of matrix metalloproteinase-2 and 9 in MK2 Ϫ/Ϫ and wild-type mice after SCI. Significant reduction was also seen in the expression of proinflammatory cytokines and protein nitrosylation in the injured spinal cord of MK2 Ϫ/Ϫ mice. Our previous work has shown that macrophages lacking MK2 have an anti-inflammatory phenotype. We now show that there is no difference in the number of macrophages in the injured spinal cord between the two mouse strains and little if any difference in their phagocytic capacity, suggesting that macrophages lacking MK2 have a beneficial phenotype. These findings suggest that a lack of MK2 can reduce tissue damage after SCI and improve locomotor recovery. MK2 may therefore be a useful target to treat acute SCI.

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“…Previous studies have reported increased levels of p38 MAPK after spinal cord injury (Horiuchi et al, 2003;Yune et al, 2003;Z. Xu et al, 2006).…”

Section: Discussionmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MK2) Contributes to Secondary Damage after Spinal Cord Injury

Ghasemlou¹,

López-Vales²,

Lachance³

et al. 2010

J. Neurosci.

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“…Inhibition of NFκB by melatonin has been also previously reported in other experimental models that showed how melatonin prevented NFκB activation by oxidative stress (Veneroso et al 2009). Previous studies also showed that melatonin inhibited phosphorylation of p38 MAPK and to a lesser extent of ERK1/2 thus reducing iNOS mRNA expression and rescuing neurons from apoptosis after acute traumatic SCI (Xu et al 2006).…”

Section: Discussionmentioning

confidence: 87%

Melatonin and oestrogen treatments were able to improve neuroinflammation and apoptotic processes in dentate gyrus of old ovariectomized female rats

Kireev

Vara

Viña

et al. 2014

AGE

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The aim of this study was to determine the outcomes of oestrogen and melatonin treatments following long-term ovarian hormone depletion on neuroinflammation and apoptotic processes in dentate gyrus of hippocampi. Forty-six female Wistar rats of 22 months of age were used. Twelve of them remained intact, and the other 34 were ovariectomized at 12 months of age. Ovariectomized animals were divided into three groups and treated for 10 weeks with oestrogens, melatonin or saline. All rats were killed by decapitation at 24 months of age, and dentate gyri were collected. A group of 2 month-old intact female rats was used as young control. The levels of pro-inflammatory cytokines and heat shock protein 70 (HSP 70) were analysed by ELISA. The expressions of TNFα, IL1β, GFAP, nNOS, iNOS, HO-1, NFκB, Bax, Bad, AIF, Bcl2 and SIRT1 genes were detected by real-time (RT)-PCR. Western blots were used to measure the protein expression of NFκB p65, NFκB p50/105, IκBα, IκBβ, p38 MAPK, MAP-2 and synapsin I. We have assessed the ability of 17β-oestradiol and melatonin administration to downregulate markers of neuroinflammation in the dentate gyrus of ovariectomized female rats. Results indicated that 17β-oestradiol and melatonin treatments were able to significantly decrease expression of pro-inflammatory cytokines, iNOS and HO-1 in the hippocampus when compared to non-treated animals. A similar age-and long-term ovarian hormone depletion-related increase in GFAP was also attenuated after both melatonin and oestradiol treatments. In a similar way to oestradiol, melatonin decreased the activation of p38 MAPK and NFκB pathways. The treatments enhanced the levels of synaptic molecules synapsin I and MAP-2 and have been shown to modulate the pro-antiapoptotic ratio favouring the second and to increase SIRT1 expression. These findings support the potential therapeutic role of melatonin and oestradiol as protective antiinflammatory agents for the central nervous system during menopause.

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“…PRAS40 protects motor neurons from death after SCI F Yu et al (Xu et al, 2006). Nuclei translocation of apoptosisinducing factor and endonuclease G induces neuronal apoptosis through caspase-independent pathways after SCI (Yu et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Increased Expression of a Proline-Rich Akt Substrate (PRAS40) in Human Copper/Zinc-Superoxide Dismutase Transgenic Rats Protects Motor Neurons from Death after Spinal Cord Injury

Narasimhan

Saito

et al. 2007

J Cereb Blood Flow Metab

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The serine-threonine kinase, Akt, plays an important role in the cell survival signaling pathway. A proline-rich Akt substrate, PRAS40, has been characterized, and an increase in phospho-PRAS40 (pPRAS40) is neuroprotective after transient focal cerebral ischemia. However, the involvement of PRAS40 in the cell death/survival pathway after spinal cord injury (SCI) is unclear. Liposomemediated PRAS40 transfection was performed to study whether overexpression of pPRAS40 is neuroprotective. We further examined the expression of pPRAS40 after SCI by immunohistochemistry and Western blot using copper/zinc-superoxide dismutase (SOD1) transgenic (Tg) rats and wild-type (Wt) littermates. We then examined the relationship between PRAS40 and Akt by injection of LY294002, a phosphatidylinositol 3-kinase (PI3K) pathway inhibitor, or Akt inhibitor IV, a compound that inhibits Akt activation after SCI. Our data demonstrated that increased pPRAS40 resulted in survival of more motor neurons compared with control complementary DNA transfection. Phosphorylated PRAS40 increased in the Wt rats after SCI, whereas there was a greater and prolonged increase in the SOD1 Tg rats. Coimmunoprecipitation showed that binding of pPRAS40 with 14-3-3 increased 1 day after SCI in the Wt rats, whereas there was a significant increase in the Tg rats. The inhibitor studies showed that phospho-Akt and pPRAS40 were decreased after injection of LY294002 or Akt inhibitor IV. We conclude that an increase in pPRAS40 by transfection after SCI results in survival of motor neurons, and overexpression of SOD1 in the Tg rats results in an increase in endogenous pPRAS40 and a decrease in motor neuron death through the PI3K/Akt pathway.

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ERK1/2 and p38 mitogen-activated protein kinase mediate iNOS-induced spinal neuron degeneration after acute traumatic spinal cord injury

Cited by 105 publications

References 38 publications

Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MK2) Contributes to Secondary Damage after Spinal Cord Injury

Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MK2) Contributes to Secondary Damage after Spinal Cord Injury

Melatonin and oestrogen treatments were able to improve neuroinflammation and apoptotic processes in dentate gyrus of old ovariectomized female rats

Increased Expression of a Proline-Rich Akt Substrate (PRAS40) in Human Copper/Zinc-Superoxide Dismutase Transgenic Rats Protects Motor Neurons from Death after Spinal Cord Injury

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