Reduction of Perinatal Hypoxic-Ischemic Brain Damage with Allopurinol

Palmer, Charles; Vannucci, Robert C.; Towfighi, Javad

doi:10.1203/00006450-199004000-00003

Cited by 219 publications

(102 citation statements)

References 25 publications

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“…Thus, the left hemisphere was unaffected (p Ͼ 0.05) by the HI procedure, as expected (29). The percent reduction in right hemispheric weight is shown in Figure 3.…”

Section: Resultsmentioning

confidence: 59%

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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“…Thus, the left hemisphere was unaffected (p Ͼ 0.05) by the HI procedure, as expected (29). The percent reduction in right hemispheric weight is shown in Figure 3.…”

Section: Resultsmentioning

confidence: 59%

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

2002

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“…Right hemisphere weight 22 days after injury was reduced by 16.2 ± 4.4% in the 22 pups treated with 250 mg/kg nicotinamide and by 25.2 ± 4.8% in the corresponding vehicle group (P = 0.18 versus vehicle). Left hemisphere weight is unchanged by hypoxia [31] (vehicle 509 ± 6 mg, 500 mg/kg nicotinamide 492 ± 6 mg, P > 0.05; 250 mg/kg nicotinamide 518 ± 7 mg, vehicle 516 ± 7.2 mg, P > 0.05).…”

Section: Neuroprotective Effects Of Nicotinamidementioning

confidence: 91%

“…The brains were removed, scored and weighed by an observer blind to the code. Brains were scored normal, mild, moderate or severe by the method of Palmer et al [31]. "Normal (1)" meant no reduction in the size of the right hemisphere, "mild (2)" meant visible reduction in right hemisphere size, "moderate (3)" meant large reduction in hemisphere size with a visible infarct in the right parietal area, and "severe (4)" meant near total destruction of the hemisphere.…”

Section: Gross Brain Damage Gradingmentioning

confidence: 99%

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Nicotinamide reduces hypoxic ischemic brain injury in the newborn rat

Feng¹,

Paul²,

LeBlanc³

2006

Brain Research Bulletin

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Nicotinamide reduces ischemic brain injury in adult rats. Can similar brain protection be seen in newborn animals? Seven-day-old rat pups had the right carotid artery permanently ligated followed by 2.5 h of 8% oxygen. Nicotinamide 250 or 500 mg/kg was administered i.p. 5 min after reoxygenation, with a second dose given at 6 h after the first. Brain damage was evaluated by weight deficit of the right hemisphere at 22 days following hypoxia. Nicotinamide 500 mg/kg reduced brain weight loss from 24.6 ± 3.6% in vehicle pups (n = 28) to 11.9 ± 2.6% in the treated pups (n = 29, P < 0.01), but treatment with 250 mg/kg did not affect brain weight. Nicotinamide 500 mg/kg also improved behavior in rotarod performance. Levels of 8-isoprostaglandin F 2α measured in the cortex by enzyme immune assay 16 h after reoxygenation was 115 ± 7 pg/g in the shams (n = 6), 175 ± 17 pg/g in the 500 mg/kg nicotinamide treated (n = 7), and 320 ± 79 pg/g in the vehicle treated pups (n = 7, P < 0.05 versus sham, P < 0.05 versus nicotinamide). Nicotinamide reduced the increase in caspase-3 activity caused by hypoxic ischemia (P < 0.01). Nicotinamide reduces brain injury in the neonatal rat, possibly by reducing oxidative stress and caspase-3 activity.

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“…Evaluation of the presence and extent of chronic gross morphologic and microscopic alterations was performed by two investigators, each blinded to group assignment. For gross examination, the type and extent of changes such as atrophy and cavitation were noted, as previously described (18,19). The severity of damage within each brain was grossly scored as follows.…”

Section: Neuropathologic Analysismentioning

confidence: 99%