Neurotensin Receptor Involvement in the Rise of Extracellular Glutamate Levels and Apoptotic Nerve Cell Death in Primary Cortical Cultures after Oxygen and Glucose Deprivation

Antonelli, Tiziana; Tomasini, Maria Cristina; Fournier, Jacqueline; Mazza, Roberta; Tanganelli, Sergio; Pirondi, Stefania; Fuxé, Kjell; Ferraro, Luca

doi:10.1093/cercor/bhm217

Cited by 26 publications

(23 citation statements)

References 45 publications

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“…1A); additionally, apoptotic neurons showed reduced and irregular MAP2 staining (Fig. 1A), consistent with previous observations (51)(52)(53)(54). This approach revealed that tatCN21 significantly reduced glutamate-induced neuronal death, indicating that CaMKII stimulation promotes excitotoxicity (Fig.…”

Section: Tatcn21 Protects Neurons From Excitotoxic Death-supporting

confidence: 91%

Effective Post-insult Neuroprotection by a Novel Ca2+/ Calmodulin-dependent Protein Kinase II (CaMKII) Inhibitor

Vest

O’Leary

Coultrap

et al. 2010

Journal of Biological Chemistry

109

185

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Ca 2؉ /calmodulin (CaM)-dependent protein kinase II (CaMKII) is a major mediator of physiological glutamate signaling involved in higher brain functions. Here, we show CaMKII involvement in pathological glutamate signaling relevant in stroke. The novel inhibitor tatCN21 was neuroprotective even when added hours after glutamate insults. By contrast, the "traditional" inhibitor KN93 attenuated excitotoxicity only when present during the insult. Both inhibitors efficiently blocked Ca 2؉ /CaM-stimulated CaMKII activity, CaMKII interaction with NR2B and aggregation of CaMKII holoenzymes. However, only tatCN21 but not KN93 blocked the Ca 2؉ -independent "autonomous" activity generated by Thr-286 autophosphorylation, the hallmark feature of CaMKII regulation. Mutational analysis further validated autonomous CaMKII activity as the drug target crucial for post-insult neuroprotection. Overexpression of CaMKII wild type but not the autonomy-deficient T286A mutant significantly increased glutamate-induced neuronal death. Maybe most importantly, tatCN21 also significantly reduced infarct size in a mouse stroke model (middle cerebral arterial occlusion) when injected (1 mg/kg intravenously) 1 h after onset of arterial occlusion. Together, these data demonstrate that inhibition of autonomous CaMKII activity provides a promising therapeutic avenue for post-insult neuro-protection after stroke.Glutamate is the most abundant excitatory neurotransmitter in the mammalian brain. However, excessive glutamate release causes Ca 2ϩ -dependent excitotoxic neuronal death in pathological situations such as focal cerebral ischemia (stroke) (for review see Refs. 1-4). Most glutamate receptors are involved in excitotoxicity, but especially important are the Ca 2ϩ -permeable ionotropic receptors such as the NMDA 4 -type glutamate receptor (NMDAR) (5-8). Extensive attempts to develop a stroke therapy by targeting glutamate receptors have resulted in disappointment (for review see Refs. 9, 10), suggesting that alternative strategies will be necessary. Currently, the only approved pharmacological treatment of stroke patients is hemolytic therapy with tissue plasminogen activator. However, less than 2% of patients actually receive tissue plasminogen activator. Although tissue plasminogen activator is effective in stroke caused by blood clots, it is actually contraindicated in hemorrhagic stroke, and diagnostic evaluation pushes most patients beyond the therapeutically effective time window (11-13).The Ca 2ϩ /calmodulin (Ca 2ϩ /CaM)-dependent protein kinase II (CaMKII) is a major physiological downstream target of glutamate-induced Ca 2ϩ signaling (for review see Refs. 14 -17) and was examined in this study for involvement in pathological excitotoxic glutamate signaling. CaMKII is highly expressed in brain where it participates in NMDAR-dependent long term potentiation and learning and memory (14 -17). CaMKII forms multimeric holoenzymes, and each kinase subunit is activated separately by Ca 2ϩ /CaM. An inter-subunit autophosphorylation at Thr-286 ...

