Hypoxia-Ischemia in the Neonatal Rat Brain: Histopathology after Post-Treatment with NMDA and Non NMDA Receptor Antagonists

Hagberg, Henrik; Gilland, Eric; Diemer, Nils-Henrik; Andiné, Peter

doi:10.1159/000244109

Cited by 144 publications

(77 citation statements)

References 41 publications

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“…This causes activation of NMDA receptors, leading to further calcium influx, and triggering numerous and very complex cellular changes leading to cell damage. As neuroprotective agents, NMDA receptor antagonists also clearly remain potential therapeutic drugs (5)(6)(7)(8)(9)(10). Agmatine has been reported to selectively block the NMDA subclass of glutamate receptors (19 -21).…”

Section: Discussionmentioning

confidence: 99%

“…This HI model results in brain damage only on the ipsilateral side (29,30). The loss of hemispheric weight can be used as a measure of brain damage in this model, inasmuch as enough time elapsed to allow resorption of the dead tissue (8,31). Also the brain of the newborn rat is growing rapidly, and the dead tissue does not contribute to this growth.…”

Section: Methodsmentioning

confidence: 98%

“…Inhibitors of nitric oxide synthase (NOS) and antagonists of N-methyl-D-aspartate (NMDA) glutamate receptors are neuroprotective in hypoxia-ischemic (HI) brain injury (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). Formed from the decarboxylation of L-arginine by the enzyme arginine decarboxylase (11)(12)(13)(14), agmatine is a 4-carbon elongated relative of the synthetic neuroprotective agent, aminoguanidine (12).…”

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Agmatine Suppresses Nitric Oxide Production and Attenuates Hypoxic-Ischemic Brain Injury in Neonatal Rats

2002

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Nitric oxide and excitatory amino acids contribute to hypoxic-ischemic brain injury. Agmatine, an endogenous neurotransmitter or neuromodulator, is an inhibitor of nitric oxide synthase and an antagonist of N-methyl-D-aspartate receptors. Does agmatine reduce brain injury in the rat pup hypoxicischemic model? Seven-day old rat pups had right carotid arteries ligated followed by 2.5 h of hypoxia (8% oxygen). Agmatine or vehicle was administered by i.p. injection at 5 min after reoxygenation and once daily thereafter for 3 d. Brain damage was evaluated by weight deficit of the right hemisphere at 22 d after hypoxia by a blinded observer. Agmatine treatments significantly reduced weight loss in the right hemisphere from Ϫ30.5 Ϯ 3.6% in vehicle-treated pups (n ϭ 22) to Ϫ15.6 Ϯ 4.4% in the group treated with 50 mg/kg (n ϭ 18, p Ͻ 0.05) and to Ϫ15.0 Ϯ 3.7% in the group treated with 100 mg/kg (n ϭ 18, p Ͻ 0.05), but the group treated with 150 mg/kg showed no reduction. Other pups received agmatine or vehicle at 5 min after reoxygenation, and brain biochemistry was assessed. Levels of endogenous brain agmatine rose 2-to 3-fold owing to hypoxic-ischemic (3 h), whereas pups treated with agmatine (100 mg/kg) showed 50-fold higher brain agmatine levels (3 h). Agmatine (100 mg/kg) blocked a hypoxia-induced increase in brain nitric oxide metabolites at 6 h (vehicle-treated, ϩ60.2 Ϯ 15.2%; agmatine-treated, ϩ4.2 Ϯ 8.4%; p Ͻ 0.05). Agmatine thus reduces brain injury in the neonatal rat hypoxic-ischemic model, probably by blunting the rise in nitric oxide metabolites normally seen after hypoxia. [11][12][13][14], agmatine is a 4-carbon elongated relative of the synthetic neuroprotective agent, aminoguanidine (12). Agmatine has long been known to exist in plants, bacteria, insects, and invertebrates (13). Only recently was it realized that agmatine is synthesized in mammalian brain (11), where agmatine acts as both a neurotransmitter and neuromodulator (12, 14 -18). From distribution studies of arginine decarboxylase in primary cell cultures, agmatine is thought to be synthesized predominantly by astroglia cells, then released and taken up into neurons by active transport (12,14). Agmatine possesses modest affinities for various receptors, including as an inhibitor of the NMDA subclass of glutamate receptors (19 -21). Agmatine also inhibits all isoforms of NOS (22-25), with highest reported activity (Ki ϭ 29 M) as an irreversible inactivator of neuronal NOS (25). Treatments with agmatine are neuroprotective in vitro (21,22), as well as in gerbil ischemic brain injury, adult rat ischemic brain injury (26), and adult rat spinal cord injury (16,27,28). The effects of agmatine in neonatal HI brain injury have not previously been tested, nor has correlation been studied between the neuroprotective properties of agmatine and NO production in the brain. HI brain injury is a serious cause of death and disability in human newborns. The developmental stage of the brain of the 7-d-old rat pup resembles that of newborn humans (29). As descr...

