Agmatine Attenuates Brain Edema and Apoptotic Cell Death after Traumatic Brain Injury

Kim, Jae Young; Lee, Yong Woo; Lee, Won Taek; Park, Kyung Ah; Lee, Jong Eun

doi:10.3346/jkms.2015.30.7.943

Cited by 26 publications

(16 citation statements)

References 37 publications

(54 reference statements)

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“…Cerebral edema is the accumulation of water molecules in brain cells and the extracellular space, which causes a pathological increase in brain volume and is one of the most serious complications of traumatic brain injury ( 13 , 14 ). Cerebral edema can be divided into cytotoxic brain edema (intracellular), vasogenic brain edema, interstitial brain edema and osmotic brain edema subtypes.…”

Section: Discussionmentioning

confidence: 99%

Expression of aquaporin-4 and pathological characteristics of brain injury in a rat model of traumatic brain injury

Zhang

Chen

2015

Molecular Medicine Reports

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Aquaporin 4 (AQP4) is a widely distributed membrane protein, which is found in glial cells, ependymocytes and capillary endothelial cells in the brain, and particularly in the choroid plexus. AQP4 is a key regulator of water metabolism, and changes in its expression following brain injury are associated with pathological changes in the damaged side of the brain; however, the effects of brain injury on AQP4 and injury-induced pathological changes in the contralateral non-damaged side of the brain remain to be fully elucidated. In the present study, male Sprague-Dawley rats were subjected to traumatic brain injury (TBI) and changes in brain water content, the expression of AQP4 expression and pathological characteristics in the damaged and contralateral non-damaged sides of the brain were examined. In the damaged side of the brain, vasogenic edema appeared first, followed by cellular edema. The aggravated cellular edema in the damaged side of the brain resulted in two periods of peak edema severity. Pathological changes in the contralateral non-damaged side of the brain occurred later than those in the damaged side; cellular edema appeared first, followed by vasogenic edema, which was alleviated earlier than the cellular edema. AQP4 was downregulated during vasogenic edema, and upregulated during cellular edema. Taken together, these results suggested that the downregulation of AQP4 was a result of vasogenic edema and that the upregulation of AQP4 may have induced cellular edema.

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Section: Discussionmentioning

confidence: 99%

Expression of aquaporin-4 and pathological characteristics of brain injury in a rat model of traumatic brain injury

Zhang

Chen

2015

Molecular Medicine Reports

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“…The following antibodies were used at a dilution of 1:1000 unless otherwise stated: anti-myelin-associated glycoprotein (MAG) (Santa Cruz Biotechnology, Santa Cruz, CA), antiphospho-p38 (pThr 180 /pTyr 182 ) (Sigma-Aldrich, Steinheim, Germany), anti-p44/42 MAPK (ERK1/2), anti-phospho-p44/42 MAPK (p-ERK1/2) (Thr 202 /Tyr 204 ), anti-phospho-SAPK/JNK (Thr 183 /Tyr 185 ), anti-phospho-c-Jun (Ser 73 ), anti-b actin (all from Cell Signalling Technology, Beverly, MA), and anti-Hsp90 (1:2,000, Santa Cruz Biotechnology, Santa Cruz, CA) (Delgado et al, 2014;Gomez et al, 2011;Hao and ElShamy, 2007;Kim et al, 2015;Liu et al, 2014;Petrov et al, 2015;Watanabe et al, 2015). The CC of each animal was homogenized in ice-cold 0.5 M Tris buffer, pH 7.4 (containing 5 M sodium chloride, 50% glycerol, 100 mM ethylene glycol tetraacetic acid, 10 mM sodium orthovanadate, 1 mM zinc chloride, 0.5 mM sodium fluoride, aprotinin, 200 mM phenylmethylsulfonyl fluoride, 10% Triton X-100, and distilled water; (all purchased from Sigma-Aldrich, Steinheim, Germany).…”

Section: Immunoblot Analysismentioning

confidence: 99%

“…The membranes were blocked in 5% nonfat dry milk or 3% bovine serum albumin in TBST and then incubated overnight with each specific antibody. The following antibodies were used at a dilution of 1:1000 unless otherwise stated: anti-myelin-associated glycoprotein (MAG) (Santa Cruz Biotechnology, Santa Cruz, CA), antiphospho-p38 (pThr 180 /pTyr 182 ) (Sigma-Aldrich, Steinheim, Germany), anti-p44/42 MAPK (ERK1/2), anti-phospho-p44/42 MAPK (p-ERK1/2) (Thr 202 /Tyr 204 ), anti-phospho-SAPK/JNK (Thr 183 /Tyr 185 ), anti-phospho-c-Jun (Ser 73 ), anti-b actin (all from Cell Signalling Technology, Beverly, MA), and anti-Hsp90 (1:2,000, Santa Cruz Biotechnology, Santa Cruz, CA) (Delgado et al, 2014;Gomez et al, 2011;Hao and ElShamy, 2007;Kim et al, 2015;Liu et al, 2014;Petrov et al, 2015;Watanabe et al, 2015). Appropriate horseradish peroxidase-conjugated secondary antibody was used at a 1:10,000 dilution (anti-rabbit IgGs; Cell Signalling Technology, Beverly, MA) and labeled proteins were visualized by enhanced chemiluminescence (Immobilon, Merck Millipore, Darmstadt, Germany).…”