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Section: Tatcn21 Protects Neurons From Excitotoxic Death-supporting

confidence: 91%

Effective Post-insult Neuroprotection by a Novel Ca2+/ Calmodulin-dependent Protein Kinase II (CaMKII) Inhibitor

Vest

O’Leary

Coultrap

et al. 2010

Journal of Biological Chemistry

109

185

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“…It is well known that during cerebral ischemia, glutamate excitotoxicity occurs when a large amount of glutamate is released from brain tissue into the extracellular space, as documented by in vitro studies [18], in vivo animal studies [19], [20], and in ischemic patients [5], [21], [22]. However the mechanism throughout temperature modifies the brain glutamate release is not completely understood.…”

Section: Discussionmentioning

confidence: 99%

Glutamate Excitoxicity Is the Key Molecular Mechanism Which Is Influenced by Body Temperature during the Acute Phase of Brain Stroke

et al. 2012

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Glutamate excitotoxicity, metabolic rate and inflammatory response have been associated to the deleterious effects of temperature during the acute phase of stroke. So far, the association of temperature with these mechanisms has been studied individually. However, the simultaneous study of the influence of temperature on these mechanisms is necessary to clarify their contributions to temperature-mediated ischemic damage. We used non-invasive Magnetic Resonance Spectroscopy to simultaneously measure temperature, glutamate excitotoxicity and metabolic rate in the brain in animal models of ischemia. The immune response to ischemia was measured through molecular serum markers in peripheral blood. We submitted groups of animals to different experimental conditions (hypothermia at 33°C, normothermia at 37°C and hyperthermia at 39°C), and combined these conditions with pharmacological modulation of glutamate levels in the brain through systemic injections of glutamate and oxaloacetate. We show that pharmacological modulation of glutamate levels can neutralize the deleterious effects of hyperthermia and the beneficial effects of hypothermia, however the analysis of the inflammatory response and metabolic rate, demonstrated that their effects on ischemic damage are less critical than glutamate excitotoxity. We conclude that glutamate excitotoxicity is the key molecular mechanism which is influenced by body temperature during the acute phase of brain stroke.

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“…Cultures of rat primary neurons were prepared from embryonic day 18 Sprague-Dawley rats according to the method described by Antonelli et al [25]. Pregnant female Sprague-Dawley rats were killed by CO 2 .…”

Section: Methodsmentioning

confidence: 99%

Palmitoylethanolamide exerts neuroprotective effects in mixed neuroglial cultures and organotypic hippocampal slices via peroxisome proliferator-activated receptor-α

Scuderi

Valenza

Stecca

et al. 2012

J Neuroinflammation

105

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BackgroundIn addition to cytotoxic mechanisms directly impacting neurons, β-amyloid (Aβ)-induced glial activation also promotes release of proinflammatory molecules that may self-perpetuate reactive gliosis and damage neighbouring neurons, thus amplifying neuropathological lesions occurring in Alzheimer's disease (AD). Palmitoylethanolamide (PEA) has been studied extensively for its anti-inflammatory, analgesic, antiepileptic and neuroprotective effects. PEA is a lipid messenger isolated from mammalian and vegetable tissues that mimics several endocannabinoid-driven actions, even though it does not bind to cannabinoid receptors. Some of its pharmacological properties are considered to be dependent on the expression of peroxisome proliferator-activated receptors-α (PPARα).FindingsIn the present study, we evaluated the effect of PEA on astrocyte activation and neuronal loss in models of Aβ neurotoxicity. To this purpose, primary rat mixed neuroglial co-cultures and organotypic hippocampal slices were challenged with Aβ1-42 and treated with PEA in the presence or absence of MK886 or GW9662, which are selective PPARα and PPARγ antagonists, respectively. The results indicate that PEA is able to blunt Aβ-induced astrocyte activation and, subsequently, to improve neuronal survival through selective PPARα activation. The data from organotypic cultures confirm that PEA anti-inflammatory properties implicate PPARα mediation and reveal that the reduction of reactive gliosis subsequently induces a marked rebound neuroprotective effect on neurons.ConclusionsIn line with our previous observations, the results of this study show that PEA treatment results in decreased numbers of infiltrating astrocytes during Aβ challenge, resulting in significant neuroprotection. PEA could thus represent a promising pharmacological tool because it is able to reduce Aβ-evoked neuroinflammation and attenuate its neurodegenerative consequences.

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Neurotensin Receptor Involvement in the Rise of Extracellular Glutamate Levels and Apoptotic Nerve Cell Death in Primary Cortical Cultures after Oxygen and Glucose Deprivation

Cited by 26 publications

References 45 publications

Effective Post-insult Neuroprotection by a Novel Ca2+/ Calmodulin-dependent Protein Kinase II (CaMKII) Inhibitor

Effective Post-insult Neuroprotection by a Novel Ca2+/ Calmodulin-dependent Protein Kinase II (CaMKII) Inhibitor

Glutamate Excitoxicity Is the Key Molecular Mechanism Which Is Influenced by Body Temperature during the Acute Phase of Brain Stroke

Palmitoylethanolamide exerts neuroprotective effects in mixed neuroglial cultures and organotypic hippocampal slices via peroxisome proliferator-activated receptor-α

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