Glutamate-induced Toxicity in Hippocampal Slices Involves Apoptotic Features and p38MAPK Signaling

Docosahexaenoic acid (DHA) is important for central nervous system function during pathological states such as ischemia. DHA reduces neuronal injury in experimental brain ischemia; however, the underlying mechanisms are not well understood. In the present study, we investigated the effects of DHA on acute hippocampal slices subjected to experimental ischemia by transient oxygen and glucose deprivation (OGD) and re-oxygenation and the possible involvement of purinergic receptors as the mechanism underlying DHAmediated neuroprotection. We observed that cellular viability reduction induced by experimental ischemia as well as cell damage and thiobarbituric acid reactive substances (TBARS) production induced by glutamate (10 mM) were prevented by hippocampal slices pretreated with DHA (5 μM). However, glutamate uptake reduction induced by OGD and reoxygenation was not prevented by DHA. The beneficial effect of DHA against cellular viability reduction induced by OGD and re-oxygenation was blocked with PPADS (3 μM), a nonselective P2X 1-5 receptor antagonist as well as with a combination of TNP-APT (100 nM) plus brilliant blue (100 nM), which blocked P2X 1 , P2X 3 , P2X 2/3 , and P2X 7 receptors, respectively. Moreover, adenosine receptors blockade with A 1 receptor antagonist DPCPX (100 nM) or with A 2B receptor antagonist alloxazine (100 nM) inhibited DHAmediated neuroprotection. The addition of an A 2A receptor antagonist ZM241385 (50 nM), or A 3 receptor antagonist VUF5574 (1 μM) was ineffective. Taken together, our results indicated that neuroprotective actions of DHA may depend on P2X, A 1 , and A 2B purinergic receptors activation. Our results reinforce the notion that dietary DHA may act as a local purinergic modulator in order to prevent neurodegenerative diseases.

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“…Thus, we also verified if DHA was able to prevent excitotoxicity-induced cell damage in hippocampal brain slices [48]. As shown in Fig.…”

Section: Ogd-induced Cell Damage Is Prevented By Dhasupporting

confidence: 52%

“…To verify the neuroprotective effect of DHA against excitotoxicity, hippocampal slices were incubated for 2 h in HF solution containing 10 mM of glutamate [48]. When present, DHA was preincubated for 15 min before adding glutamate.…”

Section: Excitotoxicity Protocolmentioning

confidence: 99%

Purine receptors are required for DHA-mediated neuroprotection against oxygen and glucose deprivation in hippocampal slices

Molz

Kraus

Ludka

et al. 2014

Purinergic Signalling

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“…In agreement, NMDA-induced activation of p38 MAPK and PARP has been well documented and linked to RGC death in vitro and in vivo. 36 -40 In addition, the neuroprotective actions of inhibiting p38 MAPK using SB203580 has been demonstrated in NMDA-injected rats, 37 as well as in hippocampal neuronal cultures 41 and in cortical cell cultures. 42 Our results showed that the neuroprotective effects of FeTPPs was associated with clear suppression of p38 MAPK activation and cleaved PARP expression.…”