Section: Immunoblot Analysismentioning

confidence: 99%

TRPA1 deficiency is protective in cuprizone-induced demyelination-A new target against oligodendrocyte apoptosis

Sághy

Sipos

Ács

et al. 2016

Glia

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Multiple sclerosis is a chronic inflammatory, demyelinating degenerative disease of the central nervous system. Current treatments target pathological immune responses to counteract the inflammatory processes. However, these drugs do not restrain the long-term progression of clinical disability. For this reason, new therapeutic approaches and identification of novel target molecules are needed to prevent demyelination or promote repair mechanisms. Transient Receptor Potential Ankyrin 1 (TRPA1) is a nonselective cation channel with relatively high Ca permeability. Its pathophysiological role in central nervous system disorders has not been elucidated yet. In the present study, we aimed to assess the distribution of TRPA1 in the mouse brain and reveal its regulatory role in the cuprizone-induced demyelination. This toxin-induced model, characterized by oligodendrocyte apoptosis and subsequent primary demyelination, allows us to investigate the nonimmune aspects of multiple sclerosis. We found that TRPA1 is expressed on astrocytes in the mouse central nervous system. Interestingly, TRPA1 deficiency significantly attenuated cuprizone-induced demyelination by reducing the apoptosis of mature oligodendrocytes. Our data suggest that TRPA1 regulates mitogen-activated protein kinase pathways, as well as transcription factor c-Jun and a proapoptotic Bcl-2 family member (Bak) expression resulting in enhanced oligodendrocyte apoptosis. In conclusion, we propose that TRPA1 receptors enhancing the intracellular Ca concentration modulate astrocyte functions, and influence the pro or anti-apoptotic pathways in oligodendrocytes. Inhibition of TRPA1 receptors might successfully diminish the degenerative pathology in multiple sclerosis and could be a promising therapeutic target to limit central nervous system damage in demyelinating diseases. GLIA 2016;64:2166-2180.

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“…Agmatine is an endogenous clonidine-displacing substance, an agonist for the α2-adrenergic and imidazoline receptors, and an antagonist for the N -methyl-D-aspartate (NMDA) receptors [ 9 10 11 12 ]. Recent studies have shown that agmatine may be neuroprotective in trauma and ischemia models [ 7 13 14 15 16 17 18 19 ]. Agmatine protects neurons against glutamate toxicity, and this effect is mediated through NMDA receptor blockade, with agmatine interacting at a site located within the NMDA channel pore [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Endogenous Agmatine Induced by Ischemic Preconditioning Regulates Ischemic Tolerance Following Cerebral Ischemia

Kim

Jung

et al. 2017

Exp Neurobiol

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Ischemic preconditioning (IP) is one of the most important endogenous mechanisms that protect the cells against ischemia-reperfusion (I/R) injury. However, the exact molecular mechanisms remain unclear. In this study, we showed that changes in the level of agmatine were correlated with ischemic tolerance. Changes in brain edema, infarct volume, level of agmatine, and expression of arginine decarboxylase (ADC) and nitric oxide synthases (NOS; inducible NOS [iNOS] and neural NOS [nNOS]) were analyzed during I/R injury with or without IP in the rat brain. After cerebral ischemia, brain edema and infarct volume were significantly reduced in the IP group. The level of agmatine was increased before and during ischemic injury and remained elevated in the early reperfusion phase in the IP group compared to the experimental control (EC) group. During IP, the level of plasma agmatine was increased in the early phase of IP, but that of liver agmatine was abruptly decreased. However, the level of agmatine was definitely increased in the ipsilateral and contralateral hemisphere of brain during the IP. IP also increased the expression of ADC—the enzyme responsible for the synthesis of endogenous agmatine—before, during, and after ischemic injury. In addition, ischemic injury increased endogenous ADC expression in the EC group. The expression of nNOS was reduced in the I/R injured brain in the IP group. These results suggest that endogenous increased agmatine may be a component of the ischemic tolerance response that is induced by IP. Agmatine may have a pivotal role in endogenous ischemic tolerance.

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Agmatine Attenuates Brain Edema and Apoptotic Cell Death after Traumatic Brain Injury

Cited by 26 publications

References 37 publications

Expression of aquaporin-4 and pathological characteristics of brain injury in a rat model of traumatic brain injury

Expression of aquaporin-4 and pathological characteristics of brain injury in a rat model of traumatic brain injury

TRPA1 deficiency is protective in cuprizone-induced demyelination-A new target against oligodendrocyte apoptosis

Endogenous Agmatine Induced by Ischemic Preconditioning Regulates Ischemic Tolerance Following Cerebral Ischemia

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