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 98%

mentioning

confidence: 99%

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Agmatine Suppresses Nitric Oxide Production and Attenuates Hypoxic-Ischemic Brain Injury in Neonatal Rats

2002

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“…Induction of Hypoxia-Ischemia-Unilateral HI was induced in 7-dayold Wistar F rats of both sexes (46,47). The pups were anesthetized with halothane (3.0% for induction and 1.0 -1.5% for maintenance) in a mixture of nitrous oxide and oxygen (1:1), and the duration of anesthesia was Ͻ10 min.…”

Section: Methodsmentioning

confidence: 99%

Synergistic Activation of Caspase-3 by m-Calpain after Neonatal Hypoxia-Ischemia

Blomgren

Zhu

Wang

et al. 2001

Journal of Biological Chemistry

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409

328

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The relative contributions of apoptosis and necrosis in brain injury have been a matter of much debate. Caspase-3 has been identified as a key protease in the execution of apoptosis, whereas calpains have mainly been implicated in excitotoxic neuronal injury. In a model of unilateral hypoxia-ischemia in 7-day-old rats, caspase-3-like activity increased 16-fold 24 h postinsult, coinciding with cleavage of the caspase-3 proenzyme and endogenous caspase-3 substrates. This activation was significantly decreased by pharmacological calpain inhibition, using CX295, a calpain inhibitor that did not inhibit purified caspase-3 in vitro. Activation of caspase-3 by m-calpain, but not -calpain, was facilitated in a dose-dependent manner in vitro by incubating cytosolic fractions, containing caspase-3 proform, with calpains. This facilitation required the presence of some active caspase-3 and could be abolished by including the specific calpain inhibitor calpastatin. This indicates that initial cleavage of caspase-3 by m-calpain, producing a 29-kDa fragment, facilitates the subsequent cleavage into active forms. This is the first report to our knowledge suggesting a direct link between the early, excitotoxic, calcium-mediated activation of calpain after cerebral hypoxia-ischemia and the subsequent activation of caspase-3, thus representing a tentative pathway of "pathological apoptosis."The relative contributions of necrosis and apoptosis to the injury that develops after cerebral hypoxia-ischemia (HI) 1 has been a matter of much debate (1). Recent studies suggest that cell death after HI is different from developmentally regulated cell death in most cases and cannot appropriately be described as apoptotic (2-5). Nevertheless, HI cell death shares important morphological and biochemical features with apoptotic cell death, such as activation of caspases and nucleosomal DNA fragmentation (6 -17). Caspases, a family of cysteine proteases with an unusual substrate specificity, requiring an aspartate residue in the P1 position, have been identified as key executors of apoptosis (18). Calpains, another family of cysteine proteases, are calcium-activated and are proposed to participate in the turnover of cytoskeletal proteins and regulation of kinases, transcription factors, and receptors (19,20). Calpains have mainly been implicated in excitotoxic neuronal injury and necrosis (21-23). Pharmacological inhibitors of calpains and caspases exert cerebroprotective effects (9, 14 -16, 24 -26). A growing body of literature has emerged, demonstrating functional connections between calpains and caspases (27). Common substrate proteins have been identified, such as fodrin (28 -31), calpastatin (32, 33), actin (34), PARP (35), and tau (36). There are reports demonstrating calpain-mediated cleavage of caspase-3 (35, 37) and caspase-7 (38, 39) as well as caspase-8 and -9 (39). Furthermore, the proapoptotic protein Bax was cleaved by calpain during drug-induced apoptosis of HL-60 cells (40), and calpain may be responsible for cleaving the loop r...

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“…We used this model previously to test the neuroprotective potential of other mGluR ligands [19,20]. The involvement of NMDARs in the mechanisms of ischemic brain damage in this experimental model is clear [9,10,11,14,38,39], but less clear is the role of particular group ImGluRs subtypes. mGluR1 and mGluR5 have significantly different developmental profiles in various brain regions and in the subcellular localization [5,18].…”

Section: Discussionmentioning

confidence: 99%

Effects of mGluR5 positive and negative allosteric modulators on brain damage evoked by hypoxia-ischemia in neonatal rats

Makarewicz

Słomka²,

Danysz³

et al. 2015

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A b s t r a c t In the present study, we examined the effects of negative and positive allosteric modulators of metabotropic glutamate receptor 5 (mGluR5), fenobam and ADX47273, respectively, on brain damage induced by hypoxia-ischemia (H-I) in 7-day-old rats. The test drugs were administered intraperitoneally 10 min after H-I. Rectal body temperature was measured for 2.5 h after the insult. The number of apoptotic neurons in the immature rat brain was evaluated after 24 h. The wet weight of both hemispheres was determined 14 days after H-I, and its loss was used as an indicator of brain damage. In the vehicle-treated groups, H-I reduced the weight of the ipsilateral (ischemic

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Hypoxia-Ischemia in the Neonatal Rat Brain: Histopathology after Post-Treatment with NMDA and Non NMDA Receptor Antagonists

Cited by 144 publications

References 41 publications

Agmatine Suppresses Nitric Oxide Production and Attenuates Hypoxic-Ischemic Brain Injury in Neonatal Rats

Agmatine Suppresses Nitric Oxide Production and Attenuates Hypoxic-Ischemic Brain Injury in Neonatal Rats

Synergistic Activation of Caspase-3 by m-Calpain after Neonatal Hypoxia-Ischemia

Effects of mGluR5 positive and negative allosteric modulators on brain damage evoked by hypoxia-ischemia in neonatal rats

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