Section: Figure 5 Fetpps Blocked Activation Of P38 Mapk Apoptosis Pamentioning

confidence: 99%

Neurovascular Protective Effect of FeTPPs in N-Methyl-D-Aspartate Model

Al‐Gayyar

Abdelsaid

Matragoon

et al. 2010

The American Journal of Pathology

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We have previously shown a causal role of peroxynitrite in mediating retinal ganglion cell (RGC) death in diabetic and neurotoxicity models. In the present study, the role of peroxynitrite in altering the antioxidant and antiapoptotic thioredoxin (Trx) system will be investigated as well as the subsequent effects on glial activation and capillary degeneration. Excitotoxicity of the retina was induced by intravitreal injection of N-methyl-Daspartate (NMDA) in rats, which also received the peroxynitrite decomposition catalyst FeTPPs. Retinal ganglion cell (RGC) death plays a critical role in the pathogenesis of many retinal neurodegenerative disorders, including glaucoma, diabetic retinopathy, traumatic optic neuropathy, uveitis, and retinal ischemia. [1][2][3][4][5] Understanding the molecular mechanism of neuronal cell death in such retinal diseases is of great clinical important for devising new treatments. In response to traumatic or ischemic injury, excessive activation of glutamate receptors has been implicated in the RGC death process. 6 Therefore, administration of N-methyl-D-aspartate (NMDA) to rodent eyes is a reliable model to study RGC death. Excessive NMDA receptor stimulation leads to excessive Ca 2ϩ influx, 7 which in turn triggers formation of nitric oxide 8 and accumulation of superoxides and their combination product peroxynitrite, causing lipid peroxidation, DNA damage and the eventual cell death. 9 Although increases in reactive oxygen species (ROS) and peroxynitrite have been implicated in mediating RGC death, 1,6 the molecular mechanisms by which peroxynitrite causes RGC death are not fully elucidated.Protection from ROS is mediated by superoxide dismutase, glutathione, and thioredoxin (Trx) systems. 10,11

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“…So far, there is still some controversy surrounded by the role of p38 MAPK in neuroprotection induced by ischemia/ hypoxia. For example, several studies have verified the inhibition of p38 MAPK by a specific small molecule that was shown to protect the brain from ischemic injury after MCAO [37][38][39]. Obviously, the results of the above were contrary with us.…”

Section: Discussionmentioning

confidence: 88%

Delayed neuroprotection induced by sevoflurane via opening mitochondrial ATP-sensitive potassium channels and p38 MAPK phosphorylation

Liu¹,

Guo²,

Wang³

et al. 2011

Neurol Sci

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This study aimed to investigate the role of p38 MAPK phosphorylation and opening of the mitoK(ATP) channels in the sevoflurane-induced delayed neuroprotection in the rat brain. Adult male Sprague-Dawley rats (250-300 g) were randomly assigned into four groups: ischemia/reperfusion (Control), sevoflurane (Sevo), 5-hydroxydecanoate (5-HD) + sevoflurane (5-HD + Sevo) and 5-HD groups and were subjected to right middle cerebral artery occlusion (MCAO) for 2 h. Sevoflurane preconditioning was induced 24 h before MCAO in sevoflurane and 5-HD + sevoflurane groups by exposing the animals to 2.4% sevoflurane in oxygen for 60 min. In control and 5-HD groups: animals were exposed to oxygen for 60 min at 24 h before MCAO. A selective mitoK(ATP) channel antagonist, 5-hydroxydecanoate (5-HD, 40 mg/kg, i.p.), was administered 30 min before sevoflurane/oxygen exposure in the 5-HD + sevoflurane and 5-HD groups, respectively. Neurological deficits scores and the protein expression of phosphorylated p38 mitogen-activated protein kinase (p-p38 MAPK) were evaluated at 24 and 72 h after reperfusion. Cerebral infarct size was evaluated at 72 h after reperfusion by 2,3,5-triphenyltetrazolium chloride staining. Sevoflurane preconditioning produced marked improvement neurological functions and a reduction in brain infarct volumes than animals with brain ischemia only. Sevoflurane treatment also caused increased phosphorylation of p38 MAPK at 24 and 72 h after reperfusion. These beneficial effects were attenuated by 5-HD. Blockade of cerebral protection with 5-HD concomitant with decrease in p38 phosphorylation suggests that mitoK(ATP) channels opening and p38 phosphorylation participate signal transduction cascade of sevoflurane preconditioning and p38 MAPK activation may be a downstream of opening mitoK(ATP) channels.

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Glutamate-induced Toxicity in Hippocampal Slices Involves Apoptotic Features and p38MAPK Signaling

Cited by 85 publications

References 64 publications

Purine receptors are required for DHA-mediated neuroprotection against oxygen and glucose deprivation in hippocampal slices

Purine receptors are required for DHA-mediated neuroprotection against oxygen and glucose deprivation in hippocampal slices

Neurovascular Protective Effect of FeTPPs in N-Methyl-D-Aspartate Model

Delayed neuroprotection induced by sevoflurane via opening mitochondrial ATP-sensitive potassium channels and p38 MAPK phosphorylation